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  • 1.
    Schenström, Karl
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics.
    Biofunctionalization of a Fiber Optics-Based LSPR Sensor2016Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    When exposed to light, metal nanoparticles exhibit a phenomenon known as LSPR, Localized Surface Plasmon Resonance. The wavelengths at which LSPR occurs is very dependent on the refractive index of the surrounding medium. Binding of biomolecules to the surface of gold nanoparticles result in a change in the refractive index that can be detected spectrophotometrically by monitoring the LSPR peak shift. When functionalized with the corresponding ligand(s), gold nanoparticles can be utilized in biosensors to detect the presence and concentration of a predetermined analyte. However, the system must exhibit high specificity and give rise to a detectable shift for analytes in the desired concentration range to be of commercial interest. The aim of the diploma project was to investigate and optimize the biofunctionalization and performance of a fiber optics based LSPR biosensor.  Three ligand systems were investigated for detection of antibodies (IgG), insulin and avidin. Binding of the analyte to the ligand caused a shift of a few nanometers when using spherical gold nanoparticles. The shifts were significantly larger when using gold nanorods. When using the IgG and insulin ligands, only minor unspecific binding was observed. The setup thus shows great potential for use in a wide range of sensing applications.

  • 2.
    Franciscus, Margaret
    et al.
    Department of Pediatric Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
    Nucci, Anita
    Department of Nutrition, Georgia State University, Atlanta, GA, USA.
    Bradley, Brenda
    Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
    Suomalainen, Heli
    Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.
    Greenberg, Ellen
    Naomi Berrie Diabetes Center, Columbia University, New York, USA.
    Laforte, Diane
    Montreal Children’s Hospital, Montreal, QC, Canada.
    Kleemola, Paivi
    Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.
    Hyytinen, Mila
    Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.
    Salonen, Marja
    Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.
    Martin, Mary Jean
    Department of Endocrinology, Hospital for Sick Children, Toronto, ONT, Canada.
    Catte, Daniel
    University of Manitoba, Winnipeg, MB, Canada.
    Catteau, Jacki
    Department of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Sydney, NSW, Australia.
    Recruitment and retention of participants for an international type 1 diabetes prevention trial: a coordinators' perspective.2014In: Clinical Trials, ISSN 1740-7745, E-ISSN 1740-7753, Vol. 11, no 2, 150-8 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The Trial to Reduce Insulin Dependent Diabetes Mellitus in the Genetically at Risk (TRIGR) is the first multicenter international type 1 diabetes (T1D) prevention trial to be undertaken. A unique feature of TRIGR has been recruitment of eligible pregnant women and enrollment of newborns for long-term follow-up assessments.

    PURPOSE: Our purpose is to summarize the recruitment and retention strategies used to conduct TRIGR from the perspective of the study coordinators.

    METHODS: TRIGR was designed to test whether weaning to formula containing hydrolyzed versus intact cow's milk protein would be efficacious in decreasing risk for development of T1D-associated autoantibodies and T1D among infants identified to be at increased risk for T1D based on their human leukocyte antigen (HLA) profile and family history. Multiple strategies tailored to local issues were required to enroll and follow the target number of infants.

    RESULTS: This study was conducted in the United States, Canada, Australia, and 12 countries in Europe. Of the 5606 mothers registered worldwide, 5000 of their infants were randomized. Of these, 2159 were HLA eligible and enrolled in the 8-month intervention and 10-year follow-up phases of this study. The TRIGR study met the accrual goal after 4.7 years of recruitment, 2.7 years longer than projected initially. Challenges included difficulty in finding fathers with T1D, a higher than expected rate of premature delivery among T1D mothers, and implementation of new privacy regulations mid-trial. The majority of participants were recruited from primary care antenatal clinics located near the study centers and from a general hospital or pediatric center that was affiliated with a TRIGR Study center. Internet and magazine advertisements were found to be useful for recruitment of families. Alternative follow-up strategies are offered to families who wish to reduce or discontinue participation.

    LIMITATIONS: Our experience is limited to a single international multicenter trial.

    CONCLUSIONS: TRIGR coordinators played key roles in the recruitment and intervention periods and continue to be instrumental in retaining families and children during the 10-year follow-up period for each child.

  • 3.
    Knip, Mikael
    et al.
    University of Helsinki, Helsinki, Finland.
    Åkerblom, Hans K
    University of Helsinki, Helsinki, Finland.
    Becker, Dorothy
    University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
    Dosch, Hans-Michael
    University of Toronto, Toronto, Ontario, Canada.
    Dupre, John
    University of Western Ontario, London, Canada.
    Fraser, William
    University of Montréal, Montréal, Québec, Canada.
    Howard, Neville
    Children’s Hospital of Westmead, Sydney, Australia.
    Ilonen, Jorma
    University of Turku, Turku, Finland.
    Krischer, Jeffrey P
    University of South Florida, Tampa, USA.
    Kordonouri, Olga
    Kinder- und Jugendkrankenhaus AUF DER BULT, Hannover, Germany.
    Lawson, Margaret L
    Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada .
    Palmer, Jerry P
    University of Washington, Seattle, USA.
    Savilahti, Erkki
    University of Helsinki, Helsinki, Finland.
    Vaarala, Outi
    National Institute for Health and Welfare, Helsinki, Finland.
    Virtanen, Suvi M
    National Institute for Health and Welfare, Helsinki, Finland.
    Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial.2014In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 311, no 22, 2279-2287 p.Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: The disease process leading to clinical type 1 diabetes often starts during the first years of life. Early exposure to complex dietary proteins may increase the risk of β-cell autoimmunity in children at genetic risk for type 1 diabetes. Extensively hydrolyzed formulas do not contain intact proteins.

    OBJECTIVE: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of diabetes-associated autoantibodies in young children.

    DESIGN, SETTING, AND PARTICIPANTS: A double-blind randomized clinical trial of 2159 infants with HLA-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1078 were randomized to be weaned to the extensively hydrolyzed casein formula and 1081 were randomized to be weaned to a conventional cows' milk-based formula. The participants were observed to April 16, 2013.

    INTERVENTIONS: The participants received either a casein hydrolysate or a conventional cows' milk formula supplemented with 20% of the casein hydrolysate.

    MAIN OUTCOMES: AND MEASURES: Primary outcome was positivity for at least 2 diabetes-associated autoantibodies out of 4 analyzed. Autoantibodies to insulin, glutamic acid decarboxylase, and the insulinoma-associated-2 (IA-2) molecule were analyzed using radiobinding assays and islet cell antibodies with immunofluorescence during a median observation period of 7.0 years (mean, 6.3 years).

    RESULTS: The absolute risk of positivity for 2 or more islet autoantibodies was 13.4% among those randomized to the casein hydrolysate formula (n = 139) vs 11.4% among those randomized to the conventional formula (n = 117). The unadjusted hazard ratio for positivity for 2 or more autoantibodies among those randomized to be weaned to the casein hydrolysate was 1.21 (95% CI, 0.94-1.54), compared with those randomized to the conventional formula, while the hazard ratio adjusted for HLA risk, duration of breastfeeding, vitamin D use, study formula duration and consumption, and region was 1.23 (95% CI, 0.96-1.58). There were no clinically significant differences in the rate of reported adverse events between the 2 groups.

    CONCLUSIONS AND RELEVANCE: Among infants at risk for type 1 diabetes, the use of a hydrolyzed formula, when compared with a conventional formula, did not reduce the incidence of diabetes-associated autoantibodies after 7 years. These findings do not support a benefit from hydrolyzed formula. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00179777.

  • 4.
    Home, P.D.
    et al.
    Newcastle Diabetes Centre, Newcastle University, Newcastle upon Tyne, United Kingdom.
    Pocock, S.J.
    Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London, United Kingdom.
    Beck-Nielsen, H.
    Department of Endocrinology and Metabolism, Odense, Denmark.
    Curtis, P.S.
    GlaxoSmithKline Research and Development, Greenford, United Kingdom.
    Gomis, R.
    Hospital Clinic, University of Barcelona, Barcelona, Spain.
    Hanefeld, M.
    Zentrum für Klinische Studien Forschungsbereich Endokrinologie und Stoffwechsel, Dresden, Germany.
    Jones, N.P.
    GlaxoSmithKline Research and Development, Harlow, United Kingdom.
    Komajda, M.
    Université Pierre et Marie Curie Paris 6, Hôpital Pitié-Salpêtrière, Département de Cardiologie, Paris, France.
    McMurray, J.J.
    British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
    Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial2009In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 373, no 9681, 2125-2135 p.Article in journal (Refereed)
    Abstract [en]

    Background: Rosiglitazone is an insulin sensitiser used in combination with metformin, a sulfonylurea, or both, for lowering blood glucose in people with type 2 diabetes. We assessed cardiovascular outcomes after addition of rosiglitazone to either metformin or sulfonylurea compared with the combination of the two over 5-7 years of follow-up. We also assessed comparative safety. Methods: In a multicentre, open-label trial, 4447 patients with type 2 diabetes on metformin or sulfonylurea monotherapy with mean haemoglobin A 1c (HbA 1c) of 7·9% were randomly assigned to addition of rosiglitazone (n=2220) or to a combination of metformin and sulfonylurea (active control group, n=2227). The primary endpoint was cardiovascular hospitalisation or cardiovascular death, with a hazard ratio (HR) non-inferiority margin of 1·20. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00379769. Findings: 321 people in the rosiglitazone group and 323 in the active control group experienced the primary outcome during a mean 5·5-year follow-up, meeting the criterion of non-inferiority (HR 0·99, 95% CI 0·85-1·16). HR was 0·84 (0·59-1·18) for cardiovascular death, 1·14 (0·80-1·63) for myocardial infarction, and 0·72 (0·49-1·06) for stroke. Heart failure causing admission to hospital or death occurred in 61 people in the rosiglitazone group and 29 in the active control group (HR 2·10, 1·35-3·27, risk difference per 1000 person-years 2·6, 1·1-4·1). Upper and distal lower limb fracture rates were increased mainly in women randomly assigned to rosiglitazone. Mean HbA 1c was lower in the rosiglitazone group than in the control group at 5 years. Interpretation: Addition of rosiglitazone to glucose-lowering therapy in people with type 2 diabetes is confirmed to increase the risk of heart failure and of some fractures, mainly in women. Although the data are inconclusive about any possible effect on myocardial infarction, rosiglitazone does not increase the risk of overall cardiovascular morbidity or mortality compared with standard glucose-lowering drugs. Funding: GlaxoSmithKline plc, UK. © 2009 Elsevier Ltd. All rights reserved.

  • 5.
    Ovrén, Caroline
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Knockdown of the ERK pathway using siRNA in cultured chicken cardiomyocytes2014Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The ancient South American birds called tinamous (Tinamidae) have the smallest hearts known among birds and their cardiomyocytes have previously been shown to express significantly lower levels of the mitogen-activated protein kinase ERK compared to the more modern chicken (Gallus gallus). ERK is a well-known mediator of growth signalling in the heart, especially in hypertrophy. The aim of this project was to assess the effect of ERK knockdown on proliferation in cultured chicken cardiomyocytes. By transfecting these cells with a lipoplexed siRNA, ERK mRNA levels were knocked down to approximately half (45%, SD: 27%) compared to cells transfected with a negative control siRNA. The knockdown was coupled with a decreased proliferative response to insulin-like growth factor 1 (IGF-1) and foetal bovine serum (FBS). In conclusion, the ERK pathway was confirmed to be instrumental also in proliferative signalling. The results also support the notion that ERK itself is the rate-limiting step of this MAPK cascade. The low native expression of ERK in tinamou cardiomyocytes is expected to impose a strict limit on proliferative growth in response to various stimuli in these hearts. The genetic changes leading to higher expression levels, and with it the potential for larger hearts, in modern birds would have led to greatly increased evolutionary fitness by way of an increased aerobic scope and the ability to sustain flight. 

  • 6.
    Dahlfors, Gunilla
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    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 glucoseManuscript (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.

  • 7.
    Hammerman, Malin
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, The Institute of Technology.
    Oxidative Stress and Protein Acetylation in Adipocytes2011Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Obesity is an increasing health problem which is causally associated with insulin resistance and type 2 diabetes. Oxidative stress, i.e. overproduction of reactive oxygen species, is associated with insulin resistance and obesity and may be a major risk factor in the onset and progression of diabetes. Bernlohr Lab at University of Minnesota have study oxidative stress in adipocytes by silencing the enzyme glutathione S-transferase A-4 (GSTA4), an enzyme detoxifying 4-hydroxynonenal formed during oxidative stress. Their results indicate that lysine acetylation, an important post-translational modification, may be involved during oxidative stress. In this study lysine acetylation has been investigated in condition of oxidative stress in 3T3-L1 adipocytes and subcutaneous adipose tissue from mice using SDS-PAGE gel electrophoresis and western blot. Lysine acetylation was analyzed in different compartments of the cell such as in cytoplasm, mitochondria as well as in whole cell extracts. Silencing of GSTA4 and stimulation by TNF-α in 3T3-L1 adipocytes resulted in an increase of lysine acetylation in cytoplasm. Furthermore, stimulation by IL-6 did not have any effect on lysine acetylation. Surprisingly, subcutaneous adipose tissue from mice fed on a high-fat diet showed a decrease of lysine acetylation in cytoplasm compare to mice fed on a chow diet. In conclusion, lysine acetylation seems to change during oxidative stress and may be an important factor during insulin resistance, type 2 diabetes and obesity. Therefore, studying lysine acetylation and enzymes modulating acetylation may potentially increase our understanding of insulin resistance, type 2 diabetes and obesity and could lead to new therapies.

  • 8.
    Krishnan, Kalaiselvan
    Linköping University, Department of Physics, Chemistry and Biology.
    Role of TRPV1 channel and P2Y1 receptor in Ca2+ signalling in β-cells: A study by single cell microfluorometry2011Independent thesis Advanced level (degree of Master (Two Years)), 60 credits / 90 HE creditsStudent thesis
    Abstract [en]

    Increase in the cytoplasmic Ca2+ concentration ([Ca2+]i) in the β-cells triggers insulin exocytosis. Among the Ca2+ channels present in the plasma membrane, the transient receptor potential (TRP) channels receptors are currently of great interest. The mechanisms by which the extracellular adenosine diphosphate ribose (ADPr) increases the [Ca2+]i is unknown. Our aims were to study the roles of the TRP channels in the tolbutamide induced [Ca2+]i increase and to identify the surface receptor that is activated by ADPr.

    We used S5 cells, a highly differentiated rat insulinoma cell line, as a model for β-cells. Single cell ratiometric microfluorometry was used to measure the [Ca2+]i changes in the Fura-2 loaded cells.

    Tolbutamide increased [Ca2+]i in the form of oscillations. After tolbutamide increased [Ca2+]i,capsazepine, a potent blocker of the transient receptor potential vanilloid subtype 1 (TRPV1) channel was added to the β-cells, which reduced the tolbutamide-induced [Ca2+]i increase. capsazepine, N-(p-Amylcinnamoyl) anthranilic acid (ACA),  TRPM2 channel blocker, and triphenyl phosphine oxide (TPPO), TRPM5 channel blocker were tested for their effect on potassium chloride (KCl) induced [Ca2+]i response. These blockers did not inhibit the KCl induced [Ca2+]i increase.  

    Adenosine diphosphate ribose (ADPr) increased [Ca2+]i in the form of initial transient peak followed by an elevated plateau. Application of ADPr shortly after a prior application and washout of Adenosine diphosphate (ADP) elicited only small [Ca2+]i increase  indicating desensitization of the receptor involved. 2´deoxy-N6-methyladenosine 3´5´bis-phosphate (MRS2179), and chloro N6-methyl-(N)-methanocarba 2´deoxyadenosine 3´5´ bis-phosphate (MRS2279), two selective inhibitors of P2Y1 receptor, abolished the ADPr-induced [Ca2+]i increase.

    Tolbutamide closes ATP sensitive potassium (KATP) channels. Our results demonstrate that besides the closure of the KATP channels, inward cation currents carried by Ca2+through the TRPV1 channel are necessary for depolarization to the threshold for the activation of the voltage gated calcium channels (VGCC) to increase the [Ca2+]i. Our results also show that ADPr increases [Ca2+]i by activating the P2Y1 receptor.

  • 9.
    Nicklagård, Erik
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Diabetes typ 3?: Molekylärfysiologiska länkar och samband från den samlade litteraturen2011Independent thesis Basic level (degree of Bachelor), 10,5 credits / 16 HE creditsStudent thesis
    Abstract [sv]

    Alzheimers sjukdom (AD) är den vanligaste formen av demens och kännetecknas av intracellulärt neurofibrillärt trassel (NFT) bestående av proteinet tau och extracellulära plack, uppbyggda av peptiden amyloid beta (Aβ). En växande skara studier har börjat peka mot att AD är en hjärnspecifik typ av diabetes. Insulinresistens följt av hyperinsulinemi och hyperglykemi är kännetecken för diabetes mellitus typ 2 (DMT2) och har visat sig vara en riskfaktor för AD. Insulin, ett hormon som kontrollerar glukoshomeostasen i perifera nervsystemet (PNS) och är viktigt för minne och inlärning, transporteras över blod-hjärnbarriären i en mättnadsbar transportmekanism och dess koncentration i centrala nervsystemet (CNS) minskar vid DMT2 och AD. Insulin-like growth factor 1 (IGF-1), ett neuronskyddande protein som minskar ogynnsam β-sekretasklyvning av amyloid precursor protein (APP) i amyloidkaskadhypotesen, minskar i koncentration i hjärnan när mycket insulin transporteras in i CNS. γ-sekretas ökar sin aktivitet på APP vid höga halter kolesterol som är vanligt vid DMT2, Aβ fungerar då som en negativ inhibitor till HMG-Coa reduktas (HMGR), enzymet som bildar kolesterol och kan därmed reglera kolesterolhalterna. Regleringssystem för Aβ i blod-hjärnbarriären (BBB) som p-GP, LRP-1 och RAGE rubbas vid DMT2. Aβ och insulin delar samma degraderingssystem, insulin degrading enzyme (IDE), som reglerar halterna Aβ och insulin. Dessutom har Aβ oligomerer visat sig kunna bryta ned insulinreceptorer (IR). Vidare har läkemedel mot diabetes visat sig lindra demens hos AD patienter. I den här rapporten gås de molekylärfysiologiska sambanden igenom i detalj. Slutligen finns det fog för ett samband mellan metabolt syndrom, en riskfaktor för DMT2, och AD.

  • 10.
    Hansson, Eva-Maria
    Linköping University, Department of Clinical and Experimental Medicine.
    Towards a mechanistic explanation of insulin resistance, which incorporates mTOR, autophagy, and mitochondrial dysfunction2010Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Type 2 diabetes is a global disease which affects an increasing number of peopleevery year. At the heart of the disease lies insulin resistance in the target tissues,primarily fat and muscle. The insulin resistance is caused by the failure of a complexsignalling network, and several mechanistic hypotheses for this failure havebeen proposed. Herein, we evaluate a hypothesis that revolves around the proteinmammalian target of rapamycin (mTOR) and its feedback signals to insulin receptorsubstrate-1 (IRS1). In particular, we have re-examined this hypothesis andrelevant biological data using a mathematical modelling approach.

    During the course of modelling we gained several important insights. For instance,the model was unable to reproduce the relation between the EC50-valuesin the dose-response curves for IRS1 and its serine residue 312 (Ser-312). Thisimplies that the presented hypothesis, where the phosphorylation of Ser-312 liesdownstream of the tyrosine phosphorylation of IRS1, is inconsistent with the provideddata, and that the hypothesis or the data might be incorrect. Similarly, wealso realized that in order to fully account for the information in the dose-responsedata, time curves needed to be incorporated into the model.

    A preliminary model is presented, which explains most of the data-sets, butstill is unable to describe all the details in the data. The originally proposed hypothesisas an explanation to the given data has been revised, and our analysisserves to exemplify that an evaluation of a mechanistic hypothesis by mere biochemicalreasoning often misses out on important details, and/or leads to incorrectconclusions. A model-based approach, on the other hand, can efficiently pin-pointsuch weaknesses, and if combined with a comprehensive understanding of biologicalvariation and generation of experimental data, mathematical modelling canprove to be a method of great potential in the search for mechanistic explanationsto the cause of insulin resistance in type 2 diabetics.

  • 11.
    Sohlstrom, A
    et al.
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    Carlsson, C
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    Uvnas-Moberg, K
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    Effects of oxytocin treatment in early life on body weight and corticosterone in adult offspring from ad libitum-fed and food-restricted rats2000In: Biology of the Neonate, ISSN 0006-3126, Vol. 78, no 1, 33-40 p.Article in journal (Refereed)
    Abstract [en]

    The aims of this study were: (1) to assess the effects of maternal undernutrition during pregnancy on adult offspring with regard to growth, body composition and plasma levels of glucose, insulin and corticosterone, and (2) to investigate whether oxytocin treatment early in life could ameliorate the adverse effects of food restriction in utero. Pups from ad libitum-fed and food-restricted (60% of ad libitum intake during pregnancy) rats were injected subcutaneously once a day with oxytocin or saline on days 1-14 after birth. At adult age (62 days), male offspring from food-restricted darns had lower body weight, less adipose tissue, lower plasma glucose but higher corticosterone levels, compared to offspring from ad libitum-fed dams. However, oxytocin-treated food-restricted males had higher body weight, higher glucose and lower corticosterone levels compared to their saline-treated counterparts. In conclusion, oxytocin treatment early in life seems to ameliorate some of the adverse effects of food restriction in utero. Copyright (C) 2000 S. Karger AG, Basel.

  • 12.
    Sohlstrom, A
    et al.
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden¤ Univ Adelaide, Dept Obstet & Gynaecol, Adelaide, SA 5005, Australia¤ Univ Adelaide, Dept Physiol, Adelaide, SA 5005, Australia.
    Fernberg, P
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden¤ Univ Adelaide, Dept Obstet & Gynaecol, Adelaide, SA 5005, Australia¤ Univ Adelaide, Dept Physiol, Adelaide, SA 5005, Australia.
    Owens, JA
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden¤ Univ Adelaide, Dept Obstet & Gynaecol, Adelaide, SA 5005, Australia¤ Univ Adelaide, Dept Physiol, Adelaide, SA 5005, Australia.
    Owens, PC
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden¤ Univ Adelaide, Dept Obstet & Gynaecol, Adelaide, SA 5005, Australia¤ Univ Adelaide, Dept Physiol, Adelaide, SA 5005, Australia.
    Maternal nutrition affects the ability of treatment with IGF-I and IGF-II to increase growth of the placenta and fetus, in guinea pigs2001In: Growth Hormone & IGF Research, ISSN 1096-6374, Vol. 11, no 6, 392-398 p.Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate how administration of IGF-I and IGF-II, during early to mid pregnancy, affects maternal growth and body composition as well as fetal and placental growth, in ad libitum fed, and in moderately, chronically food restricted guinea pigs. From day 20 of gestation, mothers (3-4 months old) were infused with IGF-I, IGF-II (565 mug/day) or vehicle for 17 days and then killed on day 40 of gestation. Maternal organ weights, fetal and placental weights were assessed. Treatment with IGFs did not alter body weight gain and had small effects on body composition in the mothers. Both IGF-I and IGF-II increased fetal and placental weights in ad libitum fed dams and IGF-I increased placental weight in food restricted dams. In conclusion, treatment with IGF-I during the first half of pregnancy stimulates placental growth in both ad libitum fed and food restricted guinea pigs without affecting maternal growth while fetal growth is stimulated by IGF treatment only in ad libitum fed animals. (C) 2001 Elsevier Science Ltd.

  • 13.
    Grant, P.A.
    et al.
    Department of Obstetrics/Gynaecology, University of Adelaide, Adelaide, SA 5005, Australia.
    Kind, K.L.
    Department of Obstetrics/Gynaecology, University of Adelaide, Adelaide, SA 5005, Australia.
    Roberts, C.T.
    Department of Obstetrics/Gynaecology, University of Adelaide, Adelaide, SA 5005, Australia.
    Sohlström, A.
    Linköping University, Department of Biomedicine and Surgery, Nutrition. Linköping University, Faculty of Health Sciences.
    Owens, P.C.
    Department of Obstetrics/Gynaecology, University of Adelaide, Adelaide, SA 5005, Australia.
    Owens, J.A.
    Department of Obstetrics/Gynaecology, University of Adelaide, Adelaide, SA 5005, Australia.
    Late pregnancy increases hepatic expression of insulin-like growth factor-I in well nourished guinea pigs2005In: Growth Hormone & IGF Research, ISSN 1096-6374, Vol. 15, no 2, 165-171 p.Article in journal (Refereed)
    Abstract [en]

    Blood IGF-I concentrations are persistently elevated throughout pregnancy in humans and guinea pigs and may regulate substrate partitioning between mother and conceptus. In the guinea pig, liver and adipose tissue have recently been suggested to contribute to the increased levels of circulating IGF-I in mid-pregnancy, but whether this persists in late pregnancy in undernutrition is not known. Therefore the effect of pregnancy and undernutrition on circulating IGF-I and hepatic expression of IGF-I in late gestation in the guinea pig was examined. Female guinea pigs (Cavia porcellus) were fed ad libitum throughout pregnancy or 70% of ad libitum intake for 28 days prior to and throughout pregnancy (term is 69 d). Non-pregnant animals were maintained for 88 days on the same diets. Plasma IGF-I was measured by RIA after molecular sieving chromatography at low pH. Abundances of IGF-I and ß-actin mRNA in maternal liver were quantified by digoxigenin-ELISA after RT PCR. Late pregnancy increased both the concentration of IGF-I protein (p < 0.001) in plasma and the relative abundance of liver IGF-I mRNA (p < 0.001) in ad libitum fed, but not in feed restricted pregnant guinea pigs. The concentration of IGF-I protein in plasma correlated positively with the relative abundance of IGF-I mRNA in liver overall (p < 0.002), suggesting the liver as a major source of endocrine IGF-I in late pregnant guinea pigs. This study demonstrates that hepatic expression of IGF-I remains elevated during late pregnancy in the well fed guinea pig, which is in contrast to that observed in other non-human species. © 2005 Elsevier Ltd. All rights reserved.

  • 14.
    Leksell, J.K.
    et al.
    Linköping University, Department of Welfare and Care (IVV). Linköping University, Faculty of Health Sciences.
    Wikblad, K.F.
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Sandberg, G.E.
    Högskolan Dalarna, Dept. of Health and Social Sciences, S-791 88, Falun, Sweden.
    Sense of coherence and power among people with blindness caused by diabetes2005In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 67, no 2, 124-129 p.Article, review/survey (Refereed)
    Abstract [en]

    The aim of the present study was to analyze whether strong sense of coherence (SOC) or power or the combination of strong SOC and power was related to blind diabetic patients' self-perceived health, burden of diabetes, glycaemic control and self-care among blind people. In some variables we wanted to compare subjects with diabetes-related blindness with people who were blind for other reasons than diabetes. The present descriptive study included 39 blind subjects from three ophthalmic outpatient clinics who agreed to participate, 23 were blind due to diabetes and 16 were blind for other reasons. Power was explored during semi-structured interviews, SOC was measured with the SOC-scale and burden of diabetes with semantic differential in diabetes (SDD) questionnaires. A single Likert scale (EVGFP) was used to measure self-perceived health. Participants with the combination of strong SOC and power perceived better health, experienced less burden of diabetes and had better glycaemic control than those with the combination of weak SOC and non-power. Nearly all participants with diabetes experienced problems with self-care, especially with the insulin treatment. The results highlight the importance of education that increases SOC and power as well as developing visual aids that assist blind people with diabetes in different self-care situations. © 2004 Elsevier Ireland Ltd. All rights reserved.

  • 15.
    Lindström, Torbjörn
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Frystyk, Jan
    The Medical Research Laboratories, Clinical Institute and Medical Department M, Aarhus University Hospital, Aarhus, Denmark.
    Hedman, Christina
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Flyvbjerg, Allan
    The Medical Research Laboratories, Clinical Institute and Medical Department M, Aarhus University Hospital, Aarhus, Denmark.
    Arnqvist, Hans
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Elevated circulating adiponectin in type 1 diabetes is associated with long diabetes duration2006In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 65, no 6, 776-782 p.Article in journal (Refereed)
    Abstract [en]

    Objective  To study circulating adiponectin concentrations in relation to diabetes duration and endogenous insulin secretion in patients with type 1 diabetes.

    Patients  Patients with haemoglobin A1c (HbA1c) < 6% (reference range 3·6–5·4%) were selected for the study. Twenty-two men and 24 women [age 41·3 ± 13·8 years (mean ± SD), diabetes duration 4 months to 52 years] participated. Healthy controls (15 women and nine men, age 41·3 ± 13·0 years) were also included. Overnight fasting serum samples were analysed for adiponectin, HbA1c, C-peptide and lipoproteins.

    Results  Significant positive associations were found between adiponectin concentrations and diabetes duration in univariate and multiple regression analyses. Serum adiponectin averaged 9·7 ± 5·3 [median 8·1, interquartile range (IQR) 3·6] mg/l in patients with diabetes duration less than 10 years and 17·8 ± 10·7 (median 14·7, IQR 7·5) mg/l in patients with longer duration (P = 0·0001). Among the patients, 24 were without detectable (< 100 pmol/l) and 22 with detectable C-peptide levels (185 ± 91 pmol/l). C-peptide levels in controls averaged 492 ± 177 pmol/l. HbA1c was 5·7 ± 0·6% in patients without detectable C-peptide and 5·6 ± 0·4% in patients with detectable C-peptide (ns). Serum adiponectin was higher in patients without detectable C-peptide than in patients with detectable C-peptide [17·3 ± 11·1 vs. 10·6 ± 5·8 mg/l (P < 0·005)] and in the controls [10·1 ± 2·9 mg/l (P < 0·001 vs. patients without detectable C-peptide)].

    Conclusions  The increase in circulating adiponectin concentrations in patients with type 1 diabetes appears to be strongly associated with long diabetes duration, irrespective of the metabolic control. Among other factors, a putative role for residual β-cell function in the regulation of circulating adiponectin levels can be considered but we did not find sufficient evidence for this in the present study.

  • 16.
    Ratziu, V
    et al.
    Université Pierre et Marie Curie.
    Bugianesi, E
    University of Torino.
    Dixon, J
    Alfred Hospital.
    Fassio, E
    Hospital Nacional Profesor Alejandro Posadas.
    Ekstedt, Mattias
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Charlotte, F
    Université Pierre et Marie Curie.
    Kechagias, Stergios
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Poynard, T
    Université Pierre et Marie Curie.
    Olsson, R
    Sahlgrenska University Hospital.
    Histological progress of non-alcoholic fatty liver disease: a critical reassessment based on liver sampling variability.2007In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, Vol. 26, 821-830 p.Article in journal (Refereed)
    Abstract [en]

      Background: In non-alcoholic fatty liver disease, histological lesions display a significant sampling variability that is ignored when interpreting histological progression during natural history or therapeutic interventions. Aim: To provide a method taking into account sampling variability when interpreting crude histological data, and to investigate how this alters the conclusions of available studies. Methods: Natural history studies detailing histological progression and therapeutic trials were compared with the results of a previously published sampling variability study. Results: Natural history studies showed an improvement in steatosis, which was significantly higher than expected from sampling variability (47% vs. 8%, P < 0.0001). In contrast, no study showed a change in activity grade or ballooning higher than that of sampling variability. There was only a marginal effect on fibrosis with no convincing demonstration of a worsening of fibrosis, a conclusion contrary to what individual studies have claimed. Some insulin sensitizing drugs and anti-obesity surgery significantly improved steatosis, while most did not significantly impact on fibrosis or activity. Conclusions: Sampling variability of liver biopsy is an overlooked confounding factor that should be considered systematically when interpreting histological progression in patients with non-alcoholic fatty liver disease.

  • 17.
    Petersson, Ulla
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Department of Health and Society, General Practice.
    Östgren, Carl-Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Department of Health and Society, General Practice. Östergötlands Läns Landsting, Local Health Care Services in the West of Östergötland.
    Brudin, Lars
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Physiology.
    brismar, kerstin
    KI.
    Nilsson, Peter M
    Malmö.
    Association between elevated blood pressure and surrogate markers for insulin resistance in a defined population. The Söderåkra Cardiovascular Risk Factor Study2006In: ESH,2006, 2006Conference paper (Other academic)
  • 18.
    Szabó, Zoltán
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Thoracic Surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Intraoperative insulin resistance during coronary surgery in diabetic and non-diabetic patients- preliminary results2007In: EASD: Diabetes Cardiovascular Disease Study Group Meeting,2007, 2007Conference paper (Other academic)
  • 19.
    Mc Gowan, BM
    et al.
    Imperial College London.
    Stanley, SA
    Imperial College London.
    White, NE
    Imperial College London.
    Spångeus, Anna
    Imperial College London.
    Patterson, M
    Imperial College London.
    Thompson, EL
    Imperial College London.
    Smith, KL
    Imperial College London.
    Donovan, J
    Imperial College London.
    Gardiner, JV
    Imperial College London.
    Ghatei, MA
    Imperial College London.
    Bloom, SR
    Imperial College London.
    Hypothalamic mapping of orexigenic action and Fos-like immunoreactivity following relaxin-3 administration in male Wistar rats.2007In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 292, 913-919 p.Article in journal (Refereed)
    Abstract [en]

      The insulin superfamily, characterized by common disulphide bonds, includes not only insulin but also insulin-like peptides such as relaxin-1 and relaxin-3. The actions of relaxin-3 are largely unknown, but recent work suggests a role in regulation of food intake. Relaxin-3 mRNA is highly expressed in the nucleus incertus, which has extensive projections to the hypothalamus, and relaxin immunoreactivity is present in several hypothalamic nuclei. In the rat, relaxin-3 binds and activates both relaxin family peptide receptor 1, which also binds relaxin-1, and a previously orphaned G protein-coupled receptor, RXFP3. These receptors are extensively expressed in the hypothalamus. The aims of these studies were twofold: 1) map the hypothalamic site(s) of the orexigenic action of relaxin-3 and 2) examine the site(s) of neuronal activation following central relaxin-3 administration. After microinjection into hypothalamic sites, human relaxin-3 (H3; 180 pmol) significantly stimulated 0- to 1-h food intake in the supraoptic nucleus (SON), arcuate nucleus (ARC), and the anterior preoptic area (APOA) [SON 0.4 ± 0.2 (vehicle) vs. 2.9 ± 0.5 g (H3), P < 0.001; ARC 0.7 ± 0.3 (vehicle) vs. 2.7 ± 0.2 g (H3), P < 0.05; and APOA 0.8 ± 0.1 (vehicle) vs. 2.2 ± 0.2 g (H3), P < 0.05]. Cumulative food intake was significantly increased 8 h following administration into the SON and 4 h into the APOA. A significant increase in Fos-like immunoreactivity was seen in the SON following central relaxin-3 administration. Relaxin-3 stimulates feeding in several hypothalamic nuclei, and these studies provide additional support for relaxin-3 as an important peptide in appetite regulation.

  • 20.
    Szabó, Zoltán
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Thoracic Surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Intraoperative insulin resistance during coronary surgery in diabetic and non-diabetic patients - parallel microdialysis and organ balance technique studying skeletal muscle and fat tissue (preliminary results)2007In: 17th Annual Meeting of the Scandinavian Society for Research in CardioThoracic Surgery,2007, 2007Conference paper (Other academic)
    Abstract [en]

         

  • 21. Frantz, S.E.A.
    et al.
    Mikael, L.A.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Inganäs, Olle
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics.
    Hammarström, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Quantum efficiency and two-photon absorption cross-section of conjugated polyelectrolytes used for protein conformation measurements with applications on amyloid structures2007In: Chemical Physics, ISSN 0301-0104, E-ISSN 1873-4421, Vol. 336, no 2-3, 121-126 p.Article in journal (Refereed)
    Abstract [en]

    Amyloid diseases such as Alzheimer's and spongiform encephalopathies evolve from aggregation of proteins due to misfolding of the protein structure. Early disease handling require sophisticated but yet simple techniques to follow the complex properties of the aggregation process. Conjugated polyelectrolytes (CPEs) have shown promising capabilities acting as optical biological sensors, since they can specifically bind to polypeptides both in solution and in solid phase. The structural changes in biomolecules can be monitored by changes of the optical spectra of the CPEs, both in absorption and emission modes. Notably, the studied CPEs possess multi-photon excitation capability, making them potential for in vivo imaging using laser scanning microscopy. Aggregation of proteins depends on concentration, temperature and pH. The optical effect on the molecular probe in various environments must also be investigated if applied in these environments. Here we present the results of quantum efficiency and two-photon absorption cross-section of three CPEs: POMT, POWT and PTAA in three different pH buffer systems. The extinction coefficient and quantum efficiency were measured. POMT was found to have the highest quantum efficiency being approximately 0.10 at pH 2.0. The two-photon absorption cross-section was measured for POMT and POWT and was found to be more than 18-25 times and 7-11 times that of Fluorescein, respectively. We also show how POMT fluorescence can be used to distinguish conformational differences between amyloid fibrils formed from reduced and non-reduced insulin in spectrally resolved images recorded with a laser scanning microscope using both one- and two-photon excitation. © 2007 Elsevier B.V. All rights reserved.

  • 22.
    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.
    Immune intervention at diagnosis - Should we treat children to preserve beta-cell function?2007In: Pediatric Diabetes, ISSN 1399-543X, Vol. 8, no SUPPL. 6, 34-39 p.Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes (T1D) is characterized by loss of beta-cell function. If beta-cell function can be preserved, it will lead to improved metabolic balance with improved quality of life and fewer acute and late complications, and if residual insulin secretion improves well enough, then that could lead to complete remission and even cure of the disease. Several efforts to save residual beta-cell function have been made for more than three decades without success. Proof of principle has been possible, and it seems clear that immune suppression or immune modulation, in fact, can stop the destructive process and thereby preserve beta-cell function. However, the effect seen in adult patients with T1D have been minimal or absent in diabetic children who seem to have another or at least more aggressive disease process. Furthermore, the immune interventions have had too serious and common adverse events in comparison to the scarce-positive effect. Recent more specific immune modulation with anti-CD3 monoclonal antibodies seems more encouraging with at least postponement of the C-peptide decline, but unfortunately still with common and quite threatening adverse effects. Even more promising are the autoantigen therapies, of which glutamic acid decarboxylase (GAD) vaccination has shown good results with impressive preservation of residual insulin secretion in 10- to 18-year-old type 1 diabetic patients with recent onset. In patients with short diabetes duration at intervention the effect was remarkable. Furthermore, these effects were achieved with no adverse events. Future studies will show whether the good effect seen so far can be confirmed. If so there is hope that GAD vaccination will cause remission and even cure and prevention of T1D will then no longer be just a dream. © 2007 The Authors Journal compilation.

  • 23.
    Szabó, Zoltán
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Thoracic Surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Andersson, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Insulin resistance during coronary surgery in diabetic and non-diabetic patients-parallel microdialysis and organ balance technique studying skeletal muscle (preliminary results)2007In: Diabetologia(ISSN 0012-186X), vol 50, 2007, Vol. 50, 275-276 p.Conference paper (Refereed)
  • 24.
    Szabó, Zoltán
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Thoracic Surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Andersson, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Insulin resistance during coronary surgery in diabetic and non-diabetic patients-parallel microdialysis and organ balance technique studying skeletal muscle (preliminary results)2007In: European Association for the Study of Diabetes EASD,2007, 2007Conference paper (Refereed)
    Abstract [en]

        

  • 25. Robertson, KJ
    et al.
    Schoenle, E
    Gucev, Z
    Mordhorst, L
    Gall, MA
    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.
    Insulin detemir compared with NPH insulin in children and adolescents with Type 1 diabetes2007In: Diabetic Medicine, ISSN 0742-3071, Vol. 24, no 1, 27-34 p.Article in journal (Refereed)
    Abstract [en]

    Aims: This study compared the effect of insulin detemir on glycaemic control (HbA1c, fasting plasma glucose and variability thereof) with that of Neutral Protamine Hagedorn human isophane (NPH) insulin, both combined with insulin aspart, in children with Type 1 diabetes mellitus, and compared the safety of these treatments. Methods: In this 26-week, open-label, randomized (2 : 1), parallel-group study, 347 (140 prepubertal and 207 pubertal) children with Type 1 diabetes, aged 6-17 years, received insulin detemir (n = 232) or NPH insulin (n = 115) once or twice daily, according to the prestudy regimen, plus premeal insulin aspart. Results: The mean HbA1c decreased by ∼0.8% with both treatments. After 26 weeks, the mean difference in HbA 1c was 0.1% (95% confidence interval -0.1, 0.3) (insulin detemir 8.0%, NPH insulin 7.9%). Within-subject variation in self-measured fasting plasma glucose was significantly lower with insulin detemir than with NPH insulin (SD 3.3 vs. 4.3, P < 0.001), as was mean fasting plasma glucose (8.4 vs. 9.6 mmol/l, P = 0.022). The risk of nocturnal hypoglycaemia (22.00-07.00 h) was 26% lower with insulin detemir (P = 0.041) and the risk of 24-h hypoglycaemia was similar with the two treatments (P = 0.351). The mean body mass index (BMI) Z-score was lower with insulin detemir (P < 0.001). Conclusions: Basal-bolus treatment with insulin detemir or NPH insulin and premeal insulin aspart in children and adolescents with Type 1 diabetes mellitus improved HbA1c to a similar degree. The lower and more predictable fasting plasma glucose, lower risk of nocturnal hypoglycaemia and lower BMI observed with insulin detemir are clinically significant advantages compared with NPH insulin. © 2007 The Authors.

  • 26.
    Svedjeholm, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Thoracic Surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Insulin-Glucose and cardiac function. Abstract Post Graduate Course Session III - Next steps to ameliorate perfusion2006In: 5th EACTS/ESTS Joint meeting,2006, Stockholm: Stockholm , 2006, 88- p.Conference paper (Refereed)
    Abstract [en]

        

  • 27.
    Hägg, Staffan
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Lindblom, Y
    Umeå.
    Mjörndal, Tom
    Umeå.
    Adolfsson, R
    Umeå.
    High prevalence of the metabolic syndrome among a Swedish cohort of patients with schizophrenia2006In: International Clinical Psychopharmacology, ISSN 0268-1315, Vol. 21, no 2, 93-98 p.Article in journal (Refereed)
    Abstract [en]

    Several cardiovascular risk factors have been linked to antipsychotic treatment and cardiovascular mortality is increased in these patients compared to the general population. The full metabolic syndrome (or its components) is associated with an increased risk of cardiovascular disorders. The prevalence of the metabolic syndrome was investigated using a cross-sectional study design in a cohort of 269 patients, aged 20-69 years, with schizophrenia living in Northern Sweden, and was defined according to the criteria of the National Cholesterol Education program. The prevalence of the metabolic syndrome was 34.6% (95% CI = 28.8-40.3) and highest (43%, 95% CI = 32-53) for participants aged 40-49 years. Clozapine treated subjects reached the highest prevalence of the metabolic syndrome (48%, 95% CI = 34-62). The prevalence was similar for men (32.8%, 95% CI = 25.8-39.8) and women (38.0%, 95% CI = 27.9-48.2). Men had a high prevalence of hypertension (49.2%, 95% CI = 41.7-56.6) and women had high prevalence of low high-density lipoprotein cholesterol (40.2%, 95% CI = 30.0-50.4) and abdominal obesity (75.0%, 95% CI = 66.0-84.0). Subjects with the metabolic syndrome had significantly higher mean body mass index (BMI) (P < 0.001), HbA1c (P = 0.002), and fasting serum insulin (P < 0.001) compared to non-metabolic syndrome subject. Subjects with the metabolic syndrome had also significantly more often a positive history of cardiovascular diseases compared to non-metabolic syndrome subjects (25.8% versus 12.5%, P = 0.01). Of all study subjects 36.8% were obese (BMI > 30). These results clearly show that the metabolic syndrome and its components are highly prevalent in patients with schizophrenia. Physicians treating patients with schizophrenia are recommended to monitor the components included in the metabolic syndrome. © 2006 Lippincott Williams & Wilkins.

  • 28.
    Fritzson, Peter
    et al.
    Linköping University, Department of Computer and Information Science.
    Ulfhielm, Erik
    Belic, Ales
    Faculty of Electrical Engineering, University of Ljubljana.
    Fransson, Martin
    Linköping University, Department of Computer and Information Science.
    Green, Henrik
    Hälsouniversitetet, Faculty of Health Sciences.
    Biochemical Mathematical Modeling with Modelica and the BioChem Library2007Conference paper (Refereed)
    Abstract [en]

    Considering the large amounts of data that is nowadays produced in the biochemistry (functional genomics) it is difficult to extract the information from the measurements. There is currently also a great interest in the development of novel analytical technologies for rapid screening of disease symptoms in pharmaceutical and clinical ap-plications. Modeling and simulation can provide a useful help in understanding the rela-tions of the measured substances and to minimize the need for measurements. The Bio-Chem library presented here is the first free Modelica library available for mathematical modeling of biochemical processes. Three examples are shown to illustrate the library. First, a simple insulin model is presented. Then a simplified model of cholesterol to-gether with simulations are shown. Next, a simple drug model together with parameter estimation in NONMEN are presented. The BioChem library allows for fast and end-user friendly modeling of biomedical systems. The graphical user interface provides graphics similar to that used in the description of metabolic pathways in biochemistry.

  • 29.
    Karlsson Faresjö, Maria
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Vaarala, Outi
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Thuswaldner, Sophie
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ilonen, Jorma
    JDRF Center for Prevention of Type 1 Diabetes in Finland and the Department of Virology, University of Turku, Turku, Finland.
    Hinkkanen, Ari
    Åbo Akademi, Turku University, Turku, Finland.
    Ludvigsson, Johnny
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Diminished IFN-γ response to diabetes-associated autoantigens in children at diagnosis and during follow up of type 1 diabetes2006In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 22, no 6, 462-470 p.Article in journal (Refereed)
    Abstract [en]

    Background

    Imbalance of T-helper (Th)1- and Th2-like cytokines has been associated with type 1 diabetes. We therefore studied the immune deviation in antigen-specific T cells from diagnosis onwards in type 1 diabetic children.

    Methods

    Peripheral blood mononuclear cells (PBMC) were collected from 15 children after 4 days, 3 months and 18 months of being diagnosed with type 1 diabetes, from 15 healthy children matched by age and gender to the type 1 diabetic children and from 14 children with and 35 children without HLA-risk genes. Secretion of interferon-γ (IFN-γ) and interleukin-4 (IL-4) was detected by ELISPOT after stimulation with glutamic acid decarboxylase (GAD65, protein and aa 247–279), recombinant tyrosinphosphatase (IA-2), insulin, ovalbumin and phytohaemagglutinin (PHA).

    Results

    Secretion of IFN-γ in PBMC stimulated with GAD65 (p < 0.05), the GAD65-peptide (p < 0.01), IA-2 (p < 0.01), and insulin (p < 0.01) was lower in diabetic children at diagnosis than in healthy children. Stimulation of PBMC with GAD65 and IA-2 decreased the secretion of IFN-γ in children with HLA-risk genotype. Spontaneous and antigen-induced IFN-γ secretion increased significantly after diagnosis of the disease, but did not exceed the levels observed in healthy children. Fasting C-peptide levels at diagnosis correlated with insulin-induced IFN-γ (R = 0.52; p = 0.05) and negatively with spontaneous IL-4 secretion (R = −0.62; p < 0.05).

    Conclusion

    A diminished IFN-γ secretion and the association of fasting C-peptide levels with cytokine response in children with type 1 diabetes suggest that factors related to β-cell function in type 1 diabetes may modify T-cell function. Thus, the T-cell responses detected at or after diagnosis may not reflect the pathogenic process leading to type 1 diabetes.

  • 30.
    Nilsson, Lennart
    et al.
    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.
    Kivling, Anna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Jalmelid, M
    Fälth-Magnusson, Karin
    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.
    Faresjö, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Combinations of common chronic paediatric diseases deviate the immune response in diverging directions2006In: Clinical and Experimental Immunology, ISSN 0009-9104, Vol. 146, no 3, 433-442 p.Article in journal (Refereed)
    Abstract [en]

    The cytokine pattern of T lymphocytes has not been characterized in children with combinations of paediatric immunological disorders. We describe cytokine secretion in children with type 1 diabetes, coeliac disease and allergy and combinations of two of these diseases after stimulation with 'disease-specific' antigens. Peripheral blood mononuclear cells (PBMC) were collected from 68 children with type 1 diabetes, allergy or coeliac disease, two of these diseases in combination or none of these diseases. Using the enzyme-linked immunospot (ELISPOT) technique, interferon (IFN)-γ and interleukin (IL)-4 were analysed from fresh PBMC spontaneously and after in vitro stimulation with antigens associated with one or more of these diseases (insulin, gluten, birch and cat extract, β-lactoglobulin, ovalbumin and phytohaemagglutinin) in order to divide T helper (Th)1- from Th2-like lymphocytes. Stimulation with birch and cat extract caused increased IL-4 secretion in allergic children. A low IFN-γ response to insulin was found in type 1 diabetic children, whereas allergic children responded to insulin by increased IL-4 secretion. Children suffering from both type 1 diabetes (Th1-prone) and allergy (Th2-prone) reacted distinctly to general mitogen stimulation. Children suffering from two Th1-dominated diseases (type 1 diabetes and coeliac disease) showed hardly any response to either food or inhalation allergens. Our results indicate an important interplay between common immunological diseases in children. The combination of two Th1-deviated diseases is associated with a suppressed immune response, whereas a combination of Th1- and Th2-dominated diseases appears to increase the general immune response. © 2006 The Author(s).

  • 31.
    Mäkelä, Miia
    et al.
    Immunogenetics Lab, University of Turku, 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.
    Hermann, Robert
    Immunogenomics Lab, Cell Screen Applied Biomedi cal Res Center, Budapest. Hungary.
    Salminen, Kimmo
    Dept of Virology, Turku, Finland.
    Vahlberg, Tero
    Dept of Biostatistics University of Turku, Finland.
    Veijola, Riita
    Dept of Pediatrics, University of Oulu, Finland.
    Hyöty, Heikki
    Dept of Virology, University of Tampere, Finland.
    Knip, Mikael
    Hospital for Children and Adolescents, University of Helsinki, Finland.
    Simell, Olli
    Immunogenetics Lab, University of Turku, Finland.
    Ilonen, Jorma
    Dept of Clin Microbiology, University of Kuopio, Finland.
    Enteral virus infections in early childhood and an enhanced type 1 diabetes-associated antibody response to dietary insulin2006In: Journal of Autoimmunity, ISSN 0896-8411, Vol. 27, no 1, 54-61 p.Article in journal (Refereed)
    Abstract [en]

    Enteral virus infections may trigger the development of β-cell-specific autoimmunity by interacting with the gut-associated lymphoid system. We analyzed the effect of three different virus infections on immunization to dietary insulin in children carrying increased genetic risk for type 1 diabetes. Forty-six of 238 children developed multiple diabetes-associated autoantibodies and 31 clinical diabetes (median follow-up time 75 months). Insulin-binding antibodies were measured with EIA method (median follow-up time 24 months). Antibodies to enteroviruses, rotavirus and adenovirus were measured with EIA in samples drawn at birth and the ages of 3 and 6 months. Nineteen enterovirus, 14 rotavirus and 8 adenovirus infections were diagnosed. At the ages of 6, 12, and 18 months, the concentrations of insulin-binding antibodies were higher in children with postnatal entero-, rota- and/or adenovirus infections than in children without these infections. Children who subsequently developed ICA or IA-2 antibodies or clinical type 1 diabetes had higher concentrations of insulin-binding antibodies than children who remained autoantibody negative. Our data suggest that enteral virus infections can enhance immune response to insulin, induced primarily by bovine insulin in cow's milk. An enhanced antibody response to dietary insulin preceded the development of β-cell specific autoimmunity and type 1 diabetes. © 2006 Elsevier Ltd. All rights reserved.

  • 32.
    Tittanden, M
    et al.
    Dept of Viral Diseases and Immunology Helsinki, Finland.
    Paronen, Johanna
    Dept of Viral Diseases and Immunology Helsinki, Finland.
    Savilahti, Erkki
    Hospital for Children And Adolescents Helsinki, Finland.
    Virtanen, Suvi
    Dept of Epidemilogy and Health Promotion National Public Health Inst, Finland.
    Ilonen, Jorma
    Dept of Clinical Microbiology University of Kuopio, Finland.
    Knip, Mikael
    Hospital for Children and Adolescents University of Helsinki, Finland.
    Åkerblom, Hans
    Hospital for chldren and Adolescents University of Helsinki, 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.
    Dietary insulin as an immunogen and tolerogen2006In: Pediatric Allergy and Immunology, ISSN 0905-6157, Vol. 17, no 7, 538-543 p.Article in journal (Refereed)
    Abstract [en]

    We have shown that exposure to bovine insulin (BI) in cow's milk (CM) formula induces an insulin-specific immune response in infants. Here we studied the role of human insulin (HI) in breast milk as a modulator of the immune response to insulin. In a group of 128 children participating in the TRIGR pilot study, maternal breast milk samples were collected 3-7 days and/or 3 months after delivery. After exclusive breast-feeding, the children received either CM formula or casein hydrolysate during the first 6-8 months of life. Insulin concentration in breast milk and immunoglobulin G (IgG) antibodies to BI in plasma samples were measured by EIA. The levels of insulin in breast milk samples were higher in mothers affected by type 1 diabetes than in non-diabetic mothers (p = 0.007 and p < 0.001). The concentration of insulin in breast milk correlated inversely with the plasma levels of IgG antibodies to BI at 6 months of age in children who received CM formula (r = -0.39, p = 0.013), and at 12 months of age in all children (r = -0.25, p = 0.029). The levels of breast milk insulin were higher in the mothers of nine children who developed beta-cell autoimmunity when compared with autoantibody-negative children (p = 0.030), this holds true also when only children of diabetic mothers were included (p = 0.045). BI in CM induces higher levels of IgG to insulin in infants than does HI in breast-fed children. Instead, HI in breast milk seems to be tolerogenic and may downregulate the IgG response to dietary BI. However, our results in infants who developed beta-cell autoimmunity suggest that in this subgroup of children breast milk insulin does not promote tolerance. © 2006 The Authors.

  • 33. Schmidt, PT
    et al.
    Degerblad, M
    Lindström, E
    Sundqvist, M
    Näslund, E
    Gillberg, PG
    Husebye, E
    Theodorsson, Elvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Hellström, PM
    Circulating ghrelin levels after food intake during different phases of the migrating motor complex in man2006In: European Journal of Clinical Investigation, ISSN 0014-2972, Vol. 36, no 7, 503-508 p.Article in journal (Refereed)
    Abstract [en]

    Background: The timing of the migrating motor complexes (MMC) at food intake may influence gastric emptying and release of regulatory hormones. This report studies the relationships between phases I (motor quiescence) and II (intermediate frequency contractions) of MMC and prandial gut hormone response. Materials and methods: Seven fasting volunteers ingested a meal during phase I or II of MMC verified by manometry, using paracetamol as a marker for gastric emptying. Blood was sampled before, during and 210 min after food intake for analysis of ghrelin, motilin, insulin and paracetamol. Results: The basal level of ghrelin during phase I was 127.5 ± 25.4 pmol L-1 and during phase II was 132.4 ± 24.8 pmol L-1. After food intake during phase I, ghrelin fell to 77.2 ± 10 pmol L-1, in phase II it fell to 82.7 ± 17.8 pmol L-1 within 60 min and returned to baseline levels after 120 min. Baseline levels of motilin were 16 ± 2 pmol L-1 and 18 ± 3 pmol L-1 during phases I and II, respectively. After food, motilin decreased to 8.5 ± 0.7 pmol L-1 and 8.7 ± 1.0 pmol L-1 within 60 min and returned to baseline after 90 min. Insulin levels in phases I and II were 8.1 ± 1.2 mU L-1 and 8.6 ± 0.7 mU L-1, respectively, reaching 138.9 ± 35.6 mU L-1 and 167.4 ± 30.0 mU L-1 at 45 min postprandially. Conclusions: The nutritional status of the gastrointestinal tract at food intake had only a limited impact on plasma ghrelin. After food intake, plasma ghrelin drops, similar to motilin, and resumes preprandial levels within 120 min. © 2006 Blackwell Publishing Ltd.

  • 34.
    Örtegren Kugelberg, Unn
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Yin, Lan
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Öst, Anita
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Karlsson, Helen
    Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences.
    Nyström, Fredrik
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Separation and characterization of caveolae subclasses in the plasma membrane of primary adipocytes: segregation of specific proteins and functions2006In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 273, no 14, 3381-3392 p.Article in journal (Refereed)
    Abstract [en]

    Caveolae are nearly ubiquitous plasma membrane domains that in adipocytes vary in size between 25 and 150 nm. They constitute sites of entry into the cell as well as platforms for cell signalling. We have previously reported that plasma membrane-associated caveolae that lack cell surface access can be identified by electron microscopy. We now report the identification, after density gradient ultracentrifugation, of a subclass of very high-density apparently closed caveolae that were not labelled by cell surface protein labelling of intact cells. These caveolae contained caveolin-1 and caveolin-2. Another class of high-density caveolae contained caveolin-1, caveolin-2 and specifically fatty acid transport protein-1, fatty acid transport protein-4, fatty acyl-CoA synthetase, hormone-sensitive lipase, perilipin, and insulin-regulated glucose transporter-4. This class of caveolae was specialized in fatty acid uptake and conversion to triacylglycerol. A third class of low-density caveolae contained the insulin receptor, class B scavenger receptor-1, and insulin-regulated glucose transporter-4. Small amounts of these proteins were also detected in the high-density caveolae. In response to insulin, the insulin receptor autophosphorylation and the amount of insulin-regulated glucose transporter-4 increased in these caveolae. The molar ratio of cholesterol to phospholipid in the three caveolae classes varied considerably, from 0.4 in very high-density caveolae to 0.9 in low-density caveolae. There was no correlation between the caveolar contents of caveolin and cholesterol. The low-density caveolae, with the highest cholesterol concentration, were particularly enriched with the cholesterol-rich lipoprotein receptor class B scavenger receptor-1, which mediated cholesteryl ester uptake from high-density lipoprotein and generation of free cholesterol in these caveolae, suggesting a specific role in cholesterol uptake/metabolism. These findings demonstrate a segregation of functions in caveolae subclasses.

  • 35.
    Hanberger, Lena
    et al.
    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.
    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.
    Nordfeldt, Sam
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Department of Health and Society, Center for Medical Technology Assessment. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Child and Adolescent Psychiatry.
    Quality of care from the patient's perspective in pediatric diabetes care2006In: Diabetes Research and Clinical Practice, ISSN 0168-8227, Vol. 72, no 2, 197-205 p.Article in journal (Refereed)
    Abstract [en]

    This study aimed to investigate perceived quality of diabetes care. A geographic population of 400 type 1 diabetes patients <20 years received the validated questionnaire quality of care from the patient's perspective (QPP) including additional context-specific items. Primary endpoints were perceived reality of care by specific items and factors and their subjective importance, respectively. Relations to severe hypoglycemia, HbA1c, insulin dose, BMI, age, duration and sociodemographic factors were also studied. On average, a high perceived quality of care was reported from both parents and adolescents (response rate 285/400 (71%) and 155/237 (65%), respectively), highest regarding possibility to talk to nurse/doctor in privacy, respect, general atmosphere, continuity in patient-physician relationship and patient participation. Lower perceived reality with higher subjective importance was seen for information about results from medical examinations and treatments and information about self-care, access to care and waiting time. While parents' and their adolescents' mean ratings correlated well for reality r = 0.95 (p < 0.001) and importance r = 0.53 (p = 0.023), parents rated reality level higher (p = 0.012) and importance even higher (p < 0.001). The QPP instrument used with additional context-specific items can provide specific information to be used in quality of care development. In our setting, improvements are needed regarding patient information, access to care and waiting time. © 2005 Elsevier Ireland Ltd. All rights reserved.

  • 36.
    Vaarala, Outi
    et al.
    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.
    Tiittanen, M
    National Public Health Institute, Helsinki, Finland.
    Huupponen, JT
    National Public Health Institute, Helsinki, Finland.
    Knip, M
    National Public Health Institute, Helsinki, Finland.
    Insulin treatment in patients with type 1 diabetes induces upregulation of regulatory T-cell markers in peripheral blood mononuclear cells stimulated with insulin in vitro2006In: Diabetes, ISSN 0012-1797, Vol. 55, no 12, 3446-3454 p.Article in journal (Refereed)
    Abstract [en]

    Patients with type 1 diabetes are treated with daily injections of human insulin, an autoantigen expressed in thymus. Natural CD4+CD25high regulatory T-cells are derived from thymus, and accordingly human insulin-specific regulatory T-cells should exist. We had a chance to study peripheral blood mononuclear cells (PBMCs) from children with type 1 diabetes both before and after starting insulin treatment, and thus we could analyze the effects of insulin treatment on regulatory T-cells in children with type 1 diabetes. PBMCs were stimulated for 72 h with bovine/human insulin. The mRNA expression of regulatory T-cell markers (transforming growth factor-β, Foxp3, cytotoxic T-lymphocyte antigen-4 [CTLA-4], and inducible co-stimulator [ICOS]) or cytokines (γ-interferon [IFN-γ], interleukin [IL]-5, IL-4) was measured by quantitative RT-PCR. The secretion of IFN-γ, IL-2, IL-4, IL-5, and IL-10 was also studied. The expression of Foxp3, CTLA-4, and ICOS mRNAs in PBMCs stimulated with bovine or human insulin was higher in patients on insulin treatment than in patients studied before starting insulin treatment. The insulin-induced Foxp3 protein expression in CD4+CD25 high cells was detectable in flow cytometry. No differences were seen in cytokine activation between the patient groups. Insulin stimulation in vitro induced increased expression of regulatory T-cell markers, Foxp3, CTLA-4, and ICOS only in patients treated with insulin, suggesting that treatment with human insulin activates insulin-specific regulatory T-cells in children with newly diagnosed type 1 diabetes. This effect of the exogenous autoantigen could explain the difficulties to detect in vitro T-cell proliferation responses to insulin in newly diagnosed patients. Furthermore, autoantigen treatment-induced activation of regulatory T-cells may contribute to the clinical remission of the disease. © 2006 by the American Diabetes Association.

  • 37.
    Jakobsson, Per
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pulmonary Medicine. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine UHL.
    Jorfeldt, Lennart
    Stockholm.
    Oxygen supplementation increases glucose tolerance during euglycaemic hyperinsulinaemic glucose clamp procedure in patients with severe COPD and chronic hypoxaemia2006In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, Vol. 26, no 5, 271-274 p.Article in journal (Refereed)
    Abstract [en]

    Investigations in chronic obstructive pulmonary disease (COPD) patients have shown impaired glucose tolerance in hypoxic COPD patients, compared with COPD patients with normal arterial blood gases. In healthy subjects, hypoxaemia or stay at altitude, have been shown to alter glucose metabolism. At altitude the effect seems to be dependent on duration of stay. A short stay is associated with insulin resistance, a longer stay gives rise to increased glucose uptake. The euglycaemic hyperinsulinaemic glucose clamp technique is a method to study glucose tolerance and enables determinations of glucose clearance in peripheral tissues. We investigated six COPD patients [forced expiratory volume in 1 s 0.7 ± 0.2 l (mean ± SD)] with chronic hypoxaemia (PaO2 7.9 ± 0.6 kPa at rest, breathing air), with and without oxygen supplementation, using the glucose clamp technique. Net peripheral glucose uptake was 5.5 ± 1.2 and 7.1 ± 1.6 mg (kg*min)-1 (+29%) breathing air and supplemental oxygen, respectively (P = 0.03). The tissue sensitivity to insulin increased 32% (P = 0.03) with oxygen supplementation. The results indicate that normalization of oxygen saturation in COPD patients with chronic hypoxaemia may have an immediate effect on glucose tolerance and tissue sensitivity to insulin in these patients. © 2006 Blackwell Publishing Ltd.

  • 38.
    Hanås, Ragnar
    et al.
    Department of Pediatrics, Uddevalla Hospital.
    Ludvigsson, Johnny
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Hypoglycemia and ketoacidosis with insulin pump therapy in children and adolescents2006In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 7, no Supp. 4, 32-38 p.Article in journal (Refereed)
    Abstract [en]

    This review deals with the two most serious side effects encountered with insulin pump therapy, severe hypoglycemia and diabetic ketoacidosis (DKA). Although clinical follow-up studies reported decreased rates of severe hypoglycemia, randomized studies have not confirmed this, showing no difference between the pump and injection groups. Less-severe hypoglycemia (mild/moderate/symptomatic hypoglycemia) was found to be more common with pump use. Some patients have inadvertently dosed or overdosed while awake or during sleep, causing fatal outcome in rare cases. Population-based or retrospective clinical studies reported a low rate of DKA in pump users that was still a higher rate than those using injection therapy, at least in some countries. In research settings and for patients with good compliance and adequate family support, the risk of DKA seems lower; many short-term studies report no DKA at all, possibly due to the increased attention given to participants. The use of continuous subcutaneous insulin infusion (CSII) seems to decrease the risk in patients who had recurrent DKA before pump start. Most episodes of DKA occur early after pump start, suggesting a learning curve occurs in all new forms of treatment. Increased teaching and awareness programs are vital to prevent severe hypoglycemia and DKA in children and adolescents using insulin pumps.

  • 39. Paronen, J
    et al.
    Björkstén, B
    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, Barn.
    Hattevig, G
    Åkerblom, H
    Vaarala, O
    Effect of maternal diet during lactation on development of bovine insulin-binding antibodies in children at risk for allergy2000In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, Vol. 106, no 2, 302-306 p.Article in journal (Refereed)
    Abstract [en]

    Background: The role of exposure to dietary antigens through maternal milk is intriguing, because it may result either in immunization or in tolerance. Exposure to cow's milk proteins results in antibody formation against bovine insulin in infants at risk for type 1 diabetes. Objective: To study the appearance of IgG antibodies to bovine and human insulin in infants with an atopic family history whose mothers followed a cow's milk-free diet during the first 3 months of lactation. Methods: In a prospective cohort study on prevention of food allergies, 123 infants were exclusively breast-fed or received supplementafion with a hydrolyzed casein-based formula (Nutramigen) until the age of 6 months. The mothers either avoided cow's milk during the first 3 months of lactation (diet group) or had an unrestricted diet (nondiet group). The levels of IgG antibodies to bovine and human insulin were determined by enzyme immunoassay at 3, 6, 12, and 18 months and at 4 years. In addition, cord blood was obtained at birth and a maternal sample at delivery. Results: At 3 months, IgG antibodies to bovine insulin were low in both dietary groups (median levels 0.150 and 0.114 optical density units in the diet and nondiet groups). After exposure to dietary insulin, IgG antibodies to bovine insulin increased in both groups, reaching a peak at 12 months in the nondiet group and at 18 months in the diet group. At 18 months, IgG antibodies to bovine insulin were lower in infants in the nondiet group than in infants in the diet group (0.287 vs 0.500, P < .0001). At 4 years, the antibodies no longer differed between the groups. Conclusion: The exposure to cow's milk proteins through breast milk during the first 3 months of life resulted in decreased levels of antibodies to dietary bovine insulin at 18 months of age, suggesting a role for breast milk antigens in early tolerance induction.

  • 40. Johansson, BL
    et al.
    Borg, K
    Fernqvist-Forbes, E
    Kernell, A
    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, Barn.
    Odergren, T
    Wahren, J
    Beneficial effects of C-peptide on incipient nephropathy and neuropathy in patients with Type 1 diabetes mellitus2000In: Diabetic Medicine, ISSN 0742-3071, Vol. 17, no 3, 181-189 p.Article in journal (Refereed)
    Abstract [en]

    Aims: Recent studies have indicated that proinsulin C-peptide shows specific binding to cell membrane binding sites and may exert biological effects when administered to patients with Type 1 diabetes mellitus. This study was undertaken to determine if combined treatment with C-peptide and insulin might reduce the level of microalbuminuria in patients with Type 1 diabetes and incipient nephropathy. Methods: Twenty-one normotensive patients with microalbuminuria were studied for 6 months in a double-blind, randomized, cross-over design. The patients received s.c. injections of either human C-peptide (600 nmol/24 h) or placebo plus their regular insulin regimen for 3 months. Results: Glycaemic control improved slightly during the study and to a similar extent in both treatment groups. Blood pressure was unaltered throughout the study. During the C-peptide treatment period, urinary albumin excretion decreased progressively on average from 58 ╡g/min (basal) to 34 ╡g/min (3 months, P < 0.01) and it tended to increase, but not significantly so, during the placebo period. The difference between the two treatment periods was statistically significant (P < 0.01). In the 12 patients with signs of autonomic neuropathy prior to the study, respiratory heart rate variability increased by 21 ▒ 9% (P < 0.05) during treatment with C-peptide but was unaltered during placebo. Thermal thresholds were significantly improved during C-peptide treatment in comparison to placebo (n = 6, P < 0.05). Conclusion: These results indicate that combined treatment with C-peptide and insulin for 3 months may improve renal function by diminishing urinary albumin excretion and ameliorate autonomic and sensory nerve dysfunction in patients with Type 1 diabetes mellitus.

  • 41.
    Leckström, A
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Lundquist, I
    Ma, Z
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Westermark, P
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Islet amyloid polypeptide and insulin relationship in a longitudinal study of the genetically obese (oblob) mouse. 1999In: Pancreas, ISSN 0885-3177, Vol. 18, 266-273 p.Article in journal (Refereed)
  • 42.
    Mia, Md. Golam Kafi Afrose
    Linköping University, Department of Physics, Chemistry and Biology, Molecular genetics .
    Characterization of the pancreatic β-cell auto antigen targeted by the IC2 monoclonal autoantibody2009Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    IC2, a well known monoclonal autoantibody, derived from newly diabetic BB rat and seems to be an important biomarker for non-invasive functional imaging of beta cells in vivo. It specially and uniquely binds with pancreatic beta cells as confirmed in some previous studies. RIN-5AH is a pancreatic beta cell, which reacts with IC2 is used here to identify and characterize the molecular nature of the IC2 auto antigen by using TLC and HPTLC following by immuno-staining. An unpublished work already had done by Spitalnik et al, 1991 with another rat pancreatic beta cell (RINm5F) extracted glycolipids. In this study, the same work was done, not only with glycolipids from various cell lines but also lipids extracted from purified plasma membrane is made to confirm or refuge that IC2 was found to bind with only the glycolipids containing galactose-3-sulfate. This highly unique observation can however hardly explain the unique beta cell surface specificity without involvement of other more beta cell specific antigenic structures. We are therefore also searching the protein part involved in the auto antigenic determinant. Analyzing the molecular nature of IC2 binding auto-antigen, will help to understand both the role it might plays in the pathogenesis of insulin dependant diabetes. It could also help to elucidate the etiology of diabetes and finally to be a new serum autoantibody biomarker.

  • 43.
    Nyman, Elin
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Hierarchical modeling of diabetes: a pilot study2009Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    In type 2 diabetes the concentration of glucose in the blood is increased, and tissues like fat and musclebecome less sensitive to insulin. These two phenomena are interrelated, but since the glucose-insulininterplay is highly complex, many aspects are still not understood. Here, a model-based approachmight help. Nevertheless, also a model-based approach has a limited impact, unless models for thesub-systems can be combined into a model for the whole-body regulation. Such a multi-level,module-based model is referred to as a hierarchical model, and this thesis is a proof-of-principle studyfor the future development of such models.

    We have extended one of the best available models for the whole-body regulations, to include azoomable module for the fat tissue. The first step was to implement the whole-body model in thesoftware MathModelica, which support hierarchical modeling. Second, the originally mergedinsulin-responding module was sub-divided, so that a fat tissue was singled out. Third, a model for theinput-output profile for the fat tissue was developed by combining mechanistic knowledge withexisting and novel data from human fat cells. Finally, this detailed model was fitted to the profile of theoriginal fat model, and inserted in the whole-body model, with negligible effect on the whole-bodysimulations.

    The resulting model has the ability to translate mechanistically oriented simulations on the biochemicallevel, which is the level were drugs act, to the whole-body level, which is of clinical interest. This is aquantum leap forward for modeling, and understanding, glucose homeostasis and type 2 diabetes.

  • 44.
    Borg, Mathias
    Linköping University, Department of Physics, Chemistry and Biology.
    Study of the insulin-like peptide 3 in human platelets2009Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The insulin-like 3 peptide is autocrine/paracrine insulin-related hormone with a size of approximately 6kDa [1]. It mediates through a leucine richG-coupled receptor named LGR8. INSL3 is mainly expressed in human Leydig cells and is directly responsible for migration of the testis during the pre-natal period in maledevelopment. [2]

    INSL3 mRNA has recently been verified in human platelets whereas no mRNA has been detected for LGR8 (by Sanofi-Aventis GmbH in Frankfurt,Germany), indicating that INSL3 might be released through paracrine functions at sites of platelet adhesion and aggregation upon a vascular injury.Furthermore, has activated platelets been shown to translate essential proteins upon activation, in a term called “signal-dependent protein synthesis”.The B-Cell lymphoma-3 protein (BCL-3) is an example of such a protein [3], and there is a possibility that INSL3 might be also.

    In this thesis we wanted to detect the relaxin- like peptide 3 hormone (INSL3). (Its function, location and the timeframe of its release, when/if it issecreated in stimulated platelets).The source of platelet-derived INSL3 can be found with Western blotting and Enzyme immunoassay.

    Detection of the insulin-like 3 peptide in human platelets turned out to be a difficult challenge due to the small amount of INSL3 secretion uponplatelet activation; hence the total amount of INSL3 produced might be below detection limit.

  • 45.
    Permert, Johan
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Glucose metabolism in patients with exocrine pancreatic adenocarcinoma1993Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Carc.inoma of the exocrine pancreas is the fifth leading cause of cancer death in the Western world and the survival rate is one of the lowest for cancers of any site. Pancreatic cancer is characterized by pronounced, early cachexia and frequent metabolic complications. An increased incidence of diabetes or impaired glucose tolerance have been reported in pancreatic cancer patients. Two different hypotheses for this association have been presented, one suggesting that diabetes is a predisposing factor for pancreatic cancer and the other suggesting that the diabetic state is a consequence of the malignant disease.

    In the present study, 50 patients with exocrine pancreatic adenocarcinoma were studied, 11 of whom were found suitable for radical surgery. These eleven patients were studied both preoperatively and 3 months after subtotal pancreatectomy. Healthy subjects, patients with cancer of other sites and diabetic patients without any malignancy were investigated as controls. The incidence of diabetes and impaired glucose tolerance was investigated. Insulin secretion from pancreatic cancer patients was evaluated in the basal state, during hyperglycemia and after glucagon stimulation. Whole-body and peripheral insulin sensitivity were determined. The abundance and distribution pattern of endocrine cells, and the concentration of pancreatic islet hormones were investigated in control tissues ·and human exocrine pancreatic adenocarcinomas. The metabolic effect of extracts of these tumors on muscle glycogen synthesis was studied in vitro. Concentrations of islet hormones were determined in plasma in the basal state, during hyperglycemia and after stimulation by glucagon. Production of islet amyloid polypeptide (IAPP) was evaluated by studies of mRNA expression and peptide immunoreactivity in pancreatic adenocarcinomas, in tissue adjacent to the tumor and in normal pancreas.

    Diabetes or impaired glucose tolerance was found in 74% of the patients with pancreatic cancer, and this high frequency resulted mainly from newly-diagnosed diabetes. The diabetic state was more a consequence of profound insulin resistance rather than an impaired insulin secretion. After subtotal pancreatectomy, the diabetic state, glucose tolerance and insulin sensitivity were improved despite a marked decrease in insulinsecretion. Endocrine cells were found in 80% of the adenocarcinomas, predominantly in well-differentiated adenocarcinomas. Extracts from the tumors contained islet hormones, but in varying concentrations and without any correlation to diabetic state. Tumor extracts from diabetic but not from non-diabetic pancreatic cancer patients inhibited glycogen synthesis in skeletal muscle. This metabolic effect could not be explained by the concentrations of the diabetogenic peptides in the extracts. Plasma IAPP, glucagon and somatostatin were normalized after subtotal pancreatectomy. The pattern of hormonal changes seen was suggestive of a paracrine action of pancreatic adenocarcinomas on the adjacent pancreatic islets. This was supported by the normal IAPP mRNA-staining in the absence of IAPP-immunoreactivity in endocrine pancreatic tissues adjacent to the tumor. In conclusion, diabetes occurs with an increased frequency in patients with exocrine pancreatic adenocarcinoma. The diabetic state is closely related to the tumor itself and is a consequence rather then the cause of the malignant disease. Overall the results indicate that the diabetic state results from the tumor acting either directly or indirectly.

  • 46.
    Holmberg, Hanna
    et al.
    Linköping University, Department of Molecular and Clinical Medicine.
    Vaarala, Outi
    Ilonen, Jorma
    Ludvigsson, Johnny
    HLA haplotypes and insulin gene VNTR polymorphism in relation to markers of beta-cell autoimmunity in children from the general populationManuscript (Other academic)
  • 47.
    Ulfhielm, Erik
    Linköping University, Department of Electrical Engineering.
    Modeling of metabolic insulin signaling in adipocytes2006Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Active insulin receptors (IR) phosphorylate insulin receptor substrate (IRS), but it is not clear whether IRS is phosphorylated mainly by IR at the plasma membrane or by internalized IR in the cytosol. In this thesis, structural identifiability analysis and parameter sensitivity analysis is performed for models of the first steps in the metabolic insulin signaling pathway. In particular, the identifiability of the kinetic parameters governing IRS phosphorylation are investigated.

    Given measurements of the relative increase in phosphorylation degree of IR and IRS, the structural identifiability analysis revealed that the parameters governing IRS phosphorylation are non-identifiable, but their ratio is identifiable. This is sufficient to study whether phosphorylation of IRS proceeds more rapidly by IR at the plasma membrane or by internalized IR in the cytosol. In the examined model structure, internalization of insulin receptors is shown to be necessary to reproduce the experimental data.

    Sensitivity analysis of the parameters governing IRS phosphorylation showed that many parameters need to be known in order to obtain ``practical identifiability'' of the interesting parameters.

  • 48.
    Kannisto, Kristina
    Linköping University, The Department of Physics, Chemistry and Biology.
    Heat-sensitive TRP channels detected in pancreatic beta cells by microfluorometry and western blot2007Independent thesis Advanced level (degree of Magister), 20 points / 30 hpStudent thesis
    Abstract [en]

    Background and aim: The calcium ion (Ca2+) is an important ion involved in intracellular signalling. An increase in the free intracellular calcium concentration ([Ca2+]i) is essential for triggering insulin secretion from pancreatic beta cells. Beta cell death or disturbed insulin secretion are key factors in the pathogenesis of type 1 and type 2 diabetes respectively. A number of Ca2+ channels located on the plasma membrane or on the endoplasmic reticulum (ER) mediate Ca2+ increase in beta cells. Among the plasma membrane Ca2+ channels, members of the Transient Receptor Potential (TRP) family are currently of great interest. Transient Receptor Potential Vanilloid subtype 1 (TRPV1) is one of the 28 members of the TRP family. This ion channel is activated by heat and pungent chemicals like capsaicin. The main aim of this study was to investigate if functional TRPV1 channels are present in insulin secreting cells. Further more we examined if TRP channels could be studied by using microfluorometry in single cells. A third objective was to investigate if members of the TRP family could be identified by western blot.

    Methods: We used S5 cells, a highly differentiated rat insulinoma cell line, as a model of beta cells. A ratiometric fluorescence technique was used for measurement of [Ca2+]i concentration from single Fura-2 loaded cells. [Ca2+]i was measured continuously using microscope based fluorometry with the time resolution of 1 Hz. For western blot we used proteins extracted from S5 cells and human islets. The blots were probed with antibodies directed against both the N-terminal and the C-terminal end of the protein.

    Results: Capsaicin, an activator of TRPV1, increased [Ca2+]i in a dose-dependent manner with a half maximal effective concentration (EC50) ~ 100 nM. In nominally Ca2+ free buffer the capsaicin-induced [Ca2+]i increase was completely lost, while the intracellular depots of Ca2+ were not emptied as shown by administration of carbachol. The capsaicin-induced [Ca2+]i increase was completely blocked by capsazepine, an antagonist of TRPV1. An increase in temperature in the range of 43 – 49 °C increased [Ca2+]i, whereas temperatures < 42 °C did not. In nominally Ca2+ free medium the response to heat was reduced. Subsequent administration of carbachol showed that intracellular depots of Ca2+ were not emptied. Ruthenium red, an antagonist of TRPV1, also reduced the heat induced [Ca2+]i response. Another heat-sensitive, Ca2+ permeable protein Transient Receptor Potential Melastatin-like subtype 2 (TRPM2) was detected in S5 cells and human islets by western blot. The 171 kDa band represents the full length TRPM2 and is clearly visible in human islets, while the 95 KDa band represents the truncated form of TRPM2 and is more prominent in S5 cells.

    Interpretation and conclusions: Microscope based fluorometry is a powerful method for studying ion channels of the TRP family in single living cells. We found that pancreatic beta cells express functional TRPV1 channels that were activated by capsaicin and heat. TRPV1 channels of beta cells are located on the plasma membrane and not on the ER. TRP channel proteins can also be detected by the western blot technique. The ease of studying TRP channels by microfluorometry and our demonstration of functionalTRPV1 channels in beta cells paves the way for studying the role of these channels in insulin secretion and in the pathogenesis of diabetes.

  • 49.
    Salagic, Belma
    Linköping University, The Department of Physics, Chemistry and Biology.
    Enhanced amyloid fibril formation of insulin in contact with catalytic hydrophobic surfaces2007Independent thesis Basic level (degree of Bachelor), 10 points / 15 hpStudent thesis
    Abstract [en]

    The important protein hormone insulin, responsible for different kind of functions in our body but mainly storage of nutrients, has for a long time been used for treatment of diabetic patients. This important protein is both physically and chemically unstable. Especially during production where the insulin protein is exposed to unnatural environmental conditions such as acidic pH has this been causing problems since huge volumes of the product go to waste.

    In the human body the environment for the protein is tolerable with normal body temperature and the right pH, but when the protein is commercially synthesised the environmental conditions are not ultimate. What happens during these unfavourable conditions is that the insulin starts to fibrillate. Meaning that linear, biologically inactive aggregates are formed. If then under these kinds of conditions such as high temperature and acidic pH, the insulin comes in contact with hydrophobic surfaces then the fibrillation of the protein goes even faster.

    In the following experiment I am going to investigate if the experiments and conclusions done before, where different kinds of additives to insulin solutions have been used to enhance the amyloid fibrillation of insulin, are as effective as it has been proposed and I am going to prove that the presence of hydrophobic surfaces, such as coated silicon surfaces or glass and addition of preformed fibrils, so called seeds, increase amyloid fibrillation of the insulin protein under certain conditions, in comparison with the normal fibrillation under the same conditions.

  • 50.
    Bergenholm, Linnéa
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Health Sciences.
    Modeling as a Tool to Support Self-Management of Type 1 Diabetes2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Type 1 diabetes (T1D) is an auto-immune disease characterized by insulin-deficiency. Insulin is a metabolic hormone that is involved in lowering blood glucose (BG) levels in order to control BG level to a tight range. In T1D this glycemic control is lost, causing chronic hyperglycemia (excess glucose in blood stream). Chronic hyperglycemia damages vital tissues. Therefore, glycemic control must be restored.

    A common therapy for restoring glycemic control is intensive insulin therapy, where the missing insulin is replaced with regular insulin injections. When dosing this compensatory insulin many factors that affect glucose metabolism must be considered. Linkura is a company that has developed tools for monitoring the most important factors, which are meals and exercise. In the Linkura meal and exercise tools, the nutrition content in meals and the calorie consumption during exercise are estimated. Another tool designed to aid control of BG is the bolus calculator. Bolus calculators use input of BG level, carbohydrate intake, and insulin history to estimate insulin need. The accuracy of these insulin bolus calculations suffer from two problems. First, errors occur when users inaccurately estimate the carbohydrate content in meals. Second, exercise is not included in bolus calculations. To reduce these problems, it was suggested that the Linkura web tools could be utilized in combination with a bolus calculator.

    For this purpose, a bolus calculator was developed. The bolus calculator was based on existing models that utilize clinical parameters to relate changes in BG levels to meals, insulin, and exercise stimulations. The bolus calculator was evaluated using data collected from Linkura's web tools. The collected data showed some inconsistencies which cannot be explained by any model.  The performance of the bolus calculator in predicting BG levels using general equations to derive the clinical parameters was inadequate. Performance was increased by adopting an update-algorithm where the clinical parameters were updated daily using previous data. Still, better model performance is prefered for use in a bolus calculator.  

    The results show potential in developing bolus calculator tools combined with the Linkura tools. For such bolus calculator, further evaluation on modeling long-term exercise and additional safety features minimizing risk of hypoglycemia are required.

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