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  • 1.
    Östlund, Martin
    et al.
    Linnaeus University, Kalmar.
    Dahlbäck, Nils
    Linköping University, Department of Computer and Information Science, NLPLAB - Natural Language Processing Laboratory. Linköping University, Faculty of Arts and Sciences.
    Petersson, Göran Ingemar
    Linnaeus University, Kalmar.
    3D Visualization as a Communicative Aid in Pharmaceutical Advice-Giving over Distance2011In: Journal of Medical Internet Research, ISSN 1438-8871, Vol. 13, no 3Article in journal (Refereed)
    Abstract [en]

    Background: Medication misuse results in considerable problems for both patient and society. It is a complex problem with many contributing factors, including timely access to product information. less thanbrgreater than less thanbrgreater thanObjective: To investigate the value of 3-dimensional (3D) visualization paired with video conferencing as a tool for pharmaceutical advice over distance in terms of accessibility and ease of use for the advice seeker. less thanbrgreater than less thanbrgreater thanMethods: We created a Web-based communication service called AssistancePlus that allows an advisor to demonstrate the physical handling of a complex pharmaceutical product to an advice seeker with the aid of 3D visualization and audio/video conferencing. AssistancePlus was tested in 2 separate user studies performed in a usability lab, under realistic settings and emulating a real usage situation. In the first study, 10 pharmacy students were assisted by 2 advisors from the Swedish National Co-operation of Pharmacies call centre on the use of an asthma inhaler. The student-advisor interview sessions were filmed on video to qualitatively explore their experience of giving and receiving advice with the aid of 3D visualization. In the second study, 3 advisors from the same call centre instructed 23 participants recruited from the general public on the use of 2 products: (1) an insulin injection pen, and (2) a growth hormone injection syringe. First, participants received advice on one product in an audio-recorded telephone call and for the other product in a video-recorded AssistancePlus session (product order balanced). In conjunction with the AssistancePlus session, participants answered a questionnaire regarding accessibility, perceived expressiveness, and general usefulness of 3D visualization for advice-giving over distance compared with the telephone and were given a short interview focusing on their experience of the 3D features. less thanbrgreater than less thanbrgreater thanResults: In both studies, participants found the AssistancePlus service helpful in providing clear and exact instructions. In the second study, directly comparing AssistancePlus and the telephone, AssistancePlus was judged positively for ease of communication (P = .001), personal contact (P = .001), explanatory power (P andlt;.001), and efficiency (P andlt;.001). Participants in both studies said that they would welcome this type of service as an alternative to the telephone and to face-to-face interaction when a physical meeting is not possible or not convenient. However, although AssistancePlus was considered as easy to use as the telephone, they would choose AssistancePlus over the telephone only when the complexity of the question demanded the higher level of expressiveness it offers. For simpler questions, a simpler service was preferred. less thanbrgreater than less thanbrgreater thanConclusions: 3D visualization paired with video conferencing can be useful for advice-giving over distance, specifically for issues that require a higher level of communicative expressiveness than the telephone can offer. 3D-supported advice-giving can increase the range of issues that can be handled over distance and thus improve access to product information.

  • 2.
    Hammarström, Per
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Ali Malik, Muhammad
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Mishra, Rajesh
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Svensson, Samuel
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Tengvall, Pentti
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics . Linköping University, The Institute of Technology.
    Lundström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics . Linköping University, The Institute of Technology.
    A catalytic surface for amyloid fibril formation2008In: Journal of Physics, Conference Series, ISSN 1742-6588, E-ISSN 1742-6596, Vol. 100Article in journal (Refereed)
    Abstract [en]

    A hydrophobic surface incubated in a solution of protein molecules (insulin monomers) was made into a catalytic surface for amyloid fibril formation by repeatedly incubate, rinse and dry the surface. The present contribution describes how this unexpected transformation occurred and its relation to rapid fibrillation of insulin solutions in contact with the surface. A tentative model of the properties of the catalytic surface is given, corroborated by ellipsometric measurements of the thickness of the organic layer on the surface and by atomic force microscopy. The surfaces used were spontaneously oxidized silicon made hydrophobic through treatment in dichlorodimethylsilane.

  • 3.
    Petersson, Ulla
    et al.
    Linköping University, Department of Medical and Health Sciences, General Practice. Linköping University, Faculty of Health Sciences.
    Östgren, Carl Johan
    Linköping University, Department of Medical and Health Sciences, General Practice. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in West Östergötland, Primary Health Care in Motala.
    Brudin, Lars
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences.
    Nilsson, Peter
    Department of Clinical Sciences, Lund University, University Hospital, Malmö , Sweden.
    A consultation-based method is equal to SCORE and an extensive laboratory-based method in predicting risk of future cardiovascular disease2009In: European Journal of Cardiovascular Prevention & Rehabilitation, ISSN 1741-8267, E-ISSN 1741-8275, Vol. 16, no 5, 536-540 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: As cardiovascular disease (CVD) is one of the most common causes of mortality worldwide, much interest has been focused on reliable methods to predict cardiovascular risk.

    DESIGN: A cross-sectional, population-based screening study with 17-year follow-up in Southern Sweden.

    METHODS: We compared a non-laboratory, consultation-based risk assessment method comprising age, sex, present smoking, prevalent diabetes or hypertension at baseline, blood pressure (systolic >/=140 or diastolic >/=90), waist/height ratio and family history of CVD to Systemic COronary Risk Evaluation (SCORE) and a third model including several laboratory analyses, respectively, in predicting CVD risk. The study included clinical baseline data on 689 participants aged 40-59 years without CVD. Blood samples were analyzed for blood glucose, serum lipids, insulin, insulin-like growth factor-I, insulin-like growth factor binding protein-1, C-reactive protein, asymmetric dimethyl arginine and symmetric dimethyl arginine. During 17 years, the incidence of total CVD (first event) and death was registered.

    RESULTS: A non-laboratory-based risk assessment model, including variables easily obtained during one consultation visit to a general practitioner, predicted cardiovascular events as accurately [hazard ratio (HR): 2.72; 95% confidence interval (CI): 2.18-3.39, P<0.001] as the established SCORE algorithm (HR: 2.73; 95% CI: 2.10-3.55, P<0.001), which requires laboratory testing. Furthermore, adding a combination of sophisticated laboratory measurements covering lipids, inflammation and endothelial dysfunction, did not confer any additional value to the prediction of CVD risk (HR: 2.72; 95% CI: 2.19-3.37, P<0.001). The c-statistics for the consultation model (0.794; 95% CI: 0.762-0.823) was not significantly different from SCORE (0.767; 95% CI: 0.733-0.798, P=0.12) or the extended model (0.806; 95% CI: 0.774-0.835, P=0.55).

    CONCLUSION: A risk algorithm based on non-laboratory data from a single primary care consultation predicted long-term cardiovascular risk as accurately as either SCORE or an elaborate laboratory-based method in a defined middle-aged population.

  • 4.
    Danne, Thomas
    et al.
    Hannover, Tyskland .
    Battelino, Tadej
    Ljubljana, Slovenien .
    Kordonouri, Olga
    Berlin, Tyskland .
    Hanås, Ragnar
    Barnklin, Uddevalla .
    Klinkert, Christof
    Bad Oeynhausen, Tyskland .
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Barrio, Raquel
    Madrid, Spanien.
    Aebi, Christine
    Wildermeth, Schweiz .
    Gschwend, Sylvia
    Biel, Schweiz .
    Mullis, Primus-E
    Zug, Schweiz .
    Schumacher, Urs
    Munsterlingen, Schweiz .
    Zumsteg, Urs
    Basel, Schweiz .
    Morandi, Anita
    Verona, Italy .
    Rabbone, Ivana
    Turin, Italien .
    Cherubini, Valentino
    Marche, Italien .
    Toni, Sonia
    Florence, Italien .
    de Beauforte, Carine
    Luxemburg .
    Hindmarsh, Peter
    London, UK .
    Sumner, Alex
    Peterborough, UK.
    van Waarde, Willie M
    Groningen, Holland .
    van den Berg, Norbert
    Almere, Holland .
    Phillip, Moshe
    Petah Tikva Israel.
    A cross-sectional international survey of continuous subcutaneous insulin infusion in 377 children and adolescents with type 1 diabetes mellitus from 10 countries2005In: Pediatric Diabetes, ISSN 1399-543X, Vol. 6, no 4, 193-198 p.Article in journal (Refereed)
    Abstract [en]

    Objective: To document current practices using continuous subcutaneous insulin infusion (CSII) by downloading electronically the 90-d pump data held within the pump memory and relating that to clinical data from children and adolescents in different pediatric diabetes centers from Europe and Israel. Methods: Data of patients (1-18 yr) treated with CSII in 23 centers from nine European countries and Israel were recorded with the ENCAPTURE software (PEC International, Frankfurt, Germany). The number of patients who participated was 377 (48% female, mean diabetes duration ± SD: 6.8 ± 3.7 yr, age: 12.9 ± 3.8 yr, preschool n = 33, prepubertal n = 95, adolescent n = 249, CSII duration: 1.6 ± 1.2 yr, local HbA1c: 8.1 ± 1.2%). Results: The total insulin dose was lower than previously reported for injection therapy (0.79 ± 0.20 U/kg/d). Covariance coefficient of daily total insulin was high in all age groups (adolescents 19 ± 9%, prepubertal 18 ± 8 and preschool 17 ± 8). The distribution of basal insulin infusion rates over 24 hr (48 ± 12% of total dose) varied significantly between centers and age groups. The number of boluses per day (7 ± 3) was not significantly different between the age groups (average daily bolus amount: 0.42 ± 0.16 U /kg). The rate of severe hypoglycemia (coma/convulsions) was 12.4 episodes per 100 patient-years and the number of diabetes-related hospital days was 124 per 100 patient-years. Discussion: Pediatric CSII patients show a high variability in their insulin therapy. This relates both to age-dependent differences in the distribution of basal insulin as to the age-independent day-to-day variation in prandial insulin. © Blackwell Munksgaard, 2005.

  • 5.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Nyström, Fredrik
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Olsson, Anders
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Toss, Göran
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    A dose titration model for recombinant GH substitution aiming at normal plasma concentrations of IGF-I in hypopituitary adults2002In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 147, no 1, 49-57 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate a dose titration model for recombinant human GH substitution in adult patients with GH deficiency, aiming at normal plasma levels of IGF-I.

    DESIGN AND METHODS: Eighteen patients participated and a start dose of 0.17 mg GH/day was used except by two men who started with 0.33 mg/day. To demonstrate a clear GH effect the patients were first titrated, with steps of 0.17 mg GH/day every 6-8 weeks, to IGF-I levels in the upper range of age-adjusted reference values. The GH dose was then reduced 1 dose step and kept for a further 6 months. For comparison we investigated 17 healthy control subjects.

    RESULTS: Plasma IGF-I was increased after 2 weeks on the start dose and did not increase further for up to 8 weeks. Women had significantly lower GH sensitivity than men measured as net increment of IGF-I on the start dose of GH. GH sensitivity was not changed by age. The plasma IGF-I levels increased from 76.3+/-47.0 (s.d.) to 237+/-97 microg/l at the end of the study (P<0.001), and similar IGF-I levels were obtained in both sexes. The maintenance median GH dose was 0.33 mg/day in males and 0.83 mg/day in females (P=0.017). The GH dose correlated negatively with age in both sexes. Body weight, very low density triglycerides, lipoprotein(a) (Lp(a)), and fasting insulin increased, whereas insulin sensitivity index (QUICKI) decreased significantly. In comparison with the controls, the patients had lower fasting blood glucose, fasting insulin and Lp(a) levels at baseline, but these differences disappeared after GH substitution. The two groups had equal insulin sensitivity (QUICKI), but 2 h oral glucose tolerance test values of blood glucose and insulin were significantly higher in the patients at the end of the study.

    CONCLUSIONS: In conclusion our data suggest that the starting dose of GH substitution and the dose titration steps should be individualised according to GH sensitivity (gender) and the IGF-I level aimed for (age). The reduced insulin sensitivity induced by GH substitution could be viewed as a normalisation if compared with control subjects.

  • 6.
    Hammarström, Per
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Simon, Rozalyn
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Åslund, Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    A Fluorescent Pentameric Thiophene Derivative Detects in Vitro-Formed Prefibrillar Protein Aggregates2010In: BIOCHEMISTRY, ISSN 0006-2960, Vol. 49, no 32, 6838-6845 p.Article in journal (Refereed)
    Abstract [en]

    Protein aggregation is associated with a wide range of diseases, and molecular probes that are able to detect a diversity of misfolded protein assemblies are of great importance. The identification of prefibrillar states preceding the formation of well-defined amyloid fibrils is of particular interest both because of their likely role in the mechanism of fibril formation and because of the growing awareness that these species are likely to play a critical role in the pathogenesis of protein deposition diseases. Herein, we explore the use of an anionic oligothiophene derivative, p-FTAA, for detection of prefibrillar protein aggregates during in vitro fibrillation of three different amyloidogenic proteins (insulin, lysozyme, and prion protein). p-FTAA generally detected prefibrillar protein aggregates that could not be detected by thioflavine T fluorescence and in addition showed high fluorescence when bound to mature fibrils. Second, the kinetics of protein aggregation or the formation of amyloid fibrils of insulin was not extensively influenced by the presence of various concentrations of p-FTAA. These results establish the use of p-FTAA as an additional tool for studying the process of protein aggregation.

  • 7.
    Nyman, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Brännmark, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Palmér, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Brugård, Jan
    MathCore Engn.
    Nyström, Fredrik
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Cedersund, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    A Hierarchical Whole-body Modeling Approach Elucidates the Link between in Vitro Insulin Signaling and in Vivo Glucose Homeostasis2011In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 29, 26028-26041 p.Article in journal (Refereed)
    Abstract [en]

    Type 2 diabetes is a metabolic disease that profoundly affects energy homeostasis. The disease involves failure at several levels and subsystems and is characterized by insulin resistance in target cells and tissues (i.e. by impaired intracellular insulin signaling). We have previously used an iterative experimental-theoretical approach to unravel the early insulin signaling events in primary human adipocytes. That study, like most insulin signaling studies, is based on in vitro experimental examination of cells, and the in vivo relevance of such studies for human beings has not been systematically examined. Herein, we develop a hierarchical model of the adipose tissue, which links intracellular insulin control of glucose transport in human primary adipocytes with whole-body glucose homeostasis. An iterative approach between experiments and minimal modeling allowed us to conclude that it is not possible to scale up the experimentally determined glucose uptake by the isolated adipocytes to match the glucose uptake profile of the adipose tissue in vivo. However, a model that additionally includes insulin effects on blood flow in the adipose tissue and GLUT4 translocation due to cell handling can explain all data, but neither of these additions is sufficient independently. We also extend the minimal model to include hierarchical dynamic links to more detailed models (both to our own models and to those by others), which act as submodules that can be turned on or off. The resulting multilevel hierarchical model can merge detailed results on different subsystems into a coherent understanding of whole-body glucose homeostasis. This hierarchical modeling can potentially create bridges between other experimental model systems and the in vivo human situation and offers a framework for systematic evaluation of the physiological relevance of in vitro obtained molecular/cellular experimental data.

  • 8.
    Olausson, Hanna
    et al.
    Linköping University, Department of Biomedicine and Surgery, Nutrition. Linköping University, Faculty of Health Sciences.
    Löf, Marie
    Linköping University, Department of Biomedicine and Surgery, Nutrition. Linköping University, Faculty of Health Sciences.
    Brismar, K.
    Unit for Endocrinology and Diabetes, Karolinska Institutet, Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Lewitt, M.
    Unit for Endocrinology and Diabetes, Karolinska Institutet, Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Forsum, Elisabet
    Linköping University, Department of Biomedicine and Surgery, Nutrition. Linköping University, Faculty of Health Sciences.
    Sohlström, Annica
    Linköping University, Department of Biomedicine and Surgery, Nutrition. Linköping University, Faculty of Health Sciences.
    A longitudinal study of the insulin-like growth factor system before, during and after pregnancy in healthy womenManuscript (preprint) (Other academic)
    Abstract [en]

    The maternal insulin-like growth factor (IGF)-system is considered to influence fetal growth. In this longitudinal study of 23 healthy women we aimed 1) to assess maternal serum levels of IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-3 and protease activity against IGFBP-3 before, during and after pregnancy, and 2) to relate these levels in early and late pregnancy to fetal and birth weight. Serum was collected before pregnancy, in weeks 8, 14, 20, 32 and 35 of pregnancy and 2 weeks postpartum. IGF-I, IGF-II, IGFBP-1, and IGFBP-3 were analyzed with radioimmuno/radiometric assays and protease activity with Western blot. Fetal weight was measured by means of ultrasound (week 31 of pregnancy) and birth weight was recorded. IGF-I was initially decreased during pregnancy, compared to before conception. This early decrease was not correlated with fetal or birth weight. In late pregnancy, IGF-I and protease activity were positively related to fetal weight, whereas from week 20 of pregnancy IGFBP-1 showed an inverse association with birth weight. We suggest that in healthy pregnant women there is a fine-tuned balance within the maternal IGF-system, with components With either promoting or restricting influences on fetal growth. The results indicate that maternal IGFBP-1 cguld be used from mid-pregnancy as a marker for birth weight.

  • 9.
    Svedjeholm, Rolf
    et al.
    Linköping University, Department of Medicine and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Vidlund, Marten
    Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery. Linköping University, Faculty of Health Sciences.
    Vanhanen, Ingemar
    Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery. Linköping University, Faculty of Health Sciences.
    Hakanson, Erik
    Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery. Linköping University, Faculty of Health Sciences.
    A metabolic protective strategy could improve long-term survival in patients with LV-dysfunction undergoing CABG2010In: SCANDINAVIAN CARDIOVASCULAR JOURNAL, ISSN 1401-7431, Vol. 44, no 1, 45-58 p.Article in journal (Refereed)
    Abstract [en]

    Objective. Adverse outcome after CABG is closely related to postoperative heart failure precipitated by ischemia and myocardial infarction. Restrictive use of inotropes is therefore desirable. Patients with preoperative left ventricular dysfunction are a high-risk group in this respect. To reduce myocardial oxygen expenditure we evolved a metabolic strategy for perioperative care. Design. Observational study on 104 consecutive patients with severe left ventricular dysfunction undergoing CABG. The metabolic strategy implied physiological measures to minimize myocardial oxygen expenditure including restrictive use of inotropes and specific measures such as extended CPB and metabolic support to facilitate myocardial recovery. Hemodynamic state was primarily assessed by mixed venous oxygen saturation (SvO(2)). Follow-up averaged 9.7 +/- 1.4 years. Results. LVEF was 0.30 +/- 0.05 (range 0.20-0.37) and 3.5 +/- 1.3 vessels were bypassed. Inotropes were used in 6.7% for weaning from CPB. Increase of s-creatinine by andgt;= 50% compared to preoperative values was observed in 2.9%. Logistic EuroSCORE was 8.3% whereas observed 30-day mortality was 1.0%. Crude 5-year survival was 89.4%. Conclusions. The metabolic strategy allowed restrictive use of inotropes and was associated with encouraging long-term survival. Renal function was well preserved suggesting that SvO(2) served as an adequate marker of circulation. Randomized trials with metabolic support are warranted.

  • 10.
    Lindström, Kjell
    et al.
    Primary Health Care Centre of Habo, Göteborg University, Göteborg, Sweden.
    Berg, Lars
    Primary Health Care Centre of Tibro, Göteborg University, Göteborg, Sweden.
    Rylander, Bo
    Primary Health Care Centre of Tibro, Göteborg University, Göteborg, Sweden.
    Hagman, Anders
    Medical Departments of Falköping, Göteborg University, Göteborg, Sweden.
    Olsson, Lave
    Medical Departments of Skövde Hospitals, Göteborg University, Göteborg, Sweden.
    Bengtsson, Calle
    Department of Primary Health Care, Göteborg University, Göteborg, Sweden.
    A model for quality assessment in primary health care using the tracer condition technique with insulin treated diabetes as one of the tracers1997In: Scandinavian Journal of Primary Health Care, ISSN 0281-3432, E-ISSN 1502-7724, Vol. 15, no 2, 92-96 p.Article in journal (Refereed)
    Abstract [en]

    Objective-To find a method for quality assessment in primary health care and to apply this method on a defined disease.

    Design-General practitioners and hospital doctors worked out a programme for evaluating the quality of outpatient care of patients with insulin treated diabetes as one of five tracers. An expert committee comprising experienced general practitioners and hospital doctors compared two health centres with one outpatient medical department Data were collected during a defined period combined with a one-year retrospective view, official statistics on medical care, and a questionnaire completed by the patients.

    Setting-Two primary health care centres and one outpatient medical department in southwestern Sweden.

    Patients-243 insulin treated diabetic patients attending the hospital and 87 insulin treated patients attending the health centres.

    Main results-There were no difficulties for the expert panel to agree on which indicators were to be studied. The expert panel concluded that there was no difference between the quality of the two levels of care studied.

    Conclusions-Medical audit was a useful method for evaluating medical quality. Co-operation between hospital doctors and general practitioners was of great value for evaluation of the quality of primary health care.

  • 11.
    Stenkula, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    A molecular approach to insulin signalling and caveolae in primary adipocytes2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The prevalence of type II diabetes is increasing at an alarming rate due to the western world lifestyle. Type II diabetes is characterized by an insulin resistance distinguished by impaired glucose uptake in adipose and muscle tissues. The molecular mechanisms behind the insulin recistance and also the knowledge considering normal insulin signalling in fat cells, especially in humans, are still unclear.

    Insulin receptor substrate (IRS) is known to be important for medating the insulin-induced signal from the insulin receptor into the cell. We developed and optimized a method for transfection of primary human adipocytes by electroporation. By recombinant expression of proteins, we found a proper IRS to be crucial for both mitogenic and metabolic signalling in human adipocytes. In human, but not rat, primary adipocytes we found IRS1 to be located at the plasma membrane in non-insulin stimulated cells. Insulin stimulation resulted in a two-fold increase of the amount of IRS1 at the plasma membrane in human cells, compared with a 12-fold increase in rat cells. By recombinant expression of IRS1 we found the species difference between human and rat IRS1 to depend on the IRS proteins and not on properties of the host cell.

    The adipocytes function as an energy store, critical for maintaining the energy balance, and obesity strongly correlates with insulin resistance. The insulin sensitivity of the adipocytes with regard to the size of the cells was examined by separating small and large cells from the same subject. We found no increase of the GLUT4 translocation to the plasma membrane following insulin stimulation in the large cells, whereas there was a two-fold increase in the small cells. This finding supports the idea of a causal relationship between the enlarged fat cells and reduced insulin sensitivity found in obese subjects.

    The insulin receptor is located and functional in a specific membrane structure, the caveola. The morphology of the caveola and the localization of the caveolar marker proteins caveolin-1 and -2 were examined. Caveolae were shown to be connected to the exterior by a narrow neck. Caveolin was found to be located at the neck region of caveolae, which imply importance of caveolin for maintaining and sequestering caveolae to the plasma membrane.

    In conclusion, the transfection technique proved to be highly useful for molecular biological studies of insulin signal transduction and morphology in primary adipocytes.

    List of papers
    1. Expression of a mutant IRS inhibits metabolic and mitogenic signalling of insulin in human adipocytes
    Open this publication in new window or tab >>Expression of a mutant IRS inhibits metabolic and mitogenic signalling of insulin in human adipocytes
    Show others...
    2004 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, Vol. 221, no 1-2, 1-8 p.Article in journal (Refereed) Published
    Abstract [en]

    Adipose tissue is a primary target of insulin, but knowledge about insulin signalling in human adipocytes is limited. We developed an electroporation technique for transfection of primary human adipocytes with a transfection efficiency of 15% ± 5 (mean ± S.D.). Human adipocytes were co-transfected with a mutant of IRS-3 (all four potential PI3-kinase binding motifs mutated: IRS-3F4) and HA-tagged protein kinase B (HA-PKB/Akt). HA-PKB/Akt was immunoprecipitated from cell lysates with anti-HA antibodies, resolved with SDS-PAGE, and immunoblotted with phospho-specific antibodies. We found that IRS-3F4 blocked insulin stimulation of HA-PKB/Akt phosphorylation and in further analyses also translocation of recombinant HA-tagged glucose transporter to the plasma membrane. IRS-3F4 also blocked insulin-induced activation of the transcription factor Elk-1. Our results demonstrate the critical importance of IRS for metabolic as well as mitogenic signalling by insulin. This method for transfection of primary human adipocytes will be useful for studying insulin signalling in human adipocytes with molecular biological techniques.

    Keyword
    Insulin, Transfection, Human, Adipocytes, Protein kinase B, Elk-1
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14538 (URN)10.1016/j.mce.2004.04.011 (DOI)000222854100001 ()
    Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2013-10-22Bibliographically approved
    2. Cell surface orifices of caveolae and localization of caveolin to the necks of caveolae in adipocytes
    Open this publication in new window or tab >>Cell surface orifices of caveolae and localization of caveolin to the necks of caveolae in adipocytes
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    2003 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 14, no 10, 3967-3976 p.Article in journal (Refereed) Published
    Abstract [en]

    Caveolae are noncoated invaginations of the plasma membrane that form in the presence of the protein caveolin. Caveolae are found in most cells, but are especially abundant in adipocytes. By high-resolution electron microscopy of plasma membrane sheets the detailed structure of individual caveolae of primary rat adipocytes was examined. Caveolin-1 and -2 binding was restricted to the membrane proximal region, such as the ducts or necks attaching the caveolar bulb to the membrane. This was confirmed by transfection with myc-tagged caveolin-1 and -2. Essentially the same results were obtained with human fibroblasts. Hence caveolin does not form the caveolar bulb in these cells, but rather the neck and may thus act to retain the caveolar constituents, indicating how caveolin participates in the formation of caveolae. Caveolae, randomly distributed over the plasma membrane, were very heterogeneous, varying in size between 25 and 150 nm. There was about one million caveolae in an adipocyte, which increased the surface area of the plasma membrane by 50%. Half of the caveolae, those larger than 50 nm, had access to the outside of the cell via ducts and 20-nm orifices at the cell surface. The rest of the caveolae, those smaller than 50 nm, were not open to the cell exterior. Cholesterol depletion destroyed both caveolae and the cell surface orifices.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14539 (URN)10.1091/mbc.E03-01-0050 (DOI)
    Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2013-09-10
    3. Human, but not rat, IRS1 targets to the plasma membrane in both human and rat primary adipocytes
    Open this publication in new window or tab >>Human, but not rat, IRS1 targets to the plasma membrane in both human and rat primary adipocytes
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    2007 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, Vol. 363, no 3, 840-845 p.Article in journal (Refereed) Published
    Abstract [en]

    Adipocytes are primary targets for insulin control of metabolism. The activated insulin receptor phosphorylates insulin receptor substrate-1 (IRS1), which acts as a docking protein for downstream signal mediators. In the absence of insulin stimulation, IRS1 in rat adipocytes is intracellular but in human adipocytes IRS1 is constitutively targeted to the plasma membrane. Stimulation of adipocytes with insulin increased the amount of IRS1 at the plasma membrane 2-fold in human adipocytes, but >10-fold in rat adipocytes, with the same final amount of IRS1 at the plasma membrane in cells from both species. Cross-transfection of rat adipocytes with human IRS1, or human adipocytes with rat IRS1, demonstrated that the species difference was due to the IRS1 protein and not the cellular milieus or posttranslational modifications. Chimeric IRS1, consisting of the conserved N-terminus of rat IRS1 with the variable C-terminal of human IRS1, did not target the plasma membrane, indicating that subtle sequence differences direct human IRS1 to the plasma membrane.

    Keyword
    Insulin receptor substrate; Human; Rat; Insulin; Plasma membrane; Signaling; Transfection; Caveolae
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14540 (URN)10.1016/j.bbrc.2007.09.065 (DOI)
    Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2013-09-10
    4. Insulin-induced GLUT4 translocation to the plasma membrane is blunted in large compared with small primary fat cells isolated from the same individual
    Open this publication in new window or tab >>Insulin-induced GLUT4 translocation to the plasma membrane is blunted in large compared with small primary fat cells isolated from the same individual
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    2007 (English)In: Diabetologia, ISSN 0012-186X, Vol. 50, no 8, 1716-1722 p.Article in journal (Refereed) Published
    Abstract [en]

    Aims/hypothesis: Several studies have suggested that large fat cells are less responsive to insulin than small fat cells. However, in these studies, large fat cells from obese individuals were compared with smaller fat cells from leaner participants, in effect making it impossible to draw conclusions about whether there is a causal relationship between fat cell size and insulin sensitivity. We hypothesised that small fat cells might be more insulin-responsive than large adipocytes when obtained from the same individual.

    Materials and methods: We developed a method of sorting isolated primary human fat cells by using nylon filters of two different pore sizes. The cells were stained to visualise DNA, which allowed discrimination from artefacts such as lipid droplets. The sorted cells were left to recover overnight, since we had previously demonstrated that this is necessary for correct assessment of insulin response.

    Results: We found similar amounts of the insulin receptor (IR), IRS-1 and GLUT4 when we compared small and large adipocytes from the same volunteer by immunoblotting experiments using the same total cell volume from both cell populations. Activation of IR, IRS-1 and Akt1 (also known as protein kinase B) by insulin was similar in the two cell populations. However, immunofluorescence confocal microscopy of plasma membrane sheets did not reveal any increase in the amount of GLUT4 in the plasma membrane following insulin stimulation in the large fat cells, whereas we saw a twofold increase in the amount of GLUT4 in the small fat cells.

    Conclusions/interpretation: Our results support a causal relationship between the accumulation of large fat cells in obese individuals and reduced insulin responsiveness.

    Keyword
    Adipocyte, GLUT4, Human, Insulin, Insulin receptor, Insulin resistance, IRS-1, Primary fat cell
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14541 (URN)10.1007/s00125-007-0713-1 (DOI)
    Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2013-09-10Bibliographically approved
  • 12.
    Carlsson, Annelie
    et al.
    Lund University, Sweden .
    Forsander, Gun
    Sahlgrens University Hospital, Sweden .
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Larsen, Sara
    Novo Nordisk Scandinavia AB, Sweden .
    Ortqvist, Eva
    Karolinska University Hospital, Sweden .
    A multicenter observational safety study in Swedish children and adolescents using insulin detemir for the treatment of type 1 diabetes2013In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 14, no 5, 358-365 p.Article in journal (Refereed)
    Abstract [en]

    This 26-wk observational study in children and adolescents with type 1 diabetes (T1D) in Sweden investigated the safety and efficacy of insulin detemir (IDet) in newly diagnosed (ND) patients and those with established diabetes (ED) switching to IDet. A total of 159 patients initiated IDet as part of basal-bolus therapy, 59 in the ND stratum (mean age 9.7yr) and 97 in the ED stratum (mean age 12.5 yr). The primary outcome measure was the incidence of severe adverse drug reactions; just one major hypoglycemic event occurred in a patient in the ND stratum during the study and one patient was withdrawn due to injection-site reactions. All other events were classified as mild. In the ED stratum, there was a reduction in hypoglycemic events in the 4wk prior to study end from baseline (mean reduction of 2.46 events, not significant) and a significant reduction in nocturnal hypoglycemia (mean reduction of 2.24 events, p=0.0078). Glycemic control improved in the ND stratum as expected and, in the ED stratum, there was no significant change in HbA1c from baseline (mean reduction of -0.45%). At study end, mean daily IDet doses were 0.39U/kg (ND) and 0.54U/kg (ED). Weight increased by 5.7 and 2.0kg in the ND and ED strata, respectively, and was within the normal limits for growing children. IDet provided good glycemic control and was well tolerated, with a reduced risk of nocturnal hypoglycemia in a heterogeneous cohort of children and adolescents with T1D.

  • 13.
    Ding, Yuan C
    et al.
    City Hope National Medical Centre, CA, USA .
    McGuffog, Lesley
    University of Cambridge Worts Causeway, England .
    Healey, Sue
    Royal Brisbane Hospital, Australia .
    Friedman, Eitan
    Chaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel .
    Laitman, Yael
    Chaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel .
    Paluch-Shimon, Shani
    Chaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel .
    Kaufman, Bella
    Chaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel .
    Liljegren, Annelie
    Karolinska University Hospital, Sweden .
    Lindblom, Annika
    Karolinska University Hospital, Sweden .
    Olsson, Hakan
    University of Lund Hospital, Sweden .
    Kristoffersson, Ulf
    University of Lund Hospital, Sweden .
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Melin, Beatrice
    Umeå University, Sweden .
    Domchek, Susan M
    University of Penn, PA, USA .
    Nathanson, Katherine L
    University of Penn, PA, USA .
    Rebbeck, Timothy R
    University of Penn, PA, USA .
    Jakubowska, Anna
    Pomeranian Medical University, Poland .
    Lubinski, Jan
    Pomeranian Medical University, Poland .
    Jaworska, Katarzyna
    Pomeranian Medical University, Poland .
    Durda, Katarzyna
    Pomeranian Medical University, Poland .
    Gronwald, Jacek
    Pomeranian Medical University, Poland .
    Huzarski, Tomasz
    Pomeranian Medical University, Poland .
    Cybulski, Cezary
    Pomeranian Medical University, Poland .
    Byrski, Tomasz
    Pomeranian Medical University, Poland .
    Osorio, Ana
    Spanish National Cancer Research Centre, Spain Spanish National Cancer Research Centre, Spain Spanish Network Rare Disease CIBERER, Spain .
    Ramony Cajal, Teresa
    Hospital Santa Creu and Sant Pau, Spain .
    Stavropoulou, Alexandra V
    National Centre Science Research Demokritos, Greece .
    Benitez, Javier
    Spanish National Cancer Research Centre, Spain Spanish National Cancer Research Centre, Spain Spanish Network Rare Disease CIBERER, Spain .
    Hamann, Ute
    Deutsch Krebsforschungszentrum DKFZ, Germany .
    Rookus, Matti
    Netherlands Cancer Institute, Netherlands .
    Aalfs, Cora M
    University of Amsterdam, Netherlands .
    de Lange, Judith L
    Netherlands Cancer Institute, Netherlands .
    Meijers-Heijboer, Hanne E J
    Vrije University of Amsterdam Medical Centre, Netherlands .
    Oosterwijk, Jan C
    University of Groningen, Netherlands .
    van Asperen, Christi J
    Leiden University, Netherlands .
    Gomez Garcia, Encarna B
    MUMC, Netherlands .
    Hoogerbrugge, Nicoline
    Radboud University of Nijmegen, Netherlands .
    Jager, Agnes
    Erasmus University, Netherlands .
    van der Luijt, Rob B
    University of Medical Centre Utrecht, Netherlands .
    Easton, Douglas F
    University of Cambridge, England .
    Peock, Susan
    University of Cambridge, England .
    Frost, Debra
    University of Cambridge, England .
    Ellis, Steve D
    University of Cambridge, England .
    Platte, Radka
    University of Cambridge, England .
    Fineberg, Elena
    University of Cambridge, England .
    Evans, D Gareth
    Central Manchester University Hospital NHS Fdn Trust, England .
    Lalloo, Fiona
    Central Manchester University Hospital NHS Fdn Trust, England .
    Izatt, Louise
    Guys and St Thomas NHS Fdn Trust, England .
    Eeles, Ros
    Institute Cancer Research, England Royal Marsden NHS Fdn Trust, England .
    Adlard, Julian
    Yorkshire Regional Genet Serv, England .
    Davidson, Rosemarie
    Yorkhill Hospital, Scotland .
    Eccles, Diana
    University Hospital Southampton NHS Fdn Trust, England .
    Cole, Trevor
    Birmingham Womens Hospital Healthcare NHS Trust, England .
    Cook, Jackie
    Sheffield Childrens Hospital, England .
    Brewer, Carole
    Royal Devon and Exeter Hospital, England .
    Tischkowitz, Marc
    University of Cambridge, England .
    Godwin, Andrew K
    University of Kansas, KS, USA .
    Pathak, Harsh
    University of Kansas, KS, USA .
    Stoppa-Lyonnet, Dominique
    Institute Curie, France Institute Curie, France University of Paris 05, France .
    Sinilnikova, Olga M
    University of Lyon 1, France Centre Hospital University of Lyon, France .
    Mazoyer, Sylvie
    University of Lyon 1, France .
    Barjhoux, Laure
    University of Lyon 1, France .
    Leone, Melanie
    Centre Hospital University of Lyon, France .
    Gauthier-Villars, Marion
    Institute Curie, France .
    Caux-Moncoutier, Virginie
    Institute Curie, France .
    de Pauw, Antoine
    Institute Curie, France .
    Hardouin, Agnes
    Centre Francois Baclesse, France .
    Berthet, Pascaline
    Centre Francois Baclesse, France .
    Dreyfus, Helene
    CHU Grenoble, France University of Grenoble, France .
    Fert Ferrer, Sandra
    Hotel Dieu Centre Hospital, France .
    Collonge-Rame, Marie-Agnes
    CHU Besancon, France .
    Sokolowska, Johanna
    Nancy University, France .
    Buys, Saundra
    University of Utah, UT, USA .
    Daly, Mary
    Fox Chase Cancer Centre, PA, USA .
    Miron, Alex
    Dana Farber Cancer Institute, MA, USA .
    Terry, Mary Beth
    Columbia University, NY, USA .
    Chung, Wendy
    Columbia University, NY, USA .
    John, Esther M
    Cancer Prevent Institute Calif, CA, USA Stanford University, CA, USA Stanford Cancer Institute, CA, USA .
    Southey, Melissa
    University of Melbourne, Australia .
    Goldgar, David
    University of Utah, UT, USA .
    Singer, Christian F
    Medical University of Vienna, Austria .
    Tea, Muy-Kheng Maria
    Medical University of Vienna, Austria .
    Gschwantler-Kaulich, Daphne
    Medical University of Vienna, Austria .
    Fink-Retter, Anneliese
    Medical University of Vienna, Austria .
    Hansen, Thomas V O
    Copenhagen University Hospital, Denmark .
    Ejlertsen, Bent
    Copenhagen University Hospital, Denmark .
    Johannsson, Oskar T
    Landspitali University Hospital, Iceland University of Iceland, Iceland .
    Offit, Kenneth
    Clin Cancer Genet Lab, NY, USA .
    Sarrel, Kara
    Clin Cancer Genet Lab, NY, USA .
    Gaudet, Mia M
    Amer Cancer Soc, GA, USA .
    Vijai, Joseph
    Clin Cancer Genet Lab, NY, USA .
    Robson, Mark
    Mem Sloan Kettering Cancer Centre, NY, USA .
    Piedmonte, Marion R
    Roswell Pk Cancer Institute, NY, USA .
    Andrews, Lesley
    Australia New Zealand Gynaecol Oncology Grp, Australia .
    Cohn, David
    Ohio State University, OH, USA .
    DeMars, Leslie R
    Dartmouth Hitchcock Medical Centre, NH, USA .
    DiSilvestro, Paul
    Brown University, RI, USA .
    Rodriguez, Gustavo
    NorthShore University of Health Syst, IL, USA .
    Ewart Toland, Amanda
    Ohio State University, OH, USA Ohio State University, OH, USA .
    Montagna, Marco
    Ist Oncology Veneto IOV IRCCS, Italy .
    Agata, Simona
    Ist Oncology Veneto IOV IRCCS, Italy .
    Imyanitov, Evgeny
    NN Petrov Oncology Research Institute, Russia .
    Isaacs, Claudine
    Georgetown University, DC, USA .
    Janavicius, Ramunas
    Vilnius University Hospital, Lithuania .
    Lazaro, Conxi
    Institute Catala Oncol, Spain .
    Blanco, Ignacio
    IDIBELL Catalan Institute Oncol, Spain .
    Ramus, Susan J
    University of So Calif, CA, USA .
    Sucheston, Lara
    Roswell Pk Cancer Institute, NY, USA .
    Karlan, Beth Y
    Cedars Sinai Medical Centre, CA, USA .
    Gross, Jenny
    Cedars Sinai Medical Centre, CA, USA .
    Ganz, Patricia A
    University of Calif Los Angeles, CA, USA .
    Beattie, Mary S
    University of Calif San Francisco, CA, USA .
    Schmutzler, Rita K
    University Hospital Cologne, Germany .
    Wappenschmidt, Barbara
    University Hospital Cologne, Germany .
    Meindl, Alfons
    Technical University of Munich, Germany .
    Arnold, Norbert
    University of Kiel, Germany .
    Niederacher, Dieter
    University of Dusseldorf, Germany .
    Preisler-Adams, Sabine
    University of Munster, Germany .
    Gadzicki, Dorotehea
    Hannover Medical Sch, Germany .
    Varon-Mateeva, Raymonda
    Charite, Germany .
    Deissler, Helmut
    University Hospital Ulm, Germany .
    Gehrig, Andrea
    University of Wurzburg, Germany .
    Sutter, Christian
    University of Heidelberg Hospital, Germany .
    Kast, Karin
    Technical University of Dresden, Germany .
    Nevanlinna, Heli
    University of Helsinki, Finland .
    Aittomaki, Kristiina
    Centre Hospital University of Quebec, Canada University of Laval, Canada .
    Spurdle, Amanda B
    Royal Brisbane Hospital, Australia .
    Beesley, Jonathan
    Royal Brisbane Hospital, Australia .
    Chen, Xiaoqing
    Royal Brisbane Hospital, Australia .
    Tomlinson, Gail E
    University of Texas Health Science Centre San Antonio, TX, USA.
    Weitzel, Jeffrey
    City Hope National Medical Centre, CA, USA .
    Garber, Judy E
    Harvard University, MA, USA .
    Olopade, Olufunmilayo I
    University of Chicago, IL, USA .
    Rubinstein, Wendy S
    NorthShore University of HealthSyst, IL, USA .
    Tung, Nadine
    Beth Israel Deaconess Medical Centre, MA, USA .
    Blum, Joanne L
    Baylor Charles A Sammons Cancer Centre, TX, USA .
    Narod, Steven A
    Womens Coll Hospital, Canada .
    Brummel, Sean
    Harvard University, MA, USA .
    Gillen, Daniel L
    University of Calif Irvine, CA USA .
    Lindor, Noralane
    Mayo Clin, MN, USA .
    Fredericksen, Zachary
    Mayo Clin, MN, USA .
    Pankratz, Vernon S
    Mayo Clin, MN, USA .
    Couch, Fergus J
    Mayo Clin, MN, USA .
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy Fdn Ist FIRC Oncology Mol, Italy .
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy Fdn Ist FIRC Oncology Mol, Italy .
    Greene, Mark H
    NCI, MD, USA .
    Loud, Jennifer T
    NCI, MD, USA .
    Mai, Phuong L
    NCI, MD, USA .
    Andrulis, Irene L
    University of Toronto, Canada .
    Glendon, Gord
    University of Toronto, Canada .
    Gerdes, Anne-Marie
    Odense University Hospital, Denmark .
    Birk Jensen, Uffe
    Skejby Hospital, Denmark .
    Skytte, Anne-Bine
    Vejle Hospital, Denmark .
    Caligo, Maria A
    University of Pisa, Italy University Hospital Pisa, Italy .
    Lee, Andrew
    University of Cambridge Worts Causeway, England .
    Chenevix-Trench, Georgia
    Royal Brisbane Hospital, Australia .
    Antoniou, Antonis C
    University of Cambridge Worts Causeway, England .
    Neuhausen, Susan L
    City Hope National Medical Centre, CA, USA .
    A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers2012In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 21, no 8, 1362-1370 p.Article in journal (Refereed)
    Abstract [en]

    Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. less thanbrgreater than less thanbrgreater thanMethods: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. less thanbrgreater than less thanbrgreater thanResults: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P-difference, 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). less thanbrgreater than less thanbrgreater thanConclusion: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. less thanbrgreater than less thanbrgreater thanImpact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.

  • 14.
    Keselman, Boris
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Vergara Valgañon, Marta
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Nyberg, Sofia
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Nyström, Fredrik H
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    A randomized cross-over study of the acute effects of running 5 km on glucose, insulin, metabolic rate, cortisol and Troponin T2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 6, e0179401Article in journal (Refereed)
    Abstract [en]

    Background We aimed to study the impact by running 5 km, at maximal speed, on the normal variations of metabolic variables related to glucose, insulin, insulin sensitivity, cortisol, glucagon, Troponin T and metabolic rate. Material and methods Five women and 12 men 25.7 +/- 5.2 years of age with a body-mass-index of 22.5 +/- 2.3 kg/m(2) where recruited to run 5 km at individual maximal speed in the morning, and to a corresponding day of rest, followed by standardized breakfast and lunch meals. Blood sampling and measurement of indirect calorimetry were done before and after meals. The participants were randomized regarding the order of the two trial-days in this cross-over study. Results Insulin and cortisol levels were higher, and insulin sensitivity was lower, on the race-day compared with the day of rest (linear mixed model: pamp;lt;0.0001 for all three analyses). However, glucose levels and metabolic rate did not differ between the two trial days (p = 0.29 and p = 0.53, respectively). When analyzing specific time-points we found that glucose increased from 5.01 +/- 0.37 mmol/l to 6.36 +/- 1.3 mmol/l, pamp;lt;0.0001, by running, while serum insulin concomitantly increased from 42 21 to 90 54 pmo1/1, pamp;lt;0.0001. In accordance, the QUICKI index of serum sensitivity, 1/(log(10)insulin+log(10)glucose), was lowered post-race, pamp;lt;0.0001. Serum cortisol levels increased from 408 137 nmol/l to 644 171 nmol/l, pamp;lt;0.0001, post-race while serum glucagon levels were unaffected. Troponin T was detectable in serum post-race in 12 out of the 17 participants and reached or surpassed the clinical reference level of 15 ng/l in three subjects. Post-race electrocardiograms displayed no pathologies. Conclusions Relatively short running-races can apparently induce a reduction in insulin sensitivity that is not fully compensated by concomitantly increased insulin secretion intended to ensure euglycemia. Since also Troponin T was detected in plasma in a majority of the participants, our data suggest that it is possible to induce considerable metabolic stress by running merely 5 km, when striving for maximal speed.

  • 15.
    Fernemark, Hanna
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Jaredsson, Christine
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Bunjaku, Bekim
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Rosenqvist, Ulf
    Östergötlands Läns Landsting, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care.
    Nyström, Fredrik H
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Guldbrand, Hans
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    A Randomized Cross-Over Trial of the Postprandial Effects of Three Different Diets in Patients with Type 2 Diabetes2013In: PLoS ONE, ISSN 1932-6203, Vol. 8, no 11, e79324- p.Article in journal (Refereed)
    Abstract [en]

    Background: In the clinic setting both fasting levels of glucose and the area under the curve (AUC) of glucose, by determination of HbA1c levels, are used for risk assessments, in type 2 diabetes (NIDDM). However little is known about postprandial levels, and hence AUC, regarding other traditional risk factors such as insulin and blood-lipids and how this is affected by different diets. less thanbrgreater than less thanbrgreater thanObjective: To study postprandial effects of three diets, during a single day, in NIDDM. less thanbrgreater than less thanbrgreater thanMethods: A low-fat diet (45-56 energy-% from carbohydrates), and a low-carbohydrate diet (16-24 energy-% from carbohydrates) was compared with a Mediterranean-style diet (black coffee for breakfast and the same total-caloric intake as the other two diets for lunch with red wine, 32-35 energy-% from carbohydrates) in a randomized cross-over design. Total-caloric intake/test-day at the clinic from food was 1025-1080 kCal in men and 905-984 kCal in women. The test meals were consumed at a diabetes ward under supervision. less thanbrgreater than less thanbrgreater thanResults: Twenty-one participants were recruited and 19 completed the studies. The low-carbohydrate diet induced lower insulin and glucose excursions compared with the low-fat diet (pandlt;0.0005 for both AUC). The insulin-response following the single Mediterranean-style lunch-meal was more pronounced than during the low-fat diet lunch (insulin increase-ratio of the low-fat diet: 4.35 +/- 2.2, of Mediterranean-style diet: 8.12 +/- 5.2, p=0.001) while postprandial glucose levels were similar. The increase-ratio of insulin correlated with the elevation of the incretin glucose-dependent insulinotropic-polypeptide following the Mediterranean-style diet lunch (Spearman, r = 0.64, p = 0.003). less thanbrgreater than less thanbrgreater thanConclusions: The large Mediterranean-style lunch-meal induced similar postprandial glucose-elevations as the low-fat meal despite almost double amount of calories due to a pronounced insulin-increase. This suggests that accumulation of caloric intake from breakfast and lunch to a single large Mediterranean style lunch-meal in NIDDM might be advantageous from a metabolic perspective.

  • 16.
    Agebratt, Christian
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Ström, Edvin
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Romu, Thobias
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Dahlqvist Leinhard, Olof
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Borga, Magnus
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Leandersson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Nyström, Fredrik H.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    A Randomized Study of the Effects of Additional Fruit and Nuts Consumption on Hepatic Fat Content, Cardiovascular Risk Factors and Basal Metabolic Rate2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 1, e0147149- p.Article in journal (Refereed)
    Abstract [en]

    Background

    Fruit has since long been advocated as a healthy source of many nutrients, however, the high content of sugars in fruit might be a concern.

    Objectives

    To study effects of an increased fruit intake compared with similar amount of extra calories from nuts in humans.

    Methods

    Thirty healthy non-obese participants were randomized to either supplement the diet with fruits or nuts, each at +7 kcal/kg bodyweight/day for two months. Major endpoints were change of hepatic fat content (HFC, by magnetic resonance imaging, MRI), basal metabolic rate (BMR, with indirect calorimetry) and cardiovascular risk markers.

    Results

    Weight gain was numerically similar in both groups although only statistically significant in the group randomized to nuts (fruit: from 22.15±1.61 kg/m2 to 22.30±1.7 kg/m2, p = 0.24 nuts: from 22.54±2.26 kg/m2 to 22.73±2.28 kg/m2, p = 0.045). On the other hand BMR increased in the nut group only (p = 0.028). Only the nut group reported a net increase of calories (from 2519±721 kcal/day to 2763±595 kcal/day, p = 0.035) according to 3-day food registrations. Despite an almost three-fold reported increased fructose-intake in the fruit group (from 9.1±6.0 gram/day to 25.6±9.6 gram/day, p<0.0001, nuts: from 12.4±5.7 gram/day to 6.5±5.3 gram/day, p = 0.007) there was no change of HFC. The numerical increase in fasting insulin was statistical significant only in the fruit group (from 7.73±3.1 pmol/l to 8.81±2.9 pmol/l, p = 0.018, nuts: from 7.29±2.9 pmol/l to 8.62±3.0 pmol/l, p = 0.14). Levels of vitamin C increased in both groups while α-tocopherol/cholesterol-ratio increased only in the fruit group.

    Conclusions

    Although BMR increased in the nut-group only this was not linked with differences in weight gain between groups which potentially could be explained by the lack of reported net caloric increase in the fruit group. In healthy non-obese individuals an increased fruit intake seems safe from cardiovascular risk perspective, including measurement of HFC by MRI.

  • 17.
    Hambre, David
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Vergara, Marta
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Lood, Yvonne
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Bachrach-Lindström, Margareta
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Nyström, Fredrik H
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    A randomized trial of protein supplementation compared with extra fast food on the effects of resistance training to increase metabolism2012In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, Vol. 72, no 6, 471-478 p.Article in journal (Refereed)
    Abstract [en]

    Objective. To prospectively evaluate the effects of resistance training combined with increased energy intake or protein-supplementation on lean body-mass, resting metabolic-rate (RMR) and cardiovascular risk factors. Methods. Twenty-four healthy males (aged 19-32 years) performed resistance exercise for 12 weeks aiming for at least 1 hour training-sessions 3 times a week. The participants were randomized to consume extra protein (33 g whey protein/day) or a meal of fast-food/day (1350 kcal, 41 g protein). Body-composition was measured with Dual-Energy X-ray Absorptiometry (DEXA) and RMR by indirect calorimetry. Fasting blood samples were drawn before and after the 3-month training period and after 12 months. Results. The body weight increased from 75.1 +/- 6.9 kg to 78.7 +/- 7.2 kg (p andlt; 0.0001), without differences between the groups. RMR increased from 1787 +/- 143 kcal/24 h to 1954 +/- 187 kcal/24 h (p andlt; 0.0001, N = 24), which was more than expected from the increase in lean body-mass (increase from 59.7 +/- 4.3 kg to 61.8 +/- 4.1 kg p = 0.004). Fasting serum-insulin levels increased in the fast-food group compared with the extra-protein group (p = 0.03). ApoB increased from 0.691 +/- 0.14 g/L to 0.768 +/- 0.17 g/L, p = 0.004, in the fast-food group only. Long-term follow up after 12 months showed that RMR, body weight, total fat and lean body-masses did not differ from baseline (n = 19). Conclusions. Resistance training for 12 weeks increased RMR and lean body-mass similarly when based on either an increased energy-intake or protein supplement. However, the increase in RMR was higher than expected from the increase in lean body-mass. Thus resistance training could potentially decrease the risk of obesity by induction of increased RMR.

  • 18.
    Hahn, Robert
    et al.
    Linköping University, Department of Medical and Health Sciences, Anesthesiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Anaesthesiology and Surgery UHL.
    Ljunggren, Stefan
    Södertalje Hospital.
    Larsen, Filip
    Karolinska Institute.
    Nystrom, Thomas
    Karolinska Institute.
    A simple intravenous glucose tolerance test for assessment of insulin sensitivity2011In: Theoretical Biology Medical Modelling, ISSN 1742-4682, Vol. 8, no 12Article in journal (Refereed)
    Abstract [en]

    Background

    The aim of the study was to find a simple intravenous glucose tolerance test (IVGTT) that can be used to estimate insulin sensitivity.

    Methods

    In 20 healthy volunteers aged between 18 and 51 years (mean, 28) comparisons were made between kinetic parameters derived from a 12-sample, 75-min IVGTT and the Mbw (glucose uptake) obtained during a hyperinsulinemic euglycemic glucose clamp. Plasma glucose was used to calculate the volume of distribution (Vd) and the clearance (CL) of the injected glucose bolus. The plasma insulin response was quantified by the area under the curve (AUCins). Uptake of glucose during the clamp was corrected for body weight (Mbw).

    Results

    There was a 7-fold variation in Mbw. Algorithms based on the slope of the glucose-elimination curve (CL/Vd) in combination with AUCins obtained during the IVGTT showed statistically significant correlations with Mbw, the linearity being r2 = 0.63-0.83. The best algorithms were associated with a 25-75th prediction error ranging from -10% to +10%. Sampling could be shortened to 30-40 min without loss of linearity or precision.

    Conclusion

    Simple measures of glucose and insulin kinetics during an IVGTT can predict between 2/3 and 4/5 of the insulin sensitivity.

  • 19.
    Nyman, Elin
    et al.
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Health Sciences.
    Rohini Rajan, Meenu
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Fagerholm, Siri
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Brännmark, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Cedersund, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedical Engineering.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    A Single Mechanism Can Explain Network-wide Insulin Resistance in Adipocytes from Obese Patients with Type 2 Diabetes2014In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 289, no 48, 33215-33230 p.Article in journal (Refereed)
    Abstract [en]

    The response to insulin is impaired in type 2 diabetes. Much information is available about insulin signaling, but understanding of the cellular mechanisms causing impaired signaling and insulin resistance is hampered by fragmented data, mainly obtained from different cell lines and animals. We have collected quantitative and systems-wide dynamic data on insulin signaling in primary adipocytes and compared cells isolated from healthy and diabetic individuals. Mathematical modeling and experimental verification identified mechanisms of insulin control of the MAPKs ERK1/2. We found that in human adipocytes, insulin stimulates phosphorylation of the ribosomal protein S6 and hence protein synthesis about equally via ERK1/2 and mTORC1. Using mathematical modeling, we examined the signaling network as a whole and show that a single mechanism can explain the insulin resistance of type 2 diabetes throughout the network, involving signaling both through IRS1, PKB, and mTOR and via ERK1/2 to the nuclear transcription factor Elk1. The most important part of the insulin resistance mechanism is an attenuated feedback from the protein kinase mTORC1 to IRS1, which spreads signal attenuation to all parts of the insulin signaling network. Experimental inhibition of mTORC1 using rapamycin in adipocytes from non-diabetic individuals induced and thus confirmed the predicted network-wide insulin resistance.

  • 20.
    Bergqvist, Niclas
    et al.
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Nyman, Elin
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. AstraZeneca RandD, Sweden.
    Cedersund, Gunnar
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Stenkula, Karin G.
    Lund University, Sweden.
    A systems biology analysis connects insulin receptor signaling with glucose transporter translocation in rat adipocytes2017In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 292, no 27, 11206-11217 p.Article in journal (Refereed)
    Abstract [en]

    Type 2 diabetes is characterized by insulin resistance, which arises from malfunctions in the intracellular insulin signaling network. Knowledge of the insulin signaling network is fragmented, and because of the complexity of this network, little consensus has emerged for the structure and importance of the different branches of the network. To help overcome this complexity, systems biology mathematical models have been generated for predicting both the activation of the insulin receptor (IR) and the redistribution of glucose transporter 4 (GLUT4) to the plasma membrane. Although the insulin signal transduction between IR and GLUT4 has been thoroughly studied with modeling and time-resolved data in human cells, comparable analyses in cells from commonly used model organisms such as rats and mice are lacking. Here, we combined existing data and models for rat adipocytes with new data collected for the signaling network between IR and GLUT4 to create a model also for their interconnections. To describe all data (amp;gt;140 data points), the model needed three distinct pathways from IR to GLUT4: (i) via protein kinase B (PKB) and Akt substrate of 160 kDa (AS160), (ii) via an AS160-independent pathway from PKB, and (iii) via an additional pathway from IR, e.g. affecting the membrane constitution. The developed combined model could describe data not used for training the model and was used to generate predictions of the relative contributions of the pathways from IR to translocation of GLUT4. The combined model provides a systems-level understanding of insulin signaling in rat adipocytes, which, when combined with corresponding models for human adipocytes, may contribute to model-based drug development for diabetes.

  • 21. Bari, Muhammad Rizuanul
    et al.
    Östgren, Carl Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, General Practice. Östergötlands Läns Landsting, Local Health Care Services in the West of Östergötland.
    Rastam, Lennart
    Lindblad, Ulf
    Abdominal obesity and insulin resistance in patients with type 2 diabetes in a Swedish community - Skaraborg Hypertension and Diabetes Project2006In: Scandinavian Journal of Primary Health Care, ISSN 0281-3432, Vol. 24, no 4, 211-217 p.Article in journal (Refereed)
    Abstract [en]

    Objective. To explore the association between abdominal obesity and insulin resistance in patients with type 2 diabetes. Design. A cross-sectional observational study. Setting. Primary care in Skara, Sweden. Subjects. A total of 198 men and 186 women with type 2 diabetes who consecutively completed an annual check-up in 1992-1993. Main outcome measures. Abdominal obesity was defined according to criteria for the metabolic syndrome using the waist circumference (WC): > 102 cm for men and > 88 cm for women. Insulin resistance was estimated using the Homeostasis Model Assessment (HOMA), and was dichotomized by the 75th percentile (IR). Results. Abdominal obesity was found in 66 men (33%), and in 106 women (57%). Pearson's correlation coefficients between components of the metabolic syndrome and IR were statistically significant for WC, waist-hip ratio, serum triglycerides, and HDL cholesterol, and were higher for WC (0.40) than for waist-hip ratio (0.23) in both genders (p < 0.001). The association between WC and IR was challenged by successively entering other components of the metabolic syndrome into the model in a logistic regression. In the final model, adjusting for differences in age, systolic blood pressure, HbA1c, serum triglycerides, HDL cholesterol, and microalbuminuria, the association remained statistically significant both in men (OR 8.6, 95% CI 3.0-25.2, p < 0.001), and in women (OR 5.6, 95% CI 1.7-18.1, p = 0.004). Conclusions. WC provides a feasible measure for insulin resistance in the vast majority of subjects with type 2 diabetes. It is convenient and less expensive than direct means and could be used as a proxy for insulin resistance in population studies.

  • 22.
    Skarsvik, Susanne
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Aberrancies associated with dendritic cells and T lymphocytes in type 1 diabetes2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The incidence of type 1 diabetes has rapidly increased in the Western world and the age of onset has shifted to younger ages. Type 1 diabetes is a chronic disease caused by destruction of the insulin producing ß-cells in the pancreas leading to severe insulin deficiency. This results in hyperglycaemia and diagnosis of overt type 1 diabetes.

    The pathogenesis of type 1 diabetes is not fully understood. When diagnosed during childhood, the ß-cell destruction is believed to be caused by autoreactive T cells in the majority of cases. The effect of autoreactive T cells is limited by dendritic cells, which are involved in the induction of tolerance and in regulating T cells. Different subsets of T cells also play a role in regulating immune responses. The activation of autoreactive T cells is believed to be triggered by environmental factors e.g. coxsackievirus B4 and/or dietary factors. The major genetic determinant for type 1 diabetes is associated with the HLA class II genes encoding the HLA molecules on antigen presenting cells.

    The aim of the present study was to study the maturation of dendritic cells and how T cell reactivity is influenced by genetic and environmental factors in children with type 1 diabetes and/or children with increased genetic risk of developing type 1 diabetes in comparison to healthy children.

    The maturation of dendritic cells was studied by in vitro differentiation of monocytes into dendritic cells. Our results showed that children with type 1 diabetes and those with genetic risk of type 1 diabetes had a lower percentage of dendritic cells expressing CD11c and HLA-DR in addition to decreased secretion of TNF.

    The regulation of T cell polarization was investigated in children with type 1 diabetes and in neonates at genetic risk of type 1 diabetes by in vitro polarization of T cells. Children with newly diagnosed and longstanding type 1 diabetes had a lower number of CD4 and CD8 T cells expressing IL-12Rß2-chain and increased secretion of IL-13 from lymphocytes cultured in type 1 cytokine environment in comparison to healthy children. Neonates carrying type 1 diabetes risk associated haplotypes DQ2/DQ8 or DQ8 had a lower percentage of CD4 T cells expressing CCR4, lower mRNA levels of CCR4 and GATA-3 and lower secretion of IL-13 in lymphocytes cultured in type 2 cytokine environment compared to neonates without genetic risk of type 1 diabetes. Furthermore, we found that children with type 1 diabetes had a lower percentage of CD4 and CD8 T cells expressing CCR2, CXCR6 and IL-18R after in vitro stimulation of peripheral blood mononuclear cells with coxsackievirus B4 in comparison to healthy children with and without genetic risk of type 1 diabetes. We also found decreased secretion of IFN-γ and lower levels of Tbet mRNA from peripheral blood mononuclear cells stimulated with coxsackievirus B4 in children with type 1 diabetes compared to healthy children with and without genetic risk of type 1 diabetes.

    In conclusion, defects in the function of dendritic cells and in the polarization of T cells may contribute to an underlying immunological environment, which allows autoimmune responses to develop and impair the host defence mechanisms against pathogens. Ultimately these immunological aberrancies may lead to development of ß-cell autoimmunity.

    List of papers
    1. Poor in vitro maturation and pro-inflammatory cytokine response of dendritic cells in children at genetic risk of type 1 diabetes
    Open this publication in new window or tab >>Poor in vitro maturation and pro-inflammatory cytokine response of dendritic cells in children at genetic risk of type 1 diabetes
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    2004 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 60, no 6, 647-652 p.Article in journal (Refereed) Published
    Abstract [en]

    Type 1 diabetes (T1D) has been associated with an aberrant maturation of dendritic cells (DC). We studied the maturation of monocyte-derived DC in children with newly diagnosed T1D and in healthy children with genetic risk for T1D. Peripheral blood monocytes from children with newly diagnosed T1D (n = 12; mean age 13.2 years), children with human leukocyte antigen (HLA)-risk genotype of T1D (n = 7; mean age 12.7 years) and healthy children (n = 14; mean age 11.2 years) were in vitro differentiated into DC. Expression of HLA-DR, CD80/86 and CD11c and secretion of interleukin (IL)-12, tumor necrosis factor (TNF)-α, IL-6 and IL-10 were measured using flow cytometry. Lower percentage of DC expressed CD11c and HLA-DR, and decreased production of TNF-α was found in children with newly diagnosed T1D and in children at genetic risk when compared to healthy children. Children with risk genotype also had decreased IL-12 production by DC. Children with T1D and children at genetic risk of T1D appear to have similar aberrancies in the maturation of DC, which may predispose to β-cell autoimmunity.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-22840 (URN)10.1111/j.0300-9475.2004.01521.x (DOI)2178 (Local ID)2178 (Archive number)2178 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-02Bibliographically approved
    2. Aberrant regulation of interleukin-12 receptor β2 chain on type 1 cytokine-stimulated T lymphocytes in type 1 diabetes
    Open this publication in new window or tab >>Aberrant regulation of interleukin-12 receptor β2 chain on type 1 cytokine-stimulated T lymphocytes in type 1 diabetes
    2005 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 114, no 2, 287-293 p.Article in journal (Refereed) Published
    Abstract [en]

    An aberrant mitogen-induced polarization of peripheral blood T cells has been associated with type 1 diabetes (T1D). We studied, in T1D, type 1 and 2 cytokine-induced expression of the interleukin-12 receptor β2 chain (IL-12Rβ2 chain), which plays a critical role in regulating T-cell polarization. Peripheral blood lymphocytes from children with newly diagnosed T1D (n = 10; mean age 10 years), from children with longstanding T1D (n = 8; mean age 12·9 years) and from healthy children (n = 15; mean age 11·5 years) were stimulated with phytohaemagglutinin (PHA) in a type 1 (IL-12 and anti-IL-4) or a type 2 (IL-4 and anti-IL-12) cytokine environment. Secretion of interferon-γ (IFN-γ), IL-5 and IL-13, as detected by enzyme-linked immunosorbent assay (ELISA), and expression of the IL-12Rβ2 chain on CD4 and CD8 cells by flow cytometry, were analysed. Children with newly diagnosed and longstanding T1D had lower expression levels of the IL-12Rβ2 chain on IL-12Rβ2 chain-positive CD4 T cells (for a type 1 or a type 2 cytokine environment: P = 0·01 and P = 0·002 or P = 0·02 and P = 0·01, respectively) and on IL-12Rβ2 chain-positive CD8 T cells (for a type 1 or a type 2 cytokine environment: P = 0·007 and P = 0·0007 or P = 0·003 and P = 0·01, respectively) when compared to healthy children. A decreased percentage of IL-12Rβ2 chain-expressing CD4 T cells (P = 0·07 and P = 0·03) and CD8 T cells (P = 0·004 and P = 0·01) and increased secretion of IL-13 (P = 0·006 and P = 0·04) in a type 1 cytokine environment was seen in both groups of patients. Peripheral blood T cells from patients with both newly diagnosed and longstanding T1D showed poor polarization towards type 1 cells.

    Keyword
    IL-12R, IL-13, T cells, type 1 diabetes
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-24403 (URN)10.1111/j.1365-2567.2004.02102.x (DOI)6500 (Local ID)6500 (Archive number)6500 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-02Bibliographically approved
    3. Reduced expression of CCR4 on cord blood T lymphocytes in neonates at genetic risk of type 1 diabetes
    Open this publication in new window or tab >>Reduced expression of CCR4 on cord blood T lymphocytes in neonates at genetic risk of type 1 diabetes
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    In type 1 diabetes the T cell polarization and expression of chemokine receptors have been reported to be aberrant. We asked whether these aberrancies are present already at birth in neonates carrying HLA risk haplotypes for type 1 diabetes.

    Cord blood (CB) samples were obtained from neonates taking part in the Trial to Reduce IDDM in Genetically at Risk (TRIGR) and the Finnish Dietary Intervention Trial for Prevention of Type 1 Diabetes (FINDIA) studies and were screened for type 1 diabetes-associated HLA risk genotypes (HLA DR3-DQ2 and/or DR4-DQ8 without protective alleles). CB lymphocytes were stimulated with phytohemagglutinin (PHA) in type 1 (IL-12, anti-IL4) or type 2 (IL-4, anti-IL12) cytokine environment for 6 days. The expression of chemokine- and cytokine receptors on T cells was determined by flow cytometry, cytokines were analyzed with ELISA, and transcription factors were analyzed using real-time RT-PCR.

    When compared to the control group, neonates carrying alleles DQ2/DQ8 or DQ8 showed reduced percentage of CD4 T cells expressing CCR4 and lower levels of CCR4 mRNA after culture of CB lymphocytes in type 2 cytokine environment. In addition, these neonates had significantly lower secretion of iL-13 and expression of GATA-3 after culture of CB lymphocytes in type 2 cytok:ine environment in comparison to neonates with no increased genetic risk of type 1 diabetes.

    These results suggest aberrancies in the in vitro regulation of type 2 immune responses in children with increased genetic risk of type 1 diabetes when compared to neonates without HLA risk haplotypes suggesting that the HLA genotype may affect the T cell polarization already at birth. Aberrant induction ofT cell polarization may contribute to development of autoimmunity later in life.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-83498 (URN)
    Available from: 2012-10-02 Created: 2012-10-02 Last updated: 2012-10-02Bibliographically approved
    4. Decreased in vitro type 1 immune response against coxsackie virus B4 in children with type 1 diabetes
    Open this publication in new window or tab >>Decreased in vitro type 1 immune response against coxsackie virus B4 in children with type 1 diabetes
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    2006 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, no 4, 996-1003 p.Article in journal (Refereed) Published
    Abstract [en]

    Enteroviruses, particularly Coxsackie virus B4 (CVB4), are considered to be involved in the pathogenesis of type 1 diabetes. We wanted to compare the characteristics of T-cell immune response to CVB4 in children with type 1 diabetes and healthy children with and without HLA risk-associated haplotypes (HLA-DR3-DQ2 or HLA-DR4-DQ8) for type 1 diabetes. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured with CVB4 and analyzed for cytokine and chemokine receptors by flow cytometry and for expression of transcription factors Tbet and GATA-3 by RT-PCR and Western blot. Culture supernatants were analyzed for secretion of γ-interferon (IFN-γ). In children with type 1 diabetes, a decreased percentage of T-cells expressed CCR2, CXCR6, interleukin (IL)-18R, and IL-12Rβ2-chain after in vitro stimulation with CVB4 in comparison with healthy children with or without HLA risk genotype. Moreover, we found that children with type 1 diabetes had decreased IFN-γ secretion and expression of Tbet, both on mRNA and protein level, in CVB4-stimulated PBMCs. Accordingly, children with type 1 diabetes show an impaired type 1 immune response against CVB4 compared with healthy children. This may lead to a delayed clearance of the virus and, at least partly, explain why children with type 1 diabetes may be more prone to CVB4 infections and related complications, such as β-cell damage.

    Place, publisher, year, edition, pages
    American Diabetes Association, 2006
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-34899 (URN)10.2337/diabetes.55.04.06.db05-0630 (DOI)16567521 (PubMedID)23891 (Local ID)23891 (Archive number)23891 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2014-09-01Bibliographically approved
  • 23.
    Ljunggren, Stefan
    et al.
    Södertälje Hospital, Sweden.
    Nyström, Thomas
    Karolinska Institutet, Södersjukhuset, Stockholm, Sweden.
    Hahn, Robert G
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping. Södertälje Hospital, Sweden.
    Accuracy and precision of commonly used methods for quantifying surgery-induced insulin resistance: Prospective observational study2014In: European Journal of Anaesthesiology, ISSN 0265-0215, E-ISSN 1365-2346, Vol. 31, no 2, 110-116 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Insulin resistance develops in the perioperative setting and has an adverse influence on postoperative recovery and well-being.

    OBJECTIVES: To evaluate the effectiveness of commonly used methods for quantifying surgery-induced insulin resistance.

    DESIGN: Prospective observational study.

    SETTING: Surgery department and orthopaedic ward at two regional hospitals.

    PATIENTS: Twenty-two patients (mean age 68 years) scheduled for elective hip replacement.

    INTERVENTIONS: A short seven-sample intravenous glucose tolerance test (IVGTT) followed by a euglycaemic hyperinsulinaemic glucose clamp 1 day before and 2 days after the surgery.

    MAIN OUTCOME MEASURES: Insulin resistance shown by dynamic tests (the IVGTT and the glucose clamp) were compared to static tests [the quantitative insulin sensitivity check index (QUICKI) and the homeostatic model assessment-insulin resistance (HOMA-IR)], which use only the plasma glucose and insulin concentrations at baseline.

    RESULTS: The linear correlation coefficients for the relationship between insulin resistance as obtained with the glucose clamp and the other methods before or after surgery were 0.76 (IVGTT), 0.58 (QUICKI) and -0.65 (HOMA). The prediction errors (precision) averaged 18, 29 and 31%, respectively. Surgery-induced insulin resistance amounted to 45% (glucose clamp), 26% (IVGTT), 4% (QUICKI) and 3% (HOMA).

    CONCLUSION: Despite reasonably good linear correlations, the static tests grossly underestimated the degree of insulin resistance that developed in response to surgery.

  • 24.
    Dahlfors, Gunilla
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Action and interaction of growth factors and regulatory molecules in vascular cells: With special reference to the IGF-I-system2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Vascular function is greatly influenced by growth factors and regulatory molecules that can interact with each other in a complex pattern in the vascular wall. In this thesis we studied how different substances of special interest in the pathogenesis of vascular disease interact and regulate each other's expressions in endothelial cells and vascular smooth muscle cells (VSMCs).

    In VSMCs, angiotensin II was shown to delay PDGF-BB induced cell growth. This transient inhibitory effect of angiotensin II was mediated by the AT1-receptor, did not involve autocrine action of transforming growth factor-ß1 (TGF-ß1) and acted at a site downstream of PDGF-ß receptor phosphorylation.

    The interaction of the insulin-like growth factor-system (IGF-system) with various growth factors, glucose and nitric oxide (NO) was studied in vascular cells. Vascular endothelial growth factor (VEGF) and transforming growth factor-ß1 (TGF-ß1) regulated the expression of insulin-like growth factor-binding proteins (IGFBPs) in large vessel endothelial cells in a way that might cause an increased bioavailability of IGF-I locally in the subendothelial space. Angiotensin II, IGF-I and insulin did not affect IGFBP expression in these cells. The expression of IGFBPs was studied for the first time in human micro vessel endothelial cells. No effect of high glucose treatment on IGFBP expression was seen in either large vessel endothelial cells or microvessel endothelial cells. A possible interaction between NO and the IGF-system was studied in VSMCs. IGF-I did not have any significant effect on NO production in VSMCs and neither exogenous nor endogenous NO had any effect on IGFBP expression.

    In conclusion, we found that angiotensin II interacts with PDGF-BB in the regulation of VSMC growth. The IGF-system is regulated by VEGF and TGF-ß1 in endothelial cells while no effect of angiotensin II, IGF-I, insulin or high glucose was seen. We found no evidence for interaction of NO and the IGF-system in VSMCs.

    List of papers
    1. PDGF-BB-induced DNA synthesis is delayed by angiotensin II in vascular smooth muscle cells
    Open this publication in new window or tab >>PDGF-BB-induced DNA synthesis is delayed by angiotensin II in vascular smooth muscle cells
    1998 (English)In: American Journal of Physiology. Heart and Circulatory Physiology, ISSN 0363-6135, E-ISSN 1522-1539, Vol. 274, no 5, H1742-H1748 p.Article in journal (Refereed) Published
    Abstract [en]

    The interaction of ANG II with platelet-derived growth factor (PDGF)-BB-induced DNA synthesis was studied in cultured rat aortic smooth muscle cells. PDGF-BB-induced DNA synthesis was delayed (∼6–8 h) by ANG II as shown by a time-course experiment. Losartan, an AT1-receptor antagonist, blocked the transient inhibitory effect of ANG II, whereas the AT2-receptor antagonist PD-123319 had no effect. Autocrine- or paracrine-acting transforming growth factor-β1 (TGF-β1), believed to be a mediator of ANG II-induced inhibitory effects, was not responsible for the delay of PDGF-BB-induced DNA synthesis, because a potent TGF-β1 neutralizing antibody could not reverse this effect of ANG II, nor was the delay of the PDGF-BB effect caused by inhibition of PDGF-β-receptor phosphorylation as shown by Western blot analysis of immunoprecipitated PDGF-β receptor. In conclusion, our results show that ANG II can exert a transient inhibitory effect on PDGF-BB-induced proliferation via the AT1 receptor.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-79727 (URN)
    Available from: 2012-08-13 Created: 2012-08-13 Last updated: 2012-08-13Bibliographically approved
    2. Vascular Endothelial Growth Factor and Transforming Growth Factor-β1 Regulate the Expression of Insulin-Like Growth Factor-Binding Protein-3, -4, and -5 in Large Vessel Endothelial Cells
    Open this publication in new window or tab >>Vascular Endothelial Growth Factor and Transforming Growth Factor-β1 Regulate the Expression of Insulin-Like Growth Factor-Binding Protein-3, -4, and -5 in Large Vessel Endothelial Cells
    2000 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 141, no 6, 2062-2067 p.Article in journal (Refereed) Published
    Abstract [en]

    We investigated the effect of diabetes-associated growth factors on the expression of insulin-like growth factor-I (IGF-I) and IGF-binding proteins (IGFBPs) in cultured endothelial cells from bovine aorta. Gene expression was measured by solution hybridization, and proteins were measured by enzyme-linked immunosorbent assay, RIA, or Western blot. The cells expressed messenger RNA (mRNA) for IGFBP-2 through -6 and IGFBP-2 through -5 proteins were detected in conditioned medium. Vascular endothelial growth factor inhibited IGFBP-3 mRNA (P < 0.01) and protein expression and increased IGFBP-5 mRNA (P < 0.001) and protein. Transforming growth factor-β1 inhibited IGFBP-3 (P < 0.01), IGFBP-4 (P < 0.01), and IGF-I mRNA expression, whereas at the protein level only IGFBP-3 was significantly decreased. IGF-I, insulin, or angiotensin II did not affect IGF-I or IGFBP mRNA expression. At the protein level, IGF-I clearly increased IGFBP-5 levels in conditioned medium. In conclusion, vascular endothelial growth factor and transforming growth factor-β1 regulate IGFBP expression in bovine aortic endothelial cells. These observations provide a new aspect of regulation for the IGF-system in macrovascular endothelium, with possible implications for subendothelial smooth muscle cells and development of diabetic angiopathy.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-24909 (URN)10.1210/en.141.6.2062 (DOI)9312 (Local ID)9312 (Archive number)9312 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-08-13Bibliographically approved
    3. Expression of insulin-like growth factor binding proteins and transforming growth factor-ß1 in human microvascular endothelial and bovine aortic endothelial cells, no effects of high glucose
    Open this publication in new window or tab >>Expression of insulin-like growth factor binding proteins and transforming growth factor-ß1 in human microvascular endothelial and bovine aortic endothelial cells, no effects of high glucose
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Vascular complications are the major cause of morbidity and mortality in patients with diabetes mellitus. Insnlin-like growth factor-I (IGF-I) and transforming growth factor-ß1 (TGF-ß1) are two growth factors that regnlate vascular smooth muscle cell function in vivo and might be involved in the development of diabetic vascnlar complications. In this study we measnred the expression of IGF-binding proteins (IGFBPs) and TGF-ß1 in human dermal microvessel endothelial cells (HDMEC). We also studied the effect of high glucose levels on the expression of IGFBPs and TGF-ß1 in cnltured HDMEC and bovine aortic endothelial cells (BAEC). Gene expression was measured by an RNase-protection assay and proteins secreted into conditioned medium by ELISA or Western blot. The HDMEC expressed mRNAs for IGF-I and IGFBP-2 through -6 of which IGFBP-4 was the most excessively expressed and IGFBP-2 and -4 were detected in conditioned medium. Culture of HDMEC in high glucose (25 mM) for two passages did not change mRNA expressions for IGFBP-2, -3 or -4 significantly. Neither did low glucose+ mannitol (5.6 mM+ 20 mM) have any effect. In BAEC, high glucose (25 mM) for 48 h or 96 h did not affect IGFBP-3, -4 or -5 mRNA or protein and exposnre of BAEC to high glucose for two passages did also not affect IGFBP mRNA. TGF-ß1 mRNA was expressed by both BAEC and HDMEC. High glucose for two passages did not alter TGF-ß1 gene expression in either BAEC or HDMEC. In conclusion, we show that HDMEC express IGFBPs and TGF-ß1 andthat high glucose does not affect the expression in either HDMEC or BAEC.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-79728 (URN)
    Available from: 2012-08-13 Created: 2012-08-13 Last updated: 2012-08-13Bibliographically approved
    4. Effect of nitric oxide on vascular smooth muscle cell proliferation and insulin-like growth factor binding protein expression
    Open this publication in new window or tab >>Effect of nitric oxide on vascular smooth muscle cell proliferation and insulin-like growth factor binding protein expression
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    A possible interaction between nitric oxide (NO) and the insulin-like growth factor (IGF)-system was studied in cultured rat aortic smooth muscle cells. The NO-donor SNAP markedly inhibited basal and sernm-induced DNA synthesis while addition of L-NAME, an inhibitor of endogenous NO production, had no effect. L-NAME did also not significantly affect IGF-I, angiotensin II or TGF-ß1- induced effects on DNA synthesis. IGF-I was shown to stimulate the expression of IGFBP-4 mRNA, as measured by an RNase-protection assay, and angiotensin II inhibited expression of IGFBP-2 mRNA. Addition of L-NAME did not significantly change the effect of IGF-I or angiotensin II on IGFBP mRNA expression, neither did L-NAME or SNAP affect basal expression of IGFBP-2, -4 or -6 mRNA. In conclusion, we found no evidence for interaction of NO with the IGF-system in smooth muscle cells. Nitric oxide did not regulate the expression of IGFBPs and IGF-I-induced smooth muscle cell proliferation was not affected by inhibition of endogenous NO production.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-79729 (URN)
    Available from: 2012-08-13 Created: 2012-08-13 Last updated: 2012-08-13Bibliographically approved
  • 25.
    Bornfeldt, Karin E.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Actions and interactions of insulin-like growth factor-I and insulin in vascular smooth muscle1991Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Insulin-like growth factor-I (IGF-I) is a polypeptide with structural and biological similarities with insulin, and the receptors for IGF-I and insulin are homologous. The present investigation was devoted to the actions and interactions of IGF-I and insulin in vascular smooth muscle.

    In vascular smooth muscle from intact arteries and in cultured vascular smooth muscle cells there are abundant IGF-I receptors, but very few insulin receptors. IGF-I and insulin stimulated proliferation of cultured vascular smooth muscle cells, and the effects were probably mediated via the IGF-I receptor. However, the maximal growthpromoting effect of IGF-I was twice the maximal effect of insulin. If an acidic amino acid was substituted for the basic amino acid histidine in insulin B-chain (BlO His:::} Asp), like in IGF-I, the maximal growth-promoting activity reached the effect of IGF-1. The amino acid in position 10 in insulin B-chain may thus be important for the growthpromoting activity of insulin.

    Vascular smooth muscle cells express IGF-1 mRNA and produce imm1,1noreactive IGF-1 in vitro. Levels of IGF-1 m RNA were decreased by platelet-derived growth factor (PDGF-BB), basic fibroblast growth factor (bFGF) and serum, whereas IGF-1 and high concentrations of insulin increased IGF-I rnRNA and immunoreactive IGF-I. It is thus possible that IGF-1 is able to increase its own production in an autocrine loop withpositive feedback. The growth-promoting effects of IGF-1 and insulin were weak compared to the effects ofPDGF-BB and bFGF. The results indicate qualitative as well as quantitative differences between IGF-1 and insulin compared to PDGF-BB and bFGF.

    IGF-1 gene expression in aortic tissue was found to be decreased by diabetes and fasting in vivo, and the levels were restored if diabetic rats were treated with insulin.

    Vascular smooth muscle proliferation induced by balloon catheterization was found to be impaired by diabetes and increased by insulin-treatment in vivo, although not to the levels in normal rats. IGF-1 stimulated vascular smooth muscle proliferation in diabetic rats in vivo without affecting the diabetic state, and IGF-I gene expression was increased in proliferating vascular smooth muscle. The results suggest that IGF-I is involved in vascular smooth muscle proliferation in vivo.

    In conclusion, insulin is less potent than IGF-1 in stimulating proliferation of vascular smooth muscle, and the growth-promoting effects of insulin are weaker than the effects ofiGF-1, suggesting that insulin in concentrations found in plasma has little direct effect on vascular smooth muscle proliferation. IGF-1 is probably of importance for vascular smooth muscle proliferation, and the results suggest that IGF-1 can be locally produced and regulated in the vascular wall.

  • 26.
    Bronnikov, Gennady
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Aboulaich, Nabila
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Vener, Alexander
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Strålfors, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Acute effects of insulin on the activity of mitochondrial GPAT1 in primary adipocytes2008In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, Vol. 367, no 1, 201-207 p.Article in journal (Refereed)
    Abstract [en]

    The mitochondrial enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase (mtGPAT1) catalyzes a rate-limiting step in triacylglycerol and glycerophospholipid biosynthesis, which can be modulated by protein kinases in cell free analyses. We report that treatment of primary rat adipocytes with insulin acutely affects the activity of mtGPAT1 by increasing VMAX and KM for the substrates glycerol-3-phosphate and palmitoyl-CoA. Proteolytic cleavage of isolated mitochondrial membranes and mass spectrometric peptide sequencing identify in vivo phosphorylation of serine 632 and serine 639 in mtGPAT1. These phosphorylation sites correspond to casein kinase-2 consensus sequences and are highly conserved in chordate animal, but not fly, fungal or plant, mtGPAT1. © 2007 Elsevier Inc. All rights reserved.

  • 27.
    Eriksson, Andreas C
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Whiss, Per A
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Nilsson, Ulrika K
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Adhesion of human platelets to albumin is synergistically increased by lysophosphatidic acid and adrenaline in a donor-dependent fashion2006In: Blood Coagulation and Fibrinolysis, ISSN 0957-5235 (print), 1473-5733 (online), Vol. 17, no 5, 359-368 p.Article in journal (Refereed)
    Abstract [en]

    Lysophosphatidic acid (LPA) and adrenaline are weak platelet activators considered important for thrombus formation, and were previously shown to synergistically increase platelet aggregation. Here we investigate synergistic activation by LPA and adrenaline when measuring platelet adhesion. Platelet-rich plasma from healthy blood donors together with adrenaline and/or LPA were added to protein-coated microplates. Platelets were allowed to adhere and the amount of adhesion detected enzymatically. The LPA and adrenaline combination induced a synergistic increase of platelet adhesion to a normally non-adhesive albumin surface. The degree of synergy varied markedly between individuals; these variations could not be explained by age, gender, blood type or different amounts of platelets, oxidized low-density lipoprotein, insulin or glucose in plasma. There was a trend indicating increased synergistic effect for platelets sensitive to adrenaline stimulation. The synergistic effect was blocked by the α2-adrenoceptor antagonist yohimbine and inhibited by the ADP scavenger system creatine phosphate/creatine phosphokinase and antibodies against αIIbβ3. Furthermore, platelets adhering to albumin after adrenaline and LPA treatment expressed P-selectin. In conclusion, LPA and adrenaline act synergistically to increase αIIbβ3-mediated platelet adhesion to albumin, dependent on α2-adrenoceptor signalling and platelet secretion. We also confirm that synergistic platelet activation achieved with LPA and adrenaline is highly donor dependent.

  • 28.
    Kolak, Maria
    et al.
    Karolinska Institutet, Stockholm, Sweden .
    Westerbacka, Jukka
    University of Helsinki, Finland .
    Velagapudi, Vidya
    VTT Technical Research Centre of Finland, Espoo, Finland .
    Wågsäter, Dick
    Karolinska Institutet, Stockholm, Sweden .
    Yetukuri, Laxman
    VTT Technical Research Centre of Finland, Espoo, Finland .
    Makkonen, Janne
    University of Helsinki, Finland .
    Rissanen, Aila
    University of Helsinki, Finland .
    Häkkinen, Anna-Maija
    University of Helsinki, Finland .
    Lindell, Monica
    Karolinska Institutet, Stockholm, Sweden .
    Bergholm, Robert
    University of Helsinki, Finland .
    Hamsten, Anders
    Karolinska Institutet, Stockholm, Sweden .
    Eriksson, Per
    Karolinska Institutet, Stockholm, Sweden .
    Fisher, Rachel
    Karolinska Institutet, Stockholm, Sweden .
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland .
    Yki-Järvinen, Hannele
    Karolinska Institutet, Stockholm, Sweden .
    Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity2007In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 56, no 8, 1960-1968 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    We sought to determine whether adipose tissue is inflamed in individuals with increased liver fat (LFAT) independently of obesity.

    RESEARCH DESIGN AND METHODS:

    A total of 20 nondiabetic, healthy, obese women were divided into normal and high LFAT groups based on their median LFAT level (2.3 +/- 0.3 vs. 14.4 +/- 2.9%). Surgical subcutaneous adipose tissue biopsies were studied using quantitative PCR, immunohistochemistry, and a lipidomics approach to search for putative mediators of insulin resistance and inflammation. The groups were matched for age and BMI. The high LFAT group had increased insulin (P = 0.0025) and lower HDL cholesterol (P = 0.02) concentrations.

    RESULTS:

    Expression levels of the macrophage marker CD68, the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha, and plasminogen activator inhibitor-1 were significantly increased, and those of peroxisome proliferator-activated receptor-gamma and adiponectin decreased in the high LFAT group. CD68 expression correlated with the number of macrophages and crown-like structures (multiple macrophages fused around dead adipocytes). Concentrations of 154 lipid species in adipose tissue revealed several differences between the groups, with the most striking being increased concentrations of triacylglycerols, particularly long chain, and ceramides, specifically Cer(d18:1/24:1) (P = 0.01), in the high LFAT group. Expression of sphingomyelinases SMPD1 and SMPD3 were also significantly increased in the high compared with normal LFAT group.

    CONCLUSIONS:

    Adipose tissue is infiltrated with macrophages, and its content of long-chain triacylglycerols and ceramides is increased in subjects with increased LFAT compared with equally obese subjects with normal LFAT content. Ceramides or their metabolites could contribute to adverse effects of long-chain fatty acids on insulin resistance and inflammation.

  • 29.
    Nordfeldt, Sam
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Child and Adolescent Psychiatry . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Child and Adolescent Psychiatry.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Adverse events in intensively treated children and adolescents with type 1 diabetes1999In: Acta Paediatrica, ISSN 0001-656X, Vol. 88, no 11, 1184-1193 p.Article in journal (Refereed)
    Abstract [en]

    The main objective of this study was to examine the relation between adverse events and degree of metabolic control and multiple-dose treatment. A total of 139 children, aged between 1 and 18 y, prospectively registered severe hypoglycaemia with or without unconsciousness, as well as hospitalized ketoacidosis, during 1994-95. Treatment from onset was multiple-dose insulin (> 95% > or = 4 doses) combined with intense training and psychosocial support. Median HbA1c was 6.9% (ref. 3.6-5.4%). The incidence of severe hypoglycaemia with unconsciousness was 0.17 events per patient-year, having decreased from the 1970s to the 1990s, parallel to a change from 1-2 to > or = 4 doses per day. There was no correlation or association to the year mean HbA1c for severe hypoglycaemia. Severe hypoglycaemic episodes in 1995 correlated to severe hypoglycaemic episodes in 1994 (r=0.38; p<0.0001). Severe hypoglycaemia with unconsciousness increased during the spring season, and according to case records the assumed causes were mainly mistakes with insulin, food and exercise. Ketoacidosis was rare: 0.015 episodes per patient-year. We conclude that multiple-dose insulin therapy from the very onset of diabetes, combined with adequate self-control, active problem-based training and psycho-social support, may limit severe hypoglycaemia and ketoacidosis. Strategies aimed at minimizing severe hypoglycaemia without compromising metabolic control need to be evaluated.

  • 30.
    Van dijk, Peter R
    et al.
    Isala, Diabetes Centre, Zwolle, The Netherlands.
    Logtenberg, Susan J J
    University Medical Center Groningen, The Netherlands.
    Chisalita, Ioana Simona
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine.
    Hedman, Christina A.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Groenier, Klaas H
    University Medical Center Groningen, The Netherlands.
    Gans, Reinold O B
    University Medical Center Groningen, The Netherlands.
    Kleefstra, Nanne
    University Medical Center Groningen, The Netherlands.
    Arnqvist, Hans J.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Bilo, Henk J G
    University Medical Center Groningen, The Netherlands.
    After 6years of intraperitoneal insulin administration IGF-I concentrations in T1DM patients are at low-normal level.2015In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 25, no 6, 316-319 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Low concentrations of insulin-like growth factor-I (IGFI) have been reported in type 1 diabetes mellitus (T1DM), suggested to be due to low insulin concentrations in the portal vein. The aim was to describe the long-term course of IGFI concentrations among T1DM subjects treated with continuous intraperitoneal (IP) insulin infusion (CIPII).

    DESIGN: Nineteen patients that participated in a randomized cross-over trial comparing CIPII and subcutaneous (SC) insulin therapy in 2006 were followed until 2012. IGF-I measurements were performed at the start of the 2006 study, after the 6month SC- and CIPII treatment phase in 2006 and during CIPII therapy in 2012. Z-scores were calculated to compare the IGF-I concentrations with age-specific normative range values of a non-DM reference population.

    RESULTS: In 2012, IGF-I Z-scores (-0.7; 95% confidence interval -1.3, -0.2) were significantly higher than at the start of the 2006 study (-2.5; -3.3, -1.8), the end of the SC (-2.0; -2.6, -1.5) and CIPII (-1.6; -2.1, -1.0) treatment phase with a mean difference of: 1.8 (0.9, 2.7), 1.3 (0.5, 2.1) and 0.8 (0.1, 1.6), respectively.

    CONCLUSION: After 6years of treatment with CIPII, IGF-I concentrations among T1DM patients increased to a level that is higher than during prior SC insulin treatment and is in the lower normal range compared to a non-DM reference population. The results of this study suggest that long-term IP insulin administration influences the IGF system in T1DM.

  • 31.
    Barker, A.
    et al.
    Cambridge Institute Public Heatlh, England .
    Lauria, A.
    University of Campus Biomed, Italy .
    Schloot, N.
    University of Dusseldorf, Germany University of Dusseldorf, Germany .
    Hosszufalusi, N.
    Semmelweis University, Hungary .
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Mathieu, C.
    Katholieke University of Leuven, Belgium .
    Mauricio, D.
    Hospital Arnau Vilanova, Spain .
    Nordwall, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Norrköping.
    Van der Schueren, B.
    Katholieke University of Leuven, Belgium .
    Mandrup-Poulsen, T.
    University of Copenhagen, Denmark .
    Scherbaum, W .A.
    University of Dusseldorf, Germany .
    Weets, I.
    Vrije University of Brussel, Belgium Vrije University of Brussel, Belgium Belgian Diabet Registry BDR, Belgium .
    Gorus, F. K.
    Vrije University of Brussel, Belgium Vrije University of Brussel, Belgium Belgian Diabet Registry BDR, Belgium .
    Wareham, N.
    Cambridge Institute Public Heatlh, England .
    Leslie, R. D.
    Queen Mary University of London, England .
    Pozzilli, P.
    University of Campus Biomed, Italy Queen Mary University of London, England .
    Age-dependent decline of beta-cell function in type 1 diabetes after diagnosis: a multi-centre longitudinal study2014In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 16, no 3, 262-267 p.Article in journal (Refereed)
    Abstract [en]

    AimsC-peptide secretion is currently the only available clinical biomarker to measure residual -cell function in type 1 diabetes. However, the natural history of C-peptide decline after diagnosis can vary considerably dependent upon several variables. We investigated the shape of C-peptide decline over time from type 1 diabetes onset in relation to age at diagnosis, haemoglobin A1c (HbA1c) levels and insulin dose. MethodsWe analysed data from 3929 type 1 diabetes patients recruited from seven European centres representing all age groups at disease onset (childhood, adolescence and adulthood). The influence of the age at onset on -cell function was investigated in a longitudinal analysis at diagnosis and up to 5-years follow-up. ResultsFasting C-peptide (FCP) data at diagnosis were available in 3668 patients stratified according to age at diagnosis in four groups (less than5years, n=344; greater than5yearsless than10years, n=668; greater than10yearsless than18years, n=991; greater than18years, n=1655). FCP levels were positively correlated with age (pless than0.001); the subsequent decline in FCP over time was log-linear with a greater decline rate in younger age groups (pless than0.0001). ConclusionsThis study reveals a positive correlation between age at diagnosis of type 1 diabetes and FCP with a more rapid decline of -cell function in the very young patients. These data can inform the design of clinical trials using C-peptide values as an end-point for the effect of a given treatment.

  • 32.
    Hanberger, Lena
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Samuelsson, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Lindblad, Bengt
    Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    AlC in children and adolescents with diabetes in relation to certain clinical parameters - The Swedish Childhood Diabetes Registry SWEDIABKIDS2008In: Diabetes Care, ISSN 0149-5992, Vol. 31, no 5, 927-929 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE - We explored the relationship between AlC and insulin regimen, duration of diabetes, age, sex, and BMI as well as the differences between clinical mean AlC levels at pediatric diabetes clinics in Sweden. RESEARCH DESIGN AND METHODS - Data from 18,651 clinical outpatient visits (1,033 girls and 1,147 boys) at 20 pediatric clinics during 2001 and 2002 registered in the Swedish Childhood Diabetes Registry SWEDIABKIDS, a national quality registry, were analyzed. RESULTS - AlC was < 7.0% (target value similar to 8% per Diabetes Control and Complications Trial/National Glycohemoglobin Standardization Program standards) at 35% of the visits. Girls had significantly higher mean AlC than boys during adolescence. High mean AlC was correlated with high mean insulin dose, long duration of diabetes, and older age. Mean AlC varied between clinics (6.8-8.2%). Differences between centers could not be explained by differences in diabetes duration, age, BMI, or insulin dose. CONCLUSIONS - Adolescents with a high insulin dose and a long duration of diabetes, especially girls, need to be focused on, Differences in mean values between centers remained inexplicable and require further investigation.

  • 33.
    Ekstedt, Mattias
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Franzén, Lennart E
    Department of Histopathology and Cytology, Aleris Medilab, Täby, Sweden.
    Holmqvist, Marika
    Linköping University, Department of Medicine and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Bendtsen, Preben
    Linköping University, Department of Medicine and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in the West of Östergötland, Department of Medical Specialist.
    Mathiesen, Ulrik L
    Department of Internal Medicine, County Hospital, Oskarshamn, Sweden.
    Bodemar, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Kechagias, Stergios
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease2009In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, Vol. 44, no 3, 366-374 p.Article in journal (Refereed)
    Abstract [en]

    Objective: Moderate alcohol consumption has been reported to be inversely associated with cardiovascular disease and total mortality. The importance of non-alcoholic fatty liver disease (NAFLD) is increasing and many NAFLD patients suffer from cardiovascular disease. In these patients, moderate alcohol consumption could be beneficial. The aim of this study was to investigate whether low alcohol intake, consistent with the diagnosis of NAFLD, is associated with fibrosis progression in established NAFLD.

    Material and methods: Seventy-one patients originally referred because of chronically elevated liver enzymes and diagnosed with biopsy-proven NAFLD were re-evaluated. A validated questionnaire combined with an oral interview was used to assess weekly alcohol consumption and the frequency of episodic drinking. Significant fibrosis progression in NAFLD was defined as progression of more than one fibrosis stage or development of endstage liver disease during follow-up.

    Results: Mean follow-up (SD) was 13.8 (1.2) years between liver biopsies. At follow-up, 17 patients (24%) fulfilled the criteria for significant fibrosis progression. The proportion of patients reporting heavy episodic drinking at least once a month was higher among those with significant fibrosis progression (p=0.003) and a trend towards higher weekly alcohol consumption was also seen (p=0.061). In a multivariate binary logistic regression analysis, heavy episodic drinking (p0.001) and insulin resistance (p0.01) were independently associated with significant fibrosis progression.

    Conclusions: Moderate alcohol consumption, consistent with the diagnosis of NAFLD to be set, is associated with fibrosis progression in NAFLD. These patients should be advised to refrain from heavy episodic drinking.

  • 34.
    Herland, Anna
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics . Linköping University, The Institute of Technology.
    Björk, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics . Linköping University, The Institute of Technology.
    Hania, P. Ralph
    Department of Chemical Physics, University of Lund, Lund, Sweden.
    Scheblykin, Ivan G.
    Department of Chemical Physics, University of Lund, Lund, Sweden.
    Inganäs, Olle
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics . Linköping University, The Institute of Technology.
    Alignment of a conjugated polymer onto amyloid-like protein fibrils2007In: Small, ISSN 1613-6810, Vol. 3, no 2, 318-325 p.Article in journal (Refereed)
    Abstract [en]

    The amyloid-like fibril is a biomolecular nanowire template of very high stability. Here we describe the coordination of a conjugated polyelectrolyte, poly(thiophene acetic acid) (PTAA), to bovine insulin fibrils with widths of <10 nm and lengths of up to more than 10 m. Fibrils complexed with PTAA are aligned on surfaces through molecular combing and transfer printing. Single-molecule spectroscopy techniques are applied to chart spectral variation in the emission of these wires. When these results are combined with analysis of the polarization of the emitted light, we can conclude that the polymer chains are preferentially aligned along the fibrillar axis.

  • 35.
    Zhang, Hong
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Alloxan Toxicity to macrophages and Insulinoma Cells1995Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Alloxan induces damage and death of pancreatic islet B-cells in severalexperimental animal models, thus causing insulin-dependent diabetes mellitus (IDDM or type I diabetes). This unique cytotoxicity of alloxan has been studied for more than fifty years. The mechanisms behind the cytotoxicity of alloxan have, however, never been fully understood, although an increasing number of authors now suggest formation of reactive oxygen species, targeting the plasma membrane, mitochondria and DNA.

    In the present study, we have investigated: (i) the production of superoxide and hydrogen peroxide during reactions between alloxan and reducing agents such as cysteine, reduced glutathione, and ascorbic acid; (ii) the cytotoxic effects of alloxan in the absence of reducing agents, on model systems of cultured macrophages and insulinoma cells; (iii) the cytotoxicity of alloxan together with the reducing agents on these cultured cells; (iv) the cytotoxicity of hydrogen peroxide, used at concentrations similar to those formed during the reactions of alloxan with reducing agents; (v) the influence of iron and the iron-chelator, desferrioxamine, on the alloxan-induced cytotoxicity; and (vi) the influence of starvation-induced autophagocytosis on the sensitivity of cells to hydrogen peroxide-induced oxidative stress.

    Cell viability was estimated by a delayed trypan blue dye exclusion test and plasma membrane permeability by a modified microfluorometric combined fluorescein diacetate-propidium iodide staining technique. Lysosomal membrane stability was microfluorometrically assayed by acridine orange and neutral red relocalization techniques. The intracellular amounts of iron, reduced glutathione, antioxidant enzymes, and ATP were biochemically and cytochemically studied under a variety of conditions.

    The results showed that: (i) superoxide artion radicals and hydrogen peroxide were produced by reactions between alloxan and several reducing agents (e.g. cysteine, reduced glutathione and ascorbic acid). Hydrogen peroxide readily diffused through cellular membranes into the lysosomes if it was not previously degraded by the cellular antioxidative defence systems. Hydroxyl radicals might be produced by intralysosornal Fenton reactions, if reactive iron was present, resulting in lysosomal membrane damage followed by a leakage of lysosomal lytic enzymes with ensuing cell degeneration and eventually cell death. (ii) If iron was adsorbed to plasma membranes, extracellularly produced superoxide anion radicals and hydrogen peroxide might cause the plasma membrane damage due to Fenton reactions. (iii) Preincubation with desferrioxamine, or the presence of catalase inhibited the cytotoxicity induced by alloxan and reducing agents. (iv) The antioxidative defence activity of insulinoma cells was low. (v) Starvation in PBS enhanced the sensitivity of both macrophages and insulinoma cells to oxidative stress induced by hydrogen peroxide mediated through increased activity of autophagocytotosis. Thus, the amount of intralysosomal reactive iron consequently resulted from the degradation of various iron-containing metallo-proteins.

    We conclude that the exposure of cells to alloxan together with a reducing agent created cellular oxidative stress through extracellular formation of superoxide anion radicals and hydrogen peroxide. The latter compound easily penetrated plasma and lysosomal membranes, reaching the lysosomal interior. If enough reactive iron was present within lysosomes and the hydrogen peroxide was not degraded by catalase or glutathione peroxidase before entering the acidic vacuolar apparatus hydroxyl radicals could be produced via intralysosomal Fenton reactions.The hydroxyl radicals, in turn, would attack and damage the lysosomalmembranes, causing a leakage of lysosomal enzymes to the cytosol and eventually leading to cell death. The sensitivity of cells to alloxan-induced cytotoxicity in the presence of reducing agents was therefore a function of (i) the rate of hydrogen peroxide production, (ii) the cellular antioxidative defence systems, (iii) the lysosomal amount of reactive iron, and (iv) the capacity of autophagocytosis.

  • 36.
    Ma, Zhi
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Li, Z.-C.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Engström, U.
    Ludwig Institute of Cancer Research, Uppsala Branch, Uppsala, Sweden.
    Westermark, P.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Altered immunoreactivity of islet amyloid polypeptide (IAPP) may reflect major modifications of the IAPP molecule in amyloidogenesis1997In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 40, no 7, 793-801 p.Article in journal (Refereed)
    Abstract [en]

    We have developed a mouse monoclonal antibody against rat/mouse islet amyloid polypeptide (IAPP). The antibody recognises an epitope in the N-terminal part of the molecule, which is conserved between different species. The antibody immunohistochemically labelled beta cells in normal islets of most different mammalian species including man and in one avian species. Previous immunohistochemical studies of human pancreatic tissue from individuals with non-insulin-dependent diabetes mellitus (NIDDM) have revealed a paradoxical and unexplained lack of IAPP immunoreactivity in beta cells close to amyloid in spite of the presence of IAPP mRNA. In contrast to these findings we show that the newly developed monoclonal IAPP antibody strongly labels such beta cells while islet amyloid deposits which are labelled by polyclonal antisera do not bind the monoclonal antibody. These findings with the polyclonal antisera and the monoclonal antibody indicate that IAPP undergoes one or several structural changes during the amyloidogenesis. Knowledge of these structural changes that may include abnormal folding or chemical modification of IAPP is probably important for the understanding of the amyloidogenesis and the pathogenesis of the islet lesion in NIDDM.

  • 37.
    Nyström, Fredrik
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Ambulatory blood pressure and components of the metabolic syndrome in the population: With reference to the renin-angiotensin system, IgF-I, IGFBP-1, neuropentide Y, and leptin1997Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The term "the metabolic syndrome" has been given to the constellation of insulin resistance, high blood pressure and hyperlipidemia. In western countries it is strongly associated with obesity and atherosclerosis. The cause of the metabolic syndrome is, however, incompletely understood. Ambulatory blood pressure (ABP) is devoid of the so called white-coat effect (WCE) of clinic BP recordings and might thus better estimate the actual BP-load. This is a descriptive study of the renin-angiotensin system, IGF-I, IGFBP-1, neuropeptide Y, and leptin and their relations to ABP and components of the metabolic syndrome.

    A population-based study on 224 subjects 18-70 years old, evenly age-distributed and randomly selected from the population of Linköping, Sweden, was performed. This group was the result of a participation rate of 67%. Venous blood was drawn at 0800 a.m. and clinic BP was recorded as well as anthropometric data such as height and weight. A spacelab ABP recorder was applied. ABP reference data were calculated. It was found that clinic BP rose more steeply with age than did ABP and that predetermined day/night intervals causedmisclassification of the diurnal BP variation. The relation of the WCE, defined as the clinic BP minus daytime ABP, was shown to be positively correlated with the levels of plasma cortisol and only weakly to levels of neuropeptide Y. The renin-angiotensin system was decribed in thepopulation. It was shown that the levels of plasma renin-activity (PRA) were affected by age and oestrogen-medication, although this was not the case for plasma immuno-reactive active renin (IRR). Neither PRA nor IRR showed any age-independent correlations to BP. Refererence values were given for IGF-I and IGFBP-1. It was found that IGF-I declined with age and that it"'s binding protein, IGFBP-1, increased with age. The relations of neuropeptide Y, a BP-elevating and appetite-stimulating polypeptide, to the components of the metabolicsyndrome was described. Although no significant cotTelations were found between plasma neuropeptide Y and BP, body-mass-index (BMI) or C-peptide in either gender, a positive correlation was found between both total and LDL cholesterol and neuropeptide Y in women,but not in men. The levels of the anorexogenic substance leptin was shown to correlate positively with BMI and C-peptide in both genders in the studied population. Leptin correlated negatively with testosterone levels in men. Ten OH-deficient subjects were shown to have higher levels of leptin than controls matched for BM! and gender from the population-study. Substitution of GH lowered the levels of leptin.

    Data from this population-based study will be valuable in the further evaluation of the components of the metabolic syndrome in different populations and in diseases other than OH-deficiency.

  • 38.
    Andersson, Arne
    et al.
    Uppsala University.
    Bohman, Sara
    Uppsala University.
    Borg, L A Hakan
    Uppsala University.
    Paulsson, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Schultz, Sebastian
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Per
    Uppsala University.
    Amyloid Deposition in Transplanted Human Pancreatic Islets: A Conceivable Cause of Their Long-Term Failure2008In: EXPERIMENTAL DIABETES RESEARCH, ISSN 1687-5214, Vol. 2008, no 562985Article in journal (Refereed)
    Abstract [en]

    Following the encouraging report of the Edmonton group, there was a rejuvenation of the islet transplantation field. After that, more pessimistic views spread when long-term results of the clinical outcome were published. A progressive loss of the beta-cell function meant that almost all patients were back on insulin therapy after 5 years. More than 10 years ago, we demonstrated that amyloid deposits rapidly formed in human islets and in mouse islets transgenic for human IAPP when grafted into nude mice. It is, therefore, conceivable to consider amyloid formation as one potential candidate for the long-term failure. The present paper reviews attempts in our laboratories to elucidate the dynamics of and mechanisms behind the formation of amyloid in transplanted islets with special emphasis on the impact of long-term hyperglycemia.

  • 39.
    Lindgren, Mikael
    et al.
    Norwegian University Science and Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Amyloid oligomers: spectroscopic characterization of amyloidogenic protein states2010In: The FEBS Journal, ISSN 1742-464X, Vol. 277, no 6, 1380-1388 p.Article, review/survey (Refereed)
    Abstract [en]

    It is assumed that protein fibrils manifested in amyloidosis result from an aggregation reaction involving small misfolded protein sequences being in an oligomeric or prefibrillar state. This review covers recent optical spectroscopic studies of amyloid protein misfolding, oligomerization and amyloid fibril growth. Although amyloid fibrils have been studied using established protein-characterization techniques throughout the years, their oligomeric precursor states require sensitive detection in real-time. Here, fluorescent staining is commonly performed using thioflavin T and other small fluorescent molecules such as 4-(dicyanovinyl)- julolidine and 1-amino-8-naphtalene sulphonate that have high affinity to hydrophobic patches. Thus, populated oligomeric intermediates and related prefibrillar structures have been reported for several human amyloidogenic systems, including amyloid-beta protein, prion protein, transthyretin, alpha-synuclein, apolipoprotein C-II and insulin. To obtain information on the progression of the intermediate states, these were monitored in terms of fluorescence parameters, such as anisotropy, and quantum efficiency changes upon protein binding. Recently, new antibody stains have allowed precise monitoring of the oligomer size and distributions using multicolor labelling and single molecule detection. Moreover, a pentameric thiophene derivative (p-FTAA) was reported to indicate early precursors during A-beta(1-40) fibrillation, and was also demonstrated in real-time visualization of cerebral protein aggregates in transgenic AD mouse models by multiphoton microscopy. Conclusively, molecular probes and optical spectroscopy are now entering a phase enabling the in vivo interrogation of the role of oligomers in amyloidosis. Such techniques used in parallel with in vitro experiments, of increasing detail, will probably couple structure to pathogenesis in the near future.

  • 40.
    Hammarström, Per
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Ali, Malik M
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Mishra, Rajesh
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Salagic, Belma
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Svensson, Samuel
    AstraZeneca RandD.
    Tengvall, Pentti
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics. Linköping University, The Institute of Technology.
    Lundström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    An Auto-Catalytic Surface for Conformational Replication of Amyloid Fibrils-Genesis of an Amyloid World?2011In: Origins of life and evolution of the biosphere, ISSN 0169-6149, E-ISSN 1573-0875, Vol. 41, no 4, 373-383 p.Article in journal (Refereed)
    Abstract [en]

    Amyloid fibrils are composed of self assembled stacked peptide or protein molecules folded and trapped in a stable cross-beta-sheet conformation. The amyloid fibrillation mechanism represents an intriguing self-catalyzed process rendering replication of a molecular conformational memory of interest for prebiotic chemistry. Herein we describe how a solid surface can be rendered auto-catalytic for fibrillation of a protein solution. We have discovered that a hydrophobic silicon or glass surface can be made to continuously fibrillate solutions of insulin monomers under stressed conditions (pH 1.6, 65 degrees C). It was found that the surface acts as a platform for the formation of nascent seeds that induce fibril replication on and at the surface. This autocatalytic effect stems from a layer a few insulin molecules thick representing an oligomeric layer of misfolded, conformationally trapped, insulin molecules that rapidly through epitaxial growth catalyze the rate determining step (nucleation) during fibril replication. This autocatalytic layer is generated by the protein-solid surface interaction and conformational changes of the adsorbed protein during exposure at the air-water interface. The resulting autocatalytic surface thus both initiates local conformational molecular self-replication and acts as a reservoir for fibril seeds budding off into solution spreading fibril replication entities to the surrounding medium. The possibility of catalysis of the conformational replication process by minute amounts of nucleation sites located on a recruiting surface can evade the issue of dramatic concentration dependence of amyloidogenesis.

  • 41.
    Carlsson, Jenny
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics . Linköping University, The Institute of Technology.
    Gullstrand, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Enander, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    An indirect competitive immunoassay for insulin autoantibodies based on surface plasmon resonance2008In: Biosensors and Bioelectronics, ISSN 0956-5663, Vol. 24, no 4, 876-881 p.Article in journal (Refereed)
    Abstract [en]

    We have developed a sensitive and specific method based on surface plasmon resonance (SPR) for detection of insulin autoantibodies (IAA) in serum samples from individuals at high risk of developing type 1 diabetes (T1D). When measuring trace molecules in undiluted sera with label-free techniques like SPR, non-specific adsorption of matrix proteins to the sensor surface is often a problem, since it causes a signal that masks the analyte response. The developed method is an indirect competitive immunoassay designed to overcome these problems. Today, IAA is mainly measured in radio immunoassays (RIAs), which are time consuming and require radioactively labeled antigen. With our SPR-based immunoassay the overall assay time is reduced by a factor of >100 (4 days to 50 min), while sensitivity is maintained at a level comparable to that offered by RIA.

  • 42.
    Fulati, Alimujiang
    et al.
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Usman Ali, Syed M.
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Asif, Muhammad H.
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology. Pakistan.
    Hassan Alvi, Naveed Ul
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Willander, Magnus
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Brännmark, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Börjesson, Sara I.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Elinder, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Danielsson, Bengt
    Lund University, Sweden.
    An intracellular glucose biosensor based on nanoflake ZnO2010In: Sensors and actuators. B, Chemical, ISSN 0925-4005, Vol. 150, no 2, 673-680 p.Article in journal (Other academic)
    Abstract [en]

    In this study, an improved potentiometric intracellular glucose biosensor was fabricated with immobilization of glucose oxidase on a ZnO nanoporous material. The ZnO nanoporous material with a wall thickness around 200 nm was grown on the tip of a borosilicate glass capillary and used as a selective intracellular glucose sensor for the measurement of glucose concentrations in human adipocytes and frog oocytes. The results showed a fast response within 4 s and a linear glucosedependent electrochemical response over a wide range of glucose concentration (500 nM-10 mM). The measurements of intracellular glucose concentrations with our biosensor were consistent with the values of intracellular glucose concentrations reported in the literature. The sensor also demonstrated its capability by detecting an increase in the intracellular glucose concentration induced by insulin. We found that the ZnO nanoporous material provides sensitivity as high as 1.8 times higher than that obtained using ZnO nanorods under the same conditions. Moreover, the fabrication method in our experiment is simple and the excellent performance of the developed nanosensor in sensitivity, stability, selectivity, reproducibility and anti-interference was achieved. All these advantageous features of this intracellular glucose biosensor based on functionalised ZnO nanoporous material compared to ZnO nanorods demonstrate a promising way of enhancing glucose biosensor performance to measure reliable intracellular glucose concentrations within single living cells.

  • 43.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Karolinska Institute, Sweden .
    Angiogenesis and Vascular Functions in Modulation of Obesity, Adipose Metabolism, and Insulin Sensitivity2013In: Cell Metabolism, ISSN 1550-4131, Vol. 18, no 4, 478-489 p.Article, review/survey (Refereed)
    Abstract [en]

    White and brown adipose tissues are hypervascularized and the adipose vasculature displays phenotypic and functional plasticity to coordinate with metabolic demands of adipocytes. Blood vessels not only supply nutrients and oxygen to nourish adipocytes, they also serve as a cellular reservoir to provide adipose precursor and stem cells that control adipose tissue mass and function. Multiple signaling molecules modulate the complex interplay between the vascular system and the adipocytes. Understanding fundamental mechanisms by which angiogenesis and vasculatures modulate adipocyte functions may provide new therapeutic options for treatment of obesity and metabolic disorders by targeting the adipose vasculature.

  • 44.
    Svensson, M.
    et al.
    Lund University, Sweden .
    Ramelius, A.
    Lund University, Sweden .
    Nilsson, A.-L.
    Ostersund Hospital, Sweden .
    Delli, A.J.
    Lund University, Sweden .
    Elding Larsson, H.
    Lund University, Sweden .
    Carlsson, A.
    Lund University, Sweden .
    Forsander, G.
    Sahlgrens University Hospital, Sweden .
    Ivarsson, S.A.
    Lund University, Sweden .
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Kockum, I.
    Karolinska Institute, Sweden .
    Marcus, C.
    Karolinska Institute, Sweden .
    Samuelsson, Ulf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Ortqvist, E.
    Karolinska Institute, Sweden .
    Lernmark, A.
    Lund University, Sweden .
    Antibodies to Influenza Virus A/H1N1 Hemagglutinin in Type 1 Diabetes Children Diagnosed Before, During and After the SWEDISH A(H1N1)pdm09 Vaccination Campaign 2009-20102014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 2, 137-148 p.Article in journal (Refereed)
    Abstract [en]

    We determined A/H1N1-hemagglutinin (HA) antibodies in relation to HLAD-Q genotypes and islet autoantibodies at clinical diagnosis in 1141 incident 0.7 to 18-year-old type 1 diabetes patients diagnosed April 2009-December 2010. Antibodies to S-35-methionine-labelled A/H1N1 hemagglutinin were determined in a radio-binding assay in patients diagnosed before (n = 325), during (n = 355) and after (n = 461) the October 2009-March 2010 Swedish A(H1N1) pdm09 vaccination campaign, along with HLA-DQ genotypes and autoantibodies against GAD, insulin, IA-2 and ZnT8 transporter. Before vaccination, 0.6% patients had A/H1N1-HA antibodies compared with 40% during and 27% after vaccination (P less than 0.0001). In children less than3 years of age, A/H1N1-HA antibodies were found only during vaccination. The frequency of A/H1N1-HA antibodies during vaccination decreased after vaccination among the 3 less than 6 (P = 0.006) and 13 less than 18 (P = 0.001), but not among the 6 less than 13-year-olds. HLA-DQ2/8 positive children less than3 years decreased from 54% (15/28) before and 68% (19/28) during, to 30% (9/30) after vaccination (P = 0.014). Regardless of age, DQ2/2; 2/X (n = 177) patients had lower frequency (P = 0.020) and levels (P = 0.042) of A/H1N1-HA antibodies compared with non-DQ2/2; 2/X (n = 964) patients. GADA frequency was 50% before, 60% during and 51% after vaccination (P = 0.009). ZnT8QA frequency increased from 30% before to 34% during and 41% after vaccination (P = 0.002). Our findings suggest that young (less than3 years) along with DQ2/2; 2/X patients were low responders to Pandemrix (R). As the proportion of DQ2/8 patients less than3 years of age decreased after vaccination and the frequencies of GADA and ZnT8QA were enhanced, it cannot be excluded that the vaccine affected clinical onset of type 1 diabetes.

  • 45.
    Strollo, Rocky
    et al.
    University of Campus Biomed Roma, Italy.
    Vinci, Chiara
    University of Campus Biomed Roma, Italy; Queen Mary University of London, England.
    Napoli, Nicola
    University of Campus Biomed Roma, Italy; IRCCS Ist Ortoped Galeazzi, Italy.
    Pozzilli, Paolo
    University of Campus Biomed Roma, Italy; Queen Mary University of London, England.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Nissim, Ahuva
    Queen Mary University of London, England.
    Antibodies to post-translationally modified insulin as a novel biomarker for prediction of type 1 diabetes in children2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no 8, 1467-1474 p.Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis We have shown that autoimmunity to insulin in type 1 diabetes may result from neoepitopes induced by oxidative post-translational modifications (oxPTM). Antibodies specific to oxPTM-insulin (oxPTM-INS-Ab) are present in most newly diagnosed individuals with type 1 diabetes and are more common than autoantibodies to native insulin. In this study, we investigated whether oxPTM-INS-Ab are present before clinical onset of type 1 diabetes, and evaluated the ability of oxPTM-INS-Ab to identify children progressing to type 1 diabetes. Methods We used serum samples collected longitudinally from the All Babies in Southeast Sweden (ABIS) cohort tested for the gold standard islet autoantibodies to insulin (IAA), GAD (GADA), tyrosine phosphatase 2 (IA-2A) and zinc transporter 8 (ZnT8A). We studied 23 children who progressed to type 1 diabetes (progr-T1D) and 63 children who did not progress to type 1 diabetes (NP) after a median follow-up of 10.8 years (interquartile range 7.7-12.8). Of the latter group, 32 were positive for one or more islet autoantibodies (NP-AAB(+)). oxPTM-INS-Ab to insulinmodified by (OH)-O-center dot or HOCl were measured by our developed ELISA platform. Results Antibodies to at least one oxPTM-INS were present in 91.3% of progr-T1D children. oxPTM-INS-Ab co-existed with GADA, IA-2A, IAA or ZnT8A in 65.2%, 56.5%, 38.9% and 33.3% progr-T1D children, respectively. In addition, oxPTM-INS-Ab were present in 17.4%, 26.1%, 38.9% and 41.6% of progr-T1D children who were negative for GADA, IA-2A, IAA and ZnT8A, respectively. (OH)-O-center dot-INS-Ab were more common in progr-T1D children than in NP-AAB+ children (82.6% vs 19%; p amp;lt; 0.001) and allowed discrimination between progr-T1D and NP-AAB(+) children with 74% sensitivity and 91% specificity. None of the NP-AAB(-) children were positive for oxPTM-INS-Ab. Conclusions/interpretation oxPTM-INS-Ab are present before the clinical onset of type 1 diabetes and can identify children progressing to type 1 diabetes.

  • 46.
    Holmberg, Hanna
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Mersebach, H
    Kanck, K
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Study Group on Immunogenecity, Insulin Aspart
    Antibody response to insulin in children and adolescents with newly diagnosed Type 1 diabetes.2008In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 25, no 7, 792-797 p.Article in journal (Refereed)
    Abstract [en]

    AIMS: To compare levels of insulin antibodies in children and adolescents after initiation of insulin therapy using either insulin aspart (IAsp) or human insulin (HI) in combination with Neutral Protamine Hagedorn (NPH) insulin, and to investigate the relationships between insulin antibodies and HbA(1c) and insulin dose. METHODS: IAsp-specific antibodies (IAsp-Ab) and antibodies cross-reacting with HI and IAsp (HI-cross-Ab) were analysed by radioimmunoassay at diagnosis of diabetes and every 3-6 months for 30 months. Seventy-two patients (HI = 30, IAsp = 42) with Type 1 diabetes, aged 2-17 years were included. Data on HbA(1c), insulin dose and serious adverse events (SAEs) were collected retrospectively. RESULTS: IAsp-Ab levels remained low throughout the study. After 9 months, the level of HI-cross-Ab increased [mean (SD) HI, 48.8% (21.53), IAsp, 40.2% (17.92)] and remained elevated. Repeated measurement analysis of HI-cross-Ab levels showed no significant difference between treatments (P = 0.16). HI-cross-Ab were significantly associated with total insulin dose (U/kg) (P = 0.001) and time (P < 0.0001), but not with HbA(1c) (P = 0.24). Mean (+/- SD) HbA(1c) was similar at diagnosis (HI 9.5 +/- 1.97%, IAsp 9.6 +/- 1.62%), HbA(1c) then decreased and stabilized to about 6.0% in both groups. Few SAEs were reported, the majority being hypoglycaemic episodes. CONCLUSIONS: Treatment with IAsp and with HI was associated with an increase in HI-cross-Ab in insulin-naive children, but this did not influence treatment efficacy or safety. These results support the safe use of IAsp in children and adolescents with Type 1 diabetes.

  • 47.
    Tiittanen, Minna
    et al.
    Avd för Molekylär Medicin Helsingfors, Finland.
    Knip, Mikael
    Barn och Ungdomssjukhuset Helsingfors, Finland.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Anti-insulin activity in IgG-fractions from children with newly-diagnosed type 1 diabetes and negative for insulin autoantibodies2004In: Autoimmunity, ISSN 0891-6934, Vol. 37, no 1, 45-49 p.Article in journal (Refereed)
    Abstract [en]

    Insulin autoantibodies (IAA) are often detected as the first humoral sign of β-cell autoimmunity in prospective studies in young children with increased genetic risk of type 1 diabetes. After the appearance of IAA their level typically rise but seems to decline in many cases before the clinical presentation of type 1 diabetes. We hypothesized that the reason for the sudden drops in the levels of IAA could be the formation of immune complexes caused by binding of antibodies to free insulin in plasma. We studied whether isolation of the IgG-fraction and dissociation of immune complexes by acid treatment using protein A column results in the appearance of detectable IAA in those children with newly-diagnosed type 1 diabetes whose plasma samples test negative for IAA. IAA assay was performed in IgG-fractions and corresponding plasma samples from 17 children with type 1 diabetes and 23 unaffected children all testing negative for plasma IAA. The levels of IAA measured from IgG-fractions of diabetic children were higher than the levels of IAA measured from IgG-fractions in the control children (p = 0.004 in Mann-Whitney U-test). Forty-seven percent (8 out of 17) of newly-diagnosed patients negative for plasma IAA before IgG separation had increased levels of IAA in IgG-fractions and only 13% (3 out of 23) of controls. The levels of glutamate decarboxylase autoantibodies (GADA) did not differ between patients (n = 14) and controls (n = 21) negative for plasma GADA when measured in IgG-fractions. Our results suggest that formation of immune complexes results in false negative results in tests for IAA but not for GADA.

  • 48.
    Stenninger, Erik
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Aspects of hypoglycaemia in newborns of diabetic mothers and in children with Type 1 diabetes1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The occurrence and possible causal factors of macrosomia and postnatal hypoglycaemia were investigated in infants of diabetic mothers. Acute neurophysiological effects, the long-term nemodevelopmental outcome, and the use of glucagon in prevention and treatment of hypoglycaemia, were also studied in children with insulin-dependent diabetes mellitus (IDDM) and infants of diabetic mothers.

    Infants born 1986-1993 of diabetic mothers, and children 7-12 years of age with !DD M, were investigated at Orebro Medical Centre Hospital. Macrosomia (birth weight>+ 2SD, adjusted for gender and gestational age) occurred in 27% of infants of mothers with gestational diabetes mellitus (GDM) and in 30% of those of mothers with !DD M. Postnatal hypoglycaemia (B-glucose < 1.5 rnmol/l) was observed in 38% of the infants. A highly positive con-elation was found between cord plasma insulin growth factor-! (IGF-l) and relative birth weight ratios in infants of diabetic mothers (r ~ 0.64, p < 0.0007), suggesting a role for IGF-I in the development of macrosomia in diabetic pregnancy. Early postnatal hypoglycaemia was related to cord serum C-peptide levels, supporting the theory of foetal hyperinsulinaemia as the most important pathogenetic factor. Maternal glucose concentration at labour was also related to cord C-peptide concentration, indicating that maternal glucose regulation close to delivery is important for postnatal glucose regulation in the infants. At follow-up at the age of 8 years, children with neonatal hypoglycaemia of diabetic mothers had a lower total developmental score than control children. More difficulties at an :MBD screening test and more behavioural problems were also noted in this group. At quantitative EEG analysis, children with neonatal hypoglycaemia of diabetic mothers more often showed a pattern similar to that in children with attention deficit hyperactivity disorders/attention deficit disorders compared with those who were "normoglycaemic" in the neonatal period.

    To treat neonatal hypoglycaemia, an injection of subcutaneous glucagon, 20 Jlg/kg, was given 3 hours postnatally in addition to early oral feeding. This caused a significant rise in blood glucose concentration lasting for up to 60 min (p < 0.01), compared to oral feeding alone, without major side-effects. However, the duration of the hyperglycaemic effect was too brief to eliminate the need for additional intravenous glucose infusion.

    IDDM children, with a short duration of disease and good metabolic control, showed no progressive neurophysiological effects, as measured by brainstem auditory evoked potentials (BAEP), during short-term induced hypoglycaemia (1.7 mmolll). This suggests that children with IDDM better adapt to low blood glucose levels than adult diabetic patients. Nor did the IDDM children show permanent BAEP changes during normoglycaemia, compared with a control group of healthy children of the same age.

    In treatment of hypoglycaemia in IDDM children intranasal administration of glucagon (1 mg) and subcutaneous glucagon injection (0.5 mg) had similar hyperglycaemic effects as observed for up to 30 minutes. Fewer side-effects, including nausea and vomiting, and only minor nasal irritation were reported after intranasal glucagon administration.

  • 49.
    Åkerman, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Aspects of the Pre-Diabetic Period in Type 1 Diabetes2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Type 1 diabetes (T1D) is an autoimmune disease characterized by insulin deficiency, due to immune-mediated destruction of beta cells. Current knowledge regarding the period preceding disease onset comes, to a large extent, from studying risk cohorts based on relatives of T1D-patients, as they have an increased disease risk. Among T1D patients in general, however, few have the disease in their immediate family. It is therefore important to study risk cohorts from the general population as well. An ongoing autoimmune reaction can often be seen in the blood long before disease onset, by detection of autoantibodies directed towards beta cell antigens. By autoantibody screening among participants in the ABIS (All Babies in the South-east of Sweden) cohort, we could identify a group of children from the general population with increased risk for T1D, positive for multiple autoantibodies. They were enrolled in a 2-year prospective follow-up aiming to characterize the prediabetic period and to identify factors indicative of progression/non-progression to T1D. We assessed glucose homeostasis and autoantibody titers over time, and searched for risk-biomarkers by analyzing the expression of immune-related genes (Th1-Th2-Th3) in peripheral blood mononuclear cells (PBMC) from these children, in comparison to healthy children and newly diagnosed T1D patients. In the same groups we also compared serum micro RNA (miRNA) profiles, knowing that miRNA molecules have desirable biomarker properties. We found that two specific autoantibodies, IA2A and ZnT8A, were detected at higher concentrations in risk-individuals who progressed to overt T1D during or after the follow-up period, compared to those who still have not. We also observed disturbed glucose homeostasis long before onset in the progressors, but it was seen among those who remain symptom free as well. Further, we found support for the possible role of insulin resistance as an accelerator of the disease process. For gene expression and serum miRNA, few differences were observed between risk-individuals and healthy children overall. However, for PBMC gene expression and serum miRNA both, there were associations to beta cell function and glucose homeostasis, and for miRNA also to islet autoantibodies. Although specific profiles for prediction of disease onset or identification of risk-individuals could not be found, these results are interesting and deserve to be evaluated further. As part of another sub-study within ABIS, the effects of physical activity on glucose homeostasis were assessed in healthy schoolchildren. The level of physical activity, measured by pedometers, was related to insulin resistance and beta cell-stress, and decreased physical activity was associated with increased insulin resistance and load on the insulin-producing beta cells, already at school-age.

    List of papers
    1. Low C-peptide levels and decreased expression of TNF and CD45 in children with high risk of type 1 diabetes
    Open this publication in new window or tab >>Low C-peptide levels and decreased expression of TNF and CD45 in children with high risk of type 1 diabetes
    2013 (English)In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 148, no 1Article in journal (Refereed) Published
    Abstract [en]

    Type 1 diabetes (T1D) patients have numeral and functional defects in peripheral immune cells, but the pre-diabetic period is fairly uncharacterized. Our aim was to analyze expression of immunological markers in T1D high risk children and relate it to clinical/immunological parameters. Children from ABIS (All Babies in Southeast Sweden) with greater than= 2 diabetes related autoantibodies were considered at high risk. Age-matched controls and new-onset T1D patients were included. Expression of genes related to immune cell function and different arms of the immune system was assessed in peripheral blood mononuclear cells using PCR array. Risk children had lower TNF and CD45, and although there were few differences between the groups, expression of many genes differed when comparing children with regard to residual insulin secretion. Hence, expression of immune related genes seemed related not only to the autoimmune process but rather to residual beta-cell function, which was decreased already during the pre-diabetic phase.

    Place, publisher, year, edition, pages
    Elsevier, 2013
    Keyword
    Type 1 diabetes; Gene expression; PBMC; T1D high risk; T1D autoantibodies; PCR array
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-96458 (URN)10.1016/j.clim.2013.03.011 (DOI)000320427300002 ()
    Available from: 2013-08-23 Created: 2013-08-20 Last updated: 2016-10-19
    2. Physical Activity, Blood Glucose and C-Peptide in Healthy School-Children, a Longitudinal Study
    Open this publication in new window or tab >>Physical Activity, Blood Glucose and C-Peptide in Healthy School-Children, a Longitudinal Study
    2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 6, e0156401- p.Article in journal (Refereed) Published
    Abstract [en]

    Aim To further elucidate the relationship between physical activity and several risk factors for development of diabetes (glucose, C-peptide and obesity) over time. Methods A prospective longitudinal study where physical activity was measured on 199 children from Kalmar and Linkoping at age 8, and the same 107 children from Linkoping again at age 12. Anthropometric data was collected and blood was analyzed for C-peptide and f-glucose. The children in the study were representative for the general Swedish child population, and on an average lean. Results High physical activity was related to lower C-peptide at age 8 and 12. This correlation was especially pronounced in boys, who also were more physically active than girls at both time points. The association seen at 8 years of age was similar at age 12 in most children. Children with higher BMI Z-Score had a higher fasting C-peptide (age 12) but linear regression showed that children with more steps per day were less likely to have a higher fasting C-peptide irrespective of BMI. Longitudinal follow-up showed that a decrease in physical activity increased insulin resistance and beta-cell load. Conclusions Already in young children, physical activity improves insulin sensitivity and decreases the need of C-peptide over time. This seems to become even more pronounced with increasing age when children are followed longitudinally. Low physical activity increases the load on insulin producing beta-cells, might increase the risk for both type 1- and 2 diabetes.

    Place, publisher, year, edition, pages
    PUBLIC LIBRARY SCIENCE, 2016
    National Category
    Pediatrics
    Identifiers
    urn:nbn:se:liu:diva-130132 (URN)10.1371/journal.pone.0156401 (DOI)000377561000012 ()27270732 (PubMedID)
    Note

    Funding Agencies|Swedish Child Diabetes Foundation (Barndiabetesfonden); Novo Nordisk Foundation; Research Council of South-east Sweden (FORSS); Swedish Research Council [K2005-72X-11242-11A]; ALF/County Council of Ostergotland

    Available from: 2016-07-12 Created: 2016-07-11 Last updated: 2016-10-19
  • 50.
    Bjarnegård, Niclas
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Aspects on wall properties of the brachial artery in man: with special reference to SLE and insulin-dependent diabetes mellitus2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The mechanical properties of the arterial wall are of great importance for blood pressure regulation and cardiac load. With increasing age, large arteries are affected by increased wall stiffness. Furthermore, atherosclerotic manifestations may increase the stiffness even further, both processes acting as independent cardiovascular risk factors affecting the arterial system in a heterogeneous way.

    The aims of this thesis was to characterize the local mechanical properties of brachial artery (BA) with the aid of ultrasound technique and to evaluate the influence of 1) age, gender, sympathetic stimulation and examination site; 2) type 1 diabetes (DM) and its association to circulatory biomarkers; and 3) to evaluate the general properties of the arterial system with the aid of pulse wave velocity (PWV) as well as pulse wave analysis (PWA) in systemic lupus erythematosus (SLE) and correlate the findings to disease activity and circulatory biomarkers.

    In the most proximal arterial segment of the upper arm a pronounced age-related decrease in wall distensibility, increase in intima-media thickness (IMT), and a slight increase in diameter were seen. Sympathetic stimulation had no influence on wall mechanics. More distally in BA, no change in diameter, and only minor increase in IMT and decrease in distensibility were seen. No gender differences were found. These findings suggest that the principle transit zone between elastic and muscular artery behaviour is located in the proximal part of the upper arm.

    Women with uncomplicated insulin-dependent DM had similar diameter, IMT and distensibility in their distal BA as controls, whereas flow-mediated dilatation (FMD) was slightly, and nitrate mediated dilatation (NMD) markedly reduced. NMD was negatively correlated with higher HbA1c levels. Vascular smooth muscle cell function seems to be an early manifestation of vascular disease in women with DM, influenced by long-term hyperglycaemia.

    Women with SLE had increased aortic PWV compared to controls, a finding positively associated with increased levels of complement factor 3 (C3), but not with disease activity. The increased stiffness of central arteries may be one factor contributing to the increased cardiovascular risk seen in SLE.

    List of papers
    1. Age affects proximal brachial artery stiffness: differential behaviour within the length of the brachial artery?
    Open this publication in new window or tab >>Age affects proximal brachial artery stiffness: differential behaviour within the length of the brachial artery?
    Show others...
    2003 (English)In: Ultrasound in Medicine and Biology, ISSN 0301-5629, Vol. 29, no 8, 1115-1121 p.Article in journal (Refereed) Published
    Abstract [en]

    With increasing age, the diameter of central elastic arteries increases, whereas their distensibility decreases. The purpose of this study was to investigate the mechanical properties of the proximal brachial artery in relation to age and gender. Distensibility coefficient (DC), stiffness and compliance coefficient (CC) were calculated in 136 healthy males and females (range 9-82 y) using echo-tracking sonography. CC decreased with age in both genders, but CC was higher in males. Stiffness increased and DC decreased with age in an exponential manner, without any differences between genders. In conclusion, as in central elastic arteries, the distensibility of the proximal brachial artery decreases with age, in contrast to earlier reports on the muscular distal brachial artery. This may imply that the transition between elastic and muscular artery behavior is within the length of the brachial artery. In future studies using the brachial artery, the examination site needs to be defined.

    Keyword
    Brachial artery, Ageing, Gender, Echo-tracking, Distensibility, Stiffness
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13028 (URN)10.1016/S0301-5629(03)00052-8 (DOI)
    Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2017-03-27
    2. The effect of sympathetic stimulation on proximal brachial artery mechanics in humans: differential behaviour within the length of the brachial artery
    Open this publication in new window or tab >>The effect of sympathetic stimulation on proximal brachial artery mechanics in humans: differential behaviour within the length of the brachial artery
    2004 (English)In: Acta physiologica Scandinavica, Vol. 182, no 1, 21-27 p.Article in journal (Refereed) Published
    Abstract [en]

    Aims: The mechanical properties of arteries play a major role in the regulation of blood pressure and cardiac performance. The effect of sympathetic stimulation on the mechanical properties of the proximal brachial artery was analysed in 18 healthy volunteers, nine young (25 ± 2 years) and nine elderly (69 ± 2 years).

    Methods: A non-invasive ultrasonic echo-tracking system for measurement of systolic/diastolic variation of the proximal brachial artery diameter in combination with intra-arterial pressure measurements was used to determine wall mechanics. The pressure–diameter (P–D) relationship, distensibility coefficient (DC), compliance coefficient (CC) and stiffness(β) were obtained at rest and during sympathetic stimulation induced by lower body negative pressure (LBNP).

    Results: The peripheral vascular resistance increased by 100 and 72%, respectively in the young and elderly during LBNP (P < 0.001). Simultaneously, the mechanical properties of the proximal brachial artery remained unaltered, as estimated from both P–D relationship and stiffness in young (β-index rest: 5.2 ± 0.9, LBNP: 5.5 ± 1.3, NS) as well as elderly (β-index rest: 13.6 ± 4.6, LBNP: 16.1 ± 4.7, NS).

    Conclusions: LBNP-induced sympathetic activation does not change proximal brachial artery mechanics, in contrast to earlier reports on the muscular distal brachial artery. This may imply that the transition between elastic and muscular artery behaviour is within the length of the brachial artery, where the site of transition from elastic to muscular wall structure needs to be specified in future studies.

    Keyword
    ageing, brachial artery, distensibility, lower body negative pressure, stiffness, sympathetic stimulation
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13029 (URN)10.1111/j.1365-201X.2004.01336.x (DOI)
    Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2017-03-27
    3. Increased aortic pulse wave velocity in middle-aged women with systemic lupus erythematosus
    Open this publication in new window or tab >>Increased aortic pulse wave velocity in middle-aged women with systemic lupus erythematosus
    Show others...
    2006 (English)In: Lupus, ISSN 0961-2033, Vol. 15, no 10, 644-650 p.Article in journal (Refereed) Published
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a connective tissue disease where inflammatory activity affects several organ systems. An increased risk of cardiovascular disease has been identified in these patients, even after correction for traditional risk factors. The aim of the present study was to evaluate arterial stiffness and central hemodynamics in women with SLE in comparison to controls.

    Arterial tonometry was used to measure aortic (carotid-femoral) and arm (carotid-radial) pulse wave velocity (PWV), reflected pressure waves, and aortic augmentation index (AIx) in 27 women with SLE (52 to 68 years) and 27 controls. Aortic PWV was higher in women with SLE than controls, 9.8 m/s versus 8.2 m/s (P 0.01), after correction for mean arterial pressure and body mass index, 9.5 m/s versus 8.5 m/s (P 0.05). Other parameters were similar, arm PWV, 8.4 versus 8.5 m/s, AIx 34 versus 33% and calculated central aortic pulse pressure 48 versus 43 mmHg, in SLE and controls, respectively (NS). Aortic PWV was positively associated to C-reactive protein (CRP) and complement factor 3 (C3).

    Women with SLE have increased stiffness of their elastic central arteries. This may be one factor contributing to the increased cardiovascular risk seen in this cohort.

    Keyword
    arteries, blood pressure, elasticity, pulse, SLE, women
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13030 (URN)10.1177/0961203306071402 (DOI)
    Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2017-03-27
    4. Impaired endothelial independent vasodilatation in women with type 1 diabetes
    Open this publication in new window or tab >>Impaired endothelial independent vasodilatation in women with type 1 diabetes
    Show others...
    2008 (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13031 (URN)
    Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2017-03-27Bibliographically approved
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