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  • 1.
    Abadpour, Shadab
    et al.
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Tyrberg, Bjorn
    AstraZeneca, Sweden.
    Schive, Simen W.
    Oslo Univ Hosp, Norway.
    Wennberg Huldt, Charlotte
    AstraZeneca, Sweden.
    Gennemark, Peter
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. AstraZeneca, Sweden.
    Ryberg, Erik
    AstraZeneca, Sweden.
    Ryden-Bergsten, Tina
    AstraZeneca, Sweden.
    Smith, David M.
    AstraZeneca, Sweden; AstraZeneca, England.
    Korsgren, Olle
    Uppsala Univ, Sweden.
    Skrtic, Stanko
    AstraZeneca, Sweden; Univ Gothenburg, Sweden.
    Scholz, Hanne
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Winzell, Maria Sorhede
    AstraZeneca, Sweden.
    Inhibition of the prostaglandin D-2-GPR44/DP2 axis improves human islet survival and function2020In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 63, no 7, p. 1355-1367Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Inflammatory signals and increased prostaglandin synthesis play a role during the development of diabetes. The prostaglandin D-2 (PGD(2)) receptor, GPR44/DP2, is highly expressed in human islets and activation of the pathway results in impaired insulin secretion. The role of GPR44 activation on islet function and survival rate during chronic hyperglycaemic conditions is not known. In this study, we investigate GPR44 inhibition by using a selective GPR44 antagonist (AZ8154) in human islets both in vitro and in vivo in diabetic mice transplanted with human islets. Methods Human islets were exposed to PGD(2) or proinflammatory cytokines in vitro to investigate the effect of GPR44 inhibition on islet survival rate. In addition, the molecular mechanisms of GPR44 inhibition were investigated in human islets exposed to high concentrations of glucose (HG) and to IL-1 beta. For the in vivo part of the study, human islets were transplanted under the kidney capsule of immunodeficient diabetic mice and treated with 6, 60 or 100 mg/kg per day of a GPR44 antagonist starting from the transplantation day until day 4 (short-term study) or day 17 (long-term study) post transplantation. IVGTT was performed on mice at day 10 and day 15 post transplantation. After termination of the study, metabolic variables, circulating human proinflammatory cytokines, and hepatocyte growth factor (HGF) were analysed in the grafted human islets. Results PGD(2) or proinflammatory cytokines induced apoptosis in human islets whereas GPR44 inhibition reversed this effect. GPR44 inhibition antagonised the reduction in glucose-stimulated insulin secretion induced by HG and IL-1 beta in human islets. This was accompanied by activation of the Akt-glycogen synthase kinase 3 beta signalling pathway together with phosphorylation and inactivation of forkhead box O-1and upregulation of pancreatic and duodenal homeobox-1 and HGF. Administration of the GPR44 antagonist for up to 17 days to diabetic mice transplanted with a marginal number of human islets resulted in reduced fasting blood glucose and lower glucose excursions during IVGTT. Improved glucose regulation was supported by increased human C-peptide levels compared with the vehicle group at day 4 and throughout the treatment period. GPR44 inhibition reduced plasma levels of TNF-alpha and growth-regulated oncogene-alpha/chemokine (C-X-C motif) ligand 1 and increased the levels of HGF in human islets. Conclusions/interpretation Inhibition of GPR44 in human islets has the potential to improve islet function and survival rate under inflammatory and hyperglycaemic stress. This may have implications for better survival rate of islets following transplantation.

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  • 2.
    Acerini, Carlo L.
    et al.
    University of Cambridge, England.
    Wac, Katarzyna
    University of Geneva, Switzerland.
    Bang, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Lehwalder, Dagmar
    Merck KGaA, Germany.
    Optimizing Patient Management and Adherence for children receiving Growth Hormone2017In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 8, article id 313Article in journal (Refereed)
    Abstract [en]

    Poor adherence with growth hormone (GH) therapy has been associated with worse clinical outcomes, which in children relates specifically to their linear growth and loss of quality of life. The "360 degrees GH in Europe" meeting, held in Lisbon, Portugal, in June 2016 and funded by Merck KGaA (Germany), examined many aspects of GH diseases. The three sessions, entitled "Short Stature Diagnosis and Referral," "Optimizing Patient Management," and "Managing Transition," each benefited from three guest speaker presentations, followed by an open discussion and are reported as a manuscript, authored by the speakers. Reported here is a summary of the proceedings of the second session, which reviewed the determinants of GH therapy response, factors affecting GH therapy adherence and the development of innovative technologies to improve GH treatment in children. Response to GH therapy varies widely, particularly in regard to the underlying diagnosis, although there is little consensus on the definition of a poor response. If the growth response is seen to be less than expected, the possible reasons should be discussed with patients and their parents, including compliance with the therapy regimen. Understanding and addressing the multiple factors that influence adherence, in order to optimize GH therapy, requires a multi-disciplinary approach. Because therapy continues over many years, various healthcare professionals will be involved at different periods of the patients journey. The role of the injection device for GH therapy, frequent monitoring of response, and patient support are all important for maintaining adherence. New injection devices are incorporating electronic technologies for automated monitoring and recording of clinically relevant information on injections. Study results are indicating that such devices can at least maintain GH adherence; however, acceptance of novel devices needs to be assessed and there remains an on-going need for innovations.

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  • 3.
    af Geijerstam, Peder
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum.
    Engvall, Jan
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Heart Center, Department of Clinical Physiology in Linköping.
    Östgren, Carl Johan
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Primary Care Center, Primary Health Care Center Ekholmen.
    Nyström, Fredrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum.
    Rådholm, Karin
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Kärna. The George Institute for Global Health, University of New South Wales, Sydney, Australia.
    Home Blood Pressure Compared With Office Blood Pressure in Relation to Dysglycemia2022In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 35, no 9, p. 810-819Article in journal (Refereed)
    Abstract [en]

    Background: Masked hypertension is more common in individuals with type 2 diabetes than in individuals with normoglycemia. We aimed to explore if there is a discrepancy between office blood pressure (office BP) and home blood pressure monitoring (HBPM) in relation to HbA1c as well as glycemic status in 5,029 middle-aged individuals.

    Methods: HBPM was measured in a subsample of 5,029 participants in The Swedish CardioPulmonary BioImage Study (SCAPIS), a population-based cohort of 50–64 years old participants. Both office BP and HBPM were obtained after 5 minutes’ rest using the semiautomatic Omron M10-IT oscillometric device. White coat effect was calculated by subtracting systolic HBPM from systolic office BP. Participants were classified according to glycemic status: Normoglycemia, prediabetes, or diabetes based on fasting glucose, HbA1c value, and self-reported diabetes diagnosis.

    Results: Of the included 5,025 participants, 947 (18.8%) had sustained hypertension, 907 (18.0%) reported taking antihypertensive treatment, and 370 (7.4%) had diabetes mellitus. Both systolic office BP and HBPM increased according to worsened glycemic status (P for trend 0.002 and 0.002, respectively). Masked hypertension was more prevalent in participants with dysglycemia compared with normoglycemia (P = 0.036). The systolic white coat effect was reversely associated with HbA1c (P = 0.012).

    Conclusions: The systolic white coat effect was reversely associated with HbA1c, and the prevalence of masked hypertension increased with dysglycemia.

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  • 4.
    af Geijerstam, Peder
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum.
    Janryd, Fredrik
    Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum.
    Nyström, Fredrik
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum. Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine.
    Smoking and cardiovascular disease in patients with type 2 diabetes: a prospective observational study2023In: Journal of Cardiovascular Disease, ISSN 2330-4596, E-ISSN 2330-460X, Vol. 24, no 11, p. 802-807Article in journal (Refereed)
    Abstract [en]

    Background

    Cigarette smoking is a major risk factor for cardiovascular disease. In type 2 diabetes mellitus (T2D), medications such as antihypertensives and statins can reduce the increased cardiovascular risk. The aim of this study was to evaluate the impact of cigarette smoking on major adverse cardiovascular event (MACE) and all-cause mortality in patients with T2D in a relatively well treated Swedish cohort.

    Methods

    Seven hundred and sixty-one patients with T2D aged 55–66 years were followed in the prospective observational CArdiovascular Risk factors in patients with DIabetes – a Prospective study in Primary care (CARDIPP) study. Baseline data included blood samples of markers of dysglycemia and inflammation, blood pressure as well as questionnaire responses regarding cigarette smoking. Participants were followed for incidence of MACE and all-cause mortality.

    Results

    Of the included 663 participants, the mean age was 60.6 (SD 3.1) years and 423 (63.8%) were men. Levels of C-reactive protein and vitamin D, as well as the proportion of participants treated with antihypertensives, acetylic salicylic acid, statins, and diabetes medications, were similar between smokers and nonsmokers. Median follow-up time was 11.9 (Q1–Q3 10.8–12.7) years. Cigarette smoking was associated with all-cause mortality [hazard ratio 2.24 (95% confidence interval, 95% CI 1.40–3.56), P < 0.001], but not MACE [hazard ratio 1.30 (95% CI 0.77–2.18), P = 0.328].

    Conclusion

    In patients with T2D, cigarette smoking was not associated with an increased risk of MACE. This raises the question of whether cardioprotective drugs in individuals with T2D to some degree mitigate the cardiovascular harm of smoking, even though they do not affect other dire consequences of smoking.

  • 5.
    af Geijerstam, Peder
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum.
    Joelsson, Annelie
    Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum.
    Rådholm, Karin
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Kärna.
    Nyström, Fredrik H
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum. Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine.
    A low dose of daily licorice intake affects renin, aldosterone, and home blood pressure in a randomized crossover trial2024In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207Article in journal (Refereed)
    Abstract [en]

    BackgroundLicorice, through the effects of glycyrrhizic acid (GA), raises blood pressure (BP). The World Health Organization has suggested that 100 mg GA/d would be unlikely to cause adverse effects, but of 13 previously published studies none have been randomized and controlled and independently quantified the GA content.

    Objective

    Our aim was to analyze the effects on home BP of a daily licorice intake containing 100 mg GA.

    Methods

    Healthy volunteers were randomly assigned to start with either licorice or a control product in a nonblinded, 2 × 2 crossover study. Home BP was measured daily, and blood samples were collected at the end of each 2-wk period.

    Results

    There were 28 participants and no dropouts. The median age was 24.0 y (interquartile range 22.8–27.0 y). During the licorice compared with control intake period, the systolic home BP increased [mean difference: 3.1 mm Hg (95% confidence interval [CI]: 0.8, 5.4 mm Hg) compared with −0.3 mm Hg (95% CI: −1.8, 1.3 mm Hg); P = 0.018] and renin and aldosterone were suppressed [mean change: −30.0% (95% CI: −56.7%, −3.3%) compared with 15.8% (95% CI: −12.8%, 44.4%); P = 0.003; and −45.1% (95% CI: −61.5%, −28.7%) compared with 8.2% (95% CI: −14.7%, 31.1%); P <0.001, respectively]. In the quartile of participants with the most pronounced suppression of renin and aldosterone, N-terminal prohormone of brain natriuretic peptide concentration increased during the licorice compared with control period [mean change: 204.1% (95% CI: −11.6%, 419.7%) compared with 72.4% (95% CI: −52.2%, 197.1%); P = 0.016].

    Conclusions

    We found licorice to be more potent than previously known, with significant increases in BP, after a daily intake of only 100 mg GA. Thus, the safe limit of intake of this substance might need to be reconsidered.

  • 6.
    Agebratt, Christian
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Ström, Edvin
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Romu, Thobias
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Dahlqvist Leinhard, Olof
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Borga, Magnus
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Leandersson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Nyström, Fredrik H.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    A Randomized Study of the Effects of Additional Fruit and Nuts Consumption on Hepatic Fat Content, Cardiovascular Risk Factors and Basal Metabolic Rate2016In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 1, p. e0147149-Article in journal (Refereed)
    Abstract [en]

    Background

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

    Objectives

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

    Methods

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

    Results

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

    Conclusions

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

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  • 7.
    Ahmadi, Shilan Seyed
    et al.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden; Uddevalla Cent Hosp, Sweden.
    Pivodic, Aldina
    Stat Konsultgrp, Sweden; Univ Gothenburg, Sweden.
    Svensson, Ann-Marie
    Ctr Registers Reg Vastra Gotaland, Sweden.
    Wedel, Hans
    Univ Gothenburg, Sweden.
    Rathsman, Björn
    Sachs Children & Youth Hosp, Sweden.
    Nyström, Thomas
    Karolinska Inst, Sweden.
    Ludvigsson, Johnny
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Lind, Marcus
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden; NU Hosp Grp, Sweden.
    Risk factors for nephropathy in persons with type 1 diabetes: a population-based study2022In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 59, p. 761-772Article in journal (Refereed)
    Abstract [en]

    Aims Albuminuria is strongly associated with risk of renal dysfunction, cardiovascular disease and mortality. However, clinical guidelines diverge, and evidence is sparse on what risk factor levels regarding blood pressure, blood lipids and BMI are needed to prevent albuminuria in adolescents and young adults with type 1 diabetes. Methods A total of 9347 children and adults with type 1 diabetes [mean age 15.3 years and mean diabetes duration 1.4 years at start of follow-up] from The Swedish National Diabetes Registry were followed from first registration until end of 2017. Levels for risk factors for a risk increase in nephropathy were evaluated, and the gradient of risk per 1 SD (standard deviation) was estimated to compare the impact of each risk factor. Results During the follow-up period, 8610 (92.1%) remained normoalbuminuric, 737 (7.9%) individuals developed micro- or macroalbuminuria at any time period of whom 132 (17.9% of 737) individuals developed macroalbuminuria. Blood pressure &gt;= 140/80 mmHg was associated with increased risk of albuminuria (p &lt;= 0.0001), as were triglycerides &gt;= 1.0 mmol/L (p = 0.039), total cholesterol &gt;= 5.0 mmol/L (p = 0.0003), HDL &lt; 1.0 mmol/L (p = 0.013), LDL 3.5- &lt; 4.0 mmol/L (p = 0.020), and BMI &gt;= 30 kg/m(2) (p = 0.033). HbA1c was the strongest risk factor for any albuminuria estimated by the measure gradient of risk per 1 SD, followed by diastolic blood pressure, triglycerides, systolic blood pressure, cholesterol and LDL. In patients with HbA1c &gt; 65 mmol/mol (&gt; 8.1%), blood pressure &gt; 140/70 mmHg was associated with increased risk of albuminuria. Conclusions Preventing renal complications in adolescents and young adults with type 1 diabetes need avoidance at relatively high levels of blood pressure, blood lipids and BMI, whereas very tight control is not associated with further risk reduction. For patients with long-term poor glycaemic control, stricter blood pressure control is advocated.

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  • 8.
    Akesson, K.
    et al.
    Jonköping University, Sweden; Jonköping University, Sweden; Jonköping University, Sweden.
    Tompa, A.
    Jonköping University, Sweden; Jonköping University, Sweden.
    Ryden, A.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Novo Nordisk Inc, WA USA.
    Faresjo, M.
    Jonköping University, Sweden; Jonköping University, Sweden; Jonköping University, Sweden.
    Low expression of CD39(+)/CD45RA(+) on regulatory T cells (T-reg) cells in type 1 diabetic children in contrast to high expression of CD101(+)/CD129(+) on T-reg cells in children with coeliac disease2015In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 180, no 1, p. 70-82Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes (T1D) and coeliac disease are both characterized by an autoimmune feature. As T1D and coeliac disease share the same risk genes, patients risk subsequently developing the other disease. This study aimed to investigate the expression of T helper (Th), T cytotoxic (Tc) and regulatory T cells (T-reg) in T1D and/or coeliac disease children in comparison to healthy children. Subgroups of T cells (Th:CD4(+) or Tc:CD8(+)); naive (CD27(+)CD28(+)CD45RA(+)CCR7(+)), central memory (CD27(+)CD28(+)CD45RA(-)CCR7(+)), effector memory (early differentiated; CD27(+)CD28(+)CD45RA(-)CCR7(-) and late differentiated; CD27(-)CD28(-)CD45RA(-)CCR7(-)), terminally differentiated effector cells (TEMRA; CD27(-)CD28(-)CD45RA(+)CCR7(-)) and T-reg (CD4(+)CD25(+)FOXP3(+)CD127(-)) cells, and their expression of CD39, CD45RA, CD101 and CD129, were studied by flow cytometry in T1D and/or coeliac disease children or without any of these diseases (reference group). Children diagnosed with both T1D and coeliac disease showed a higher percentage of TEMRA CD4(+) cells (Pless than005), but lower percentages of both early and late effector memory CD8(+) cells (Pless than005) compared to references. Children with exclusively T1D had lower median fluorescence intensity (MFI) of forkhead box protein 3 (FoxP3) (Pless than005) and also a lower percentage of CD39(+) and CD45RA(+) within the T-reg population (CD4(+)CD25(+)FOXP3(+)CD127(-)) (Pless than005). Children with exclusively coeliac disease had a higher MFI of CD101 (Pless than001), as well as a higher percentage of CD129(+) (Pless than005), in the CD4(+)CD25(hi) lymphocyte population, compared to references. In conclusion, children with combined T1D and coeliac disease have a higher percentage of differentiated CD4(+) cells compared to CD8(+) cells. T1D children show signs of low CD39(+)/CD45RA(+) T-reg cells that may indicate loss of suppressive function. Conversely, children with coeliac disease show signs of CD101(+)/CD129(+) T-reg cells that may indicate suppressor activity.

  • 9.
    Albanese-ONeill, Anastasia
    et al.
    Univ Florida, FL USA.
    Grimsmann, Julia M.
    Univ Ulm, Germany; German Ctr Diabet Res DZD, Germany.
    Svensson, Ann-Marie
    Ctr Registers Reg Vastra Gotaland, Sweden; Univ Gothenburg, Sweden.
    Miller, Kellee M.
    Jaeb Ctr Hlth Res, FL USA.
    Raile, Klemens
    Charite Univ Med Berlin, Germany.
    Åkesson, Karin
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Cty Hosp Ryhov, Sweden.
    Calhoun, Peter
    Jaeb Ctr Hlth Res, FL USA.
    Biesenbach, Beate
    Kepler Univ, Austria.
    Eeg-Olofsson, Katarina
    Univ Gothenburg, Sweden.
    Holl, Reinhard W.
    Univ Ulm, Germany; German Ctr Diabet Res DZD, Germany.
    Maahs, David M.
    Stanford Diabet Res Ctr, CA USA; Stanford Univ, CA USA.
    Hanas, Ragnar
    NU Hosp Grp, Sweden; Univ Gothenburg, Sweden.
    Changes in HbA1c Between 2011 and 2017 in Germany/Austria, Sweden, and the United States: A Lifespan Perspective2022In: Diabetes Technology & Therapeutics, ISSN 1520-9156, E-ISSN 1557-8593, Vol. 24, no 1, p. 32-41Article in journal (Refereed)
    Abstract [en]

    Aims: This study assessed hemoglobin A1c (HbA1c) across the lifespan in people with type 1 diabetes (T1D) in Germany/Austria, Sweden, and the United States between 2011 and 2017 to ascertain temporal and age-related trends. Methods: Data from the Diabetes-Patienten-Verlaufsdokumentation (DPV) (n = 25,651 in 2011, n = 29,442 in 2017); Swedish Pediatric Diabetes Quality Registry (SWEDIABKIDS)/National Diabetes Register (NDR), (n = 44,474 in 2011, n = 53,690 in 2017); and T1D Exchange (n = 16,198 in 2011, n = 17,087 in 2017) registries were analyzed by linear regression to compare mean HbA1c overall and by age group. Results: Controlling for age, sex, and T1D duration, HbA1c increased in the United States between 2011 and 2017, decreased in Sweden, and did not change in Germany/Austria. Controlling for sex and T1D duration, mean HbA1c decreased between 2011 and 2017 in all age cohorts in Sweden (P &lt; 0.001). In the United States, HbA1c stayed the same for participants &lt;6 years and 45 to &lt;65 years and increased in all other age groups (P &lt; 0.05). In Germany/Austria, HbA1c stayed the same for participants &lt;6 to &lt;13 years and 18 to &lt;25 years; decreased for participants ages 13 to &lt;18 years (P &lt; 0.01); and increased for participants &gt;= 25 years (P &lt; 0.05). Conclusions: The comparison of international trends in HbA1c makes it possible to identify differences, explore underlying causes, and share quality improvement processes. National quality improvement initiatives are well accepted in Europe but have yet to be implemented systematically in the United States. However, disparities created by the lack of universal access to health care coverage, unequal access to diabetes technologies (e.g., continuous glucose monitoring) regardless of insurance status, and high out-of-pocket cost for the underinsured ultimately limit the potential of quality improvement initiatives.

  • 10.
    Albinsson-Stenholm, Erina
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Bergsen, Johannes
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Ingues, Simon
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Vilhelmsson, Nathalie
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Guldbrand, Hans
    Region Östergötland, Local Health Care Services in West Östergötland, "Primary Health Care in Motala". Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Nyström, Fredrik H
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum, Norrköping.
    Subjects with high fasting insulin also have higher postprandial GLP-1 and glucagon levels than controls with lower insulin2019In: Nutrition Research, ISSN 0271-5317, E-ISSN 1879-0739, Vol. 72, p. 111-120Article in journal (Refereed)
    Abstract [en]

    Little is known about postprandial release of serum ghrelin, glucagon, and glucagon-like peptide-1 (GLP-1) in relation with differing fasting insulin levels. We hypothesized that these hormones are affected by insulin resistance, and hence, we compared different postprandial responses of GLP-1, glucagon, and ghrelin in subjects with relatively high (RHI) or relatively low (RLI) fasting insulin levels. The trial was a randomized crossover study with 4 different meal conditions. Fourteen nonobese or obese, healthy, men and 14 women were randomly assigned to the order of supervised intake of a 750 kcal drink with the same protein contents but with 20 energy-percent (E%) or 55 E% from carbohydrates, and the remaining energy from fat. Participants were also randomized to consume the drinks as 1 large beverage or as five 150-kcal portions every 30 minutes. The 28 subjects were divided into 2 equally sized groups based on fasting insulin levels. Statistics were done with general linear mixed model. Fasting insulin levels were 3-fold higher in the group with RHI compared with the RLI group (RHI: 1004 +/- 510 pg/mL, RLI: 324 +/- 123 pg/mL, P amp;lt; .0005). Serum GLP-1 was highest in the RHI group after both single meals and after 5 drinks and following high- and low-carbohydrate meals (both P amp;lt;= .002), and this was the case also for glucagon levels (both P amp;lt;= .018), whereas ghrelin levels did not differ between groups. Thus, subjects with RHI displayed both higher postprandial serum GLP-1 and glucagon than the participants with RLI, suggesting that glucagon could play a role in the advent of dysglycemia by insulin resistance. (C) 2019 Elsevier Inc. All rights reserved.

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  • 11.
    Alfredsson, Joakim
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Duke Univ, NC USA.
    Green, Jennifer B.
    Duke Univ, NC USA.
    Stevens, Susanna R.
    Duke Univ, NC USA.
    Reed, Shelby D.
    Duke Univ, NC USA.
    Armstrong, Paul W.
    Univ Alberta, Canada.
    Bethel, M. Angelyn
    Univ Oxford, England.
    Engel, Samuel S.
    Merck and Co Inc, NJ USA.
    McGuire, Darren K.
    Univ Texas Southwestern Med Ctr Dallas, TX 75390 USA.
    Van de Werf, Frans
    Univ Leuven, Belgium.
    Hramiak, Irene
    Univ Western Ontario, Canada.
    White, Harvey D.
    Auckland City Hosp, New Zealand.
    Peterson, Eric D.
    Duke Univ, NC USA.
    Holman, Rury R.
    Univ Oxford, England.
    Sex differences in management and outcomes of patients with type 2 diabetes and cardiovascular disease: A report from TECOS2018In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 20, no 10, p. 2379-2388Article in journal (Refereed)
    Abstract [en]

    Aim: To examine sex differences in baseline characteristics and outcomes in patients with type 2 diabetes and atherosclerotic vascular disease. Materials and methods: Cox models were used to analyse the association between sex and outcomes in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, placebo-controlled trial assessing the impact of sitagliptin on cardiovascular (CV) outcomes in patients with type 2 diabetes and atherosclerotic vascular disease. Results: A total of 4297 women and 10 374 men were followed for a median of 3.0 years. Women were slightly older and more often had cerebrovascular disease and peripheral arterial disease but less often coronary heart disease than men. At baseline, women were less likely to use aspirin or statins. The primary composite outcome of CV death, myocardial infarction, stroke, or hospitalization for unstable angina occurred in 418 women (9.7%) and 1272 men (12.3%; 3.48 vs 4.38 events/100 participant-years, crude hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.71-0.89, adjusted HR 0.64, 95% CI 0.55-0.74; P amp;lt; .0001). Women also had a significantly lower risk of secondary CV outcomes and all-cause death. Conclusions: In this large prospective study of people with type 2 diabetes and CV disease, women had different CV disease burden, worse CV risk factor profiles, and less use of indicated medications than men. Despite this, women had significantly lower risk of CV events, suggesting that the cardioprotective effects of female sex extend to populations with type 2 diabetes.

  • 12.
    Andelin, M.
    et al.
    Department of Medicine, NU Hospital Group, Uddevalla, Sweden..
    Kropff, J.
    Department of Endocrinology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands..
    Matuleviciene, V.
    Institute of Medicine, University of Gothenburg, Gothenburg, Sweden..
    Joseph, J.I.
    Department of Anaesthesiology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, USA..
    Attvall, S.
    Institute of Medicine, University of Gothenburg, Gothenburg, Sweden..
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Hirsch, I.B.
    University of Washington, Seattle, WA, USA.
    Imberg, H.
    Statistiska Konsultgruppen, Gothenburg, Sweden..
    Dahlqvist, S.
    Department of Medicine, NU Hospital Group, Uddevalla, Sweden.
    Klonoff, D.
    Diabetes Research Institute, Mills-Peninsula Health Services, San Mateo, CA, USA..
    Haraldsson, B.
    Institute of Medicine, University of Gothenburg, Gothenburg, Sweden..
    DeVries, J.H.
    Department of Endocrinology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands..
    Lind, M.
    Department of Medicine, NU Hospital Group, Uddevalla, Sweden Institute of Medicine, University of Gothenburg, Gothenburg, Sweden lind.marcus@telia.com..
    Assessing the Accuracy of Continuous Glucose Monitoring (CGM) Calibrated With Capillary Values Using Capillary or Venous Glucose Levels as a Reference.2016In: Journal of Diabetes Science and Technology, E-ISSN 1932-2968, Vol. 10, no 4, p. 876-884Article in journal (Refereed)
    Abstract [en]

    Background: Using the standard venous reference for the evaluation of continuous glucose monitoring (CGM) systems could possibly negatively affect measured CGM accuracy since CGM are generally calibrated with capillary glucose and venous and capillary glucose concentrations differ. We therefore aimed to quantify the effect of using capillary versus venous glucose reference samples on estimated accuracy in capillary calibrated CGM.less thanbr /greater thanMethods: We evaluated 41 individuals with type 1 diabetes mellitus (T1DM) using the Dexcom G4 CGM system over 6 days. Patients calibrated their CGM devices with capillary glucose by means of the HemoCue system. During 2 visits, capillary and venous samples were simultaneously measured by HemoCue and compared to concomitantly obtained CGM readings. The mean absolute relative difference (MARD) was calculated using capillary and venous reference samples.less thanbr /greater thanResults: Venous glucose values were 0.83 mmol/L (15.0 mg/dl) lower than capillary values over all glycemic ranges, P less than .0001. Below 4 mmol/l (72 mg/dl), the difference was 1.25 mmol/l (22.5 mg/dl), P = .0001, at 4-10 mmol/l (72-180 mg/dl), 0.67 mmol/l (12.0 mg/dl), P less than .0001 and above 10 mmol/l (180 mg/dl), 0.95 mmol/l (17.1 mg/dl), P less than .0001. MARD was 11.7% using capillary values as reference compared to 13.7% using venous samples, P = .037. Below 4 mmol/l (72 mg/dl) MARD was 16.6% and 31.8%, P = .048, at 4-10 mmol/l (72-180 mg/dl) 12.1% and 12.6%, P = .32, above 10 mmol/l (180 mg/dl) 8.7% and 9.2%, P = .82.less thanbr /greater thanConclusion: Using capillary glucose concentrations as reference to evaluate the accuracy of CGM calibrated with capillary samples is associated with a lower MARD than using venous glucose as the reference. Capillary glucose concentrations were significantly higher than venous in all glycemic ranges.less thanbr /greater than (© 2016 Diabetes Technology Society.)

  • 13. Order onlineBuy this publication >>
    Anderzén, Johan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Differences in glycemic control in type 1 diabetes children and adolescents: in a national and international perspective and the effect on microvascular complications in young adults2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis focuses on glycemic control measured as HbA1c in type 1 diabetes (T1D) patients during childhood and especially during adolescence, both in a Swedish and an international context, and relates the glycemic control to the risk of complications in young adults.  

    In studies I and II, the Swedish Pediatric Diabetes Quality Register (SWEDIABKIDS) and the Swedish National Diabetes Register (NDR) were used. More than 4000 young adults with T1D and data on HbA1c in NDR both in 2011 and 2012 as well as data on HbA1c in SWEDIABKIDS were used. The T1D patients with poor glycemic control during their teenage period had a risk for retinopathy several times higher than those with good glycemic control. The risk for micro- and macroalbuminuria was also higher in those with poor glycemic control and was most pronounced in the T1D patients with high HbA1c in both registers. Females had worse glycemic control than males during the teenage period and an increased risk of retinopathy as young adults.  

    In studies III and IV, pediatric diabetes quality register data from, respectively, eight and seven Western high-income countries were collected in the year 2013. Data on about 60 000 T1D patients were analyzed according to mean HbA1c levels in the countries and related to actual age and T1D duration to determine if there were differences in glycemic control between the countries. There were large differences in mean HbA1c between the countries, both when related to age and T1D duration. Despite the differences in mean HbA1c, the increase in mean HbA1c with increasing age and T1D duration was very similar in all countries.  

    The overall picture of these studies is that good glycemic control is very important to avoid complications of T1D as young adults, and it seems particularly important to maintain a good glycemic control during adolescence. Furthermore large differences in glycemic control in T1D patients in Western high-income countries were found. Despite the differences in glycemic control, the pattern of rising HbA1c with increasing age and duration of T1D was very similar in all countries. Females have worse glycemic control than males during their teenage period, both in Sweden and internationally, and they also have more retinopathy as young adults.   

    This thesis shows that it is of the utmost importance to treat T1D patients intensively directly after diagnosis, to treat the young T1D patients intensely and to reduce the rise in HbA1c with increasing age and duration of T1D in order to avoid complications early in life. Diabetes quality registers give the opportunity to compare results and share experiences, both within and between countries, so treatment of T1D can be designed in the best possible way and thereby minimize T1D complications. 

    List of papers
    1. Teenagers with poor metabolic control already have a higher risk of microvascular complications as young adults
    Open this publication in new window or tab >>Teenagers with poor metabolic control already have a higher risk of microvascular complications as young adults
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    2016 (English)In: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Vol. 30, no 3, p. 533-536Article in journal (Refereed) Published
    Abstract [en]

    Aims: To evaluate how HbA1c in adolescents with type 1 diabetes affects microvascular complications in young adults. Methods: All individuals registered in the Swedish paediatric diabetes quality registry (SWEDIABKIDS) 13-18 years of age, and as adults registered in the Swedish National Diabetes Registry (NDR) in both the years 2011 and 2012 were included, in total 4250 individuals. Results: Of the individuals with mean HbA1c &gt;78 mmol/mol in SWEDIABKIDS 83.4% had retinopathy, 15.8% had microalbuminuria and 4.9% had macroalbuminuria in NDR. The logistic regression analysis showed that the OR to develop macroalbuminuria as a young adult was significantly higher in the group with mean HbA1c &gt;78 mmol/mol in SWEDIABKIDS (p &lt; 0.05). Among the patients with mean HbA1c above 78 mmol/mol in both registries there was a significantly higher proportion that had retinopathy, microalbuminuria (p &lt; 0.001) and/or macroalbuminuria (p &lt; 0.01) compared to the group with HbA1c below 57 mmol/mol in both registries. Only 6.5% of the persons in this study were over 30 years of age. Conclusions: Paediatric diabetes teams working with teenagers must be aware of the impact of good metabolic control during adolescence, and should intensify the care during this vulnerable period of life to reduce the risk of microvascular complications in young adults.

    Place, publisher, year, edition, pages
    ELSEVIER SCIENCE INC, 2016
    Keywords
    Type 1 diabetes; Teenagers; National quality register; Metabolic control; Microvasular complications
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-127423 (URN)10.1016/j.jdiacomp.2015.12.004 (DOI)000372940300024 ()26775554 (PubMedID)
    Note

    Funding Agencies|Ostergotland County Council; Futurum the Academy for Health and Care; Jonkoping County Council; FORSS- Medical Research Council of Southeast Sweden

    Available from: 2016-05-01 Created: 2016-04-26 Last updated: 2023-02-22
    2. Teenage girls with type 1 diabetes have poorer metabolic control than boys and face more complications in early adulthood
    Open this publication in new window or tab >>Teenage girls with type 1 diabetes have poorer metabolic control than boys and face more complications in early adulthood
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    2016 (English)In: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Vol. 30, no 5, p. 917-922Article in journal (Refereed) Published
    Abstract [en]

    Aims: To compare metabolic control between males and females with type 1 diabetes during adolescence and as young adults, and relate it to microvascular complications. Methods: Data concerning 4000 adolescents with type 1 diabetes registered in the Swedish paediatric diabetes quality registry, and above the age of 18 years in the Swedish National Diabetes Registry was used. Results: When dividing HbA1c values in three groups; amp;lt; 7.4% (57 mmol/mol), 7.4-93% (57-78 mmol/mol) and amp;gt;9.3% (78 mmol/mol), there was a higher proportion of females in the highest group during adolescence. In the group with the highest HbA1c values during adolescence and as adults, 51.7% were females, expected value 46.2%; in the group with low HbA1c values in both registries, 34.2% were females, p amp;lt; 0.001. As adults, more females had retinopathy, p amp;lt; 0.05. Females had higher mean HbAlc values at diagnosis, 112 vs. 10.9% (99 vs. 96 mmol/mol), p amp;lt; 0.03, during adolescence, 8.5 vs. 82% (69 vs. 66 mmol/mol) p amp;lt; 0.01, but not as young adults. Conclusions: Worse glycaemic control was found in adolescent females, and they had a higher frequency of microvascular complications. Improved paediatric diabetes care is of great importance for increasing the likelihood of lower mortality and morbidity later in life. (C) 2016 Elsevier Inc. All rights reserved.

    Place, publisher, year, edition, pages
    ELSEVIER SCIENCE INC, 2016
    Keywords
    HbA1c; Type 1 diabetes; Gender; Microvascular complications; Quality of care
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:liu:diva-130403 (URN)10.1016/j.jdiacomp.2016.02.007 (DOI)000378759700028 ()27052153 (PubMedID)
    Note

    Funding Agencies|Association of Local Authorities and Regions, SALAR; Futurum - Academy for Health and Care, Jonkoping County Council, Sweden

    Available from: 2016-08-15 Created: 2016-08-05 Last updated: 2023-02-22
    3. International benchmarking in type 1 diabetes: Large difference in childhood HbA1c between eight high-income countries but similar rise during adolescence-A quality registry study
    Open this publication in new window or tab >>International benchmarking in type 1 diabetes: Large difference in childhood HbA1c between eight high-income countries but similar rise during adolescence-A quality registry study
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    2020 (English)In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 21, no 4, p. 621-627Article in journal (Refereed) Published
    Abstract [en]

    Objectives To identify differences and similarities in HbA1c levels and patterns regarding age and gender in eight high-income countries. Subjects 66 071 children and adolescents below18 years of age with type 1 diabetes for at least 3 months and at least one HbA1c measurement during the study period. Methods Pediatric Diabetes Quality Registry data from Austria, Denmark, England, Germany, Norway, Sweden, the United States, and Wales were collected between 2013 and 2014. HbA1c, gender, age, and duration were used in the analysis. Results Distribution of gender and age groups was similar in the eight participating countries. The mean HbA1c varied from 60 to 73 mmol/mol (7.6%-8.8%) between the countries. The increase in HbA1c between the youngest (0-9 years) to the oldest (15-17 years) age group was close to 8 mmol/mol (0.7%) in all countries (P &lt; .001). Females had a 1 mmol/mol (0.1%) higher mean HbA1c than boys (P &lt; .001) in seven out of eight countries. Conclusions In spite of large differences in the mean HbA1c between countries, a remarkable similarity in the increase of HbA1c from childhood to adolescence was found.

    Place, publisher, year, edition, pages
    WILEY, 2020
    Keywords
    adolescents; children; HbA1c; quality registry; type 1 diabetes
    National Category
    Pediatrics
    Identifiers
    urn:nbn:se:liu:diva-165402 (URN)10.1111/pedi.13014 (DOI)000525890100001 ()32249476 (PubMedID)
    Note

    Funding Agencies|England Department of Health Policy Research Programme; EU-IMI2 consortium INNODIA; European Foundation for the Study of Diabetes; Futurum Academy for Health and Care; German Centre for Diabetes Research; German Diabetes Association; Health Research Fund of Central Denmark Region; Helmsley Charitable Trust; National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London; Welsh Government; South-Eastern Norway Regional Health Authority; Swedish Association of Local Authorities and Regions (SALAR); NHS England

    Available from: 2020-04-30 Created: 2020-04-30 Last updated: 2023-02-22Bibliographically approved
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  • 14.
    Andreas, Svensson
    Linköping University, Department of Electrical Engineering, Automatic Control. Linköping University, The Institute of Technology.
    Model Predictive Control with Invariant Sets in Artificial Pancreas for Type 1 Diabetes Mellitus2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    This thesis deals with Model Predictive Control (MPC) for artificial pancreas for Type 1 Diabetes Mellitus patients. A control strategy exploiting invariant sets in MPC for blood glucose level control is developed, to the authors knowledge for the first time. The work includes various types of invariant sets relevant for the artificial pancreas problem, and different ways to incorporate them into the MPC strategy. The work is an extension to the zone MPC controller for artificial pancreas developed at University of California Santa Barbara and Sansum Diabetes Research Institute.

    The evaluation of the proposed control strategy is done in silico in the U.S. Food and Drug Administration approved metabolic simulator. The trials show some promising results in terms of more rapid meal responses and decreased variability between the subjects than the zone MPC. An attempt to robust control employing invariant sets proved to be less promising in the evaluations. The results indicate that the direct application of known robust control techniques is not appropriate, and that more appropriate robust control techniques must be searched for, or developed, more specific to the artificial pancreas control.

    Altogether, this thesis pinpoints a possible future direction of artificial pancreas control design, with MPC based on invariant sets.

    Download full text (pdf)
    AndreasSvensson_ModelPredictiveControlwithInvariantSetsinArtificialPancreasforType1DiabetesMellitus
  • 15.
    Arnqvist, Hans
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology.
    Westerlund, Malin C.
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Fredrikson, Mats
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Nordwall, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Norrköping.
    Impact of HbA(1c) Followed 32 Years From Diagnosis of Type 1 Diabetes on Development of Severe Retinopathy and Nephropathy: The VISS Study2022In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 45, no 11, p. 2675-2682Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE To evaluate HbA(1c) followed from diagnosis, as a predictor of severe microvascular complications (i.e., proliferative diabetic retinopathy [PDR] and nephropathy [macroalbuminuria]). RESEARCH DESIGN AND METHODS In a population-based observational study, 447 patients diagnosed with type 1 diabetes before 35 years of age from 1983 to 1987 in southeast Sweden were followed from diagnosis until 2019. Long-term weighted mean HbA(1c) (wHbA(1c)) was calculated by integrating the area under all HbA(1c) values. Complications were analyzed in relation to wHbA(1c) categorized into five levels. RESULTS After 32 years, 9% had no retinopathy, 64% non-PDR, and 27% PDR, and 83% had no microalbuminuria, 9% microalbuminuria, and 8% macroalbuminuria. Patients with near-normal wHbA(1c) did not develop PDR or macroalbuminuria. The lowest wHbA(1c) values associated with development of PDR and nephropathy (macroalbuminuria) were 7.3% (56 mmol/mol) and 8.1% (65 mmol/mol), respectively. The prevalence of PDR and macroalbuminuria increased with increasing wHbA(1c), being 74% and 44% in the highest category, wHbA(1c) &gt;9.5% (&gt;80 mmol/mol). In comparison with the follow-up done after 20-24 years duration, the prevalence of PDR had increased from 14 to 27% and macroalbuminuria from 4 to 8%, and both appeared at lower wHbA(1c) values. CONCLUSIONS wHbA(1c) followed from diagnosis is a very strong biomarker for PDR and nephropathy, the prevalence of both still increasing 32 years after diagnosis. To avoid PDR and macroalbuminuria in patients with type 1 diabetes, an HbA(1c) &lt;7.0% (53 mmol/mol) and as normal as possible should be recommended when achievable without severe hypoglycemia and with good quality of life.

  • 16.
    Aydemir, Ozkan
    et al.
    Univ Massachusetts, MA USA.
    Noble, Janelle A.
    Childrens Hosp Oakland, CA 94609 USA.
    Bailey, Jeffrey A.
    Univ Massachusetts, MA USA.
    Lernmark, Ake
    Lund Univ, Sweden.
    Marsh, Patrick
    Univ Massachusetts, MA USA.
    Svard, Agnes Andersson
    Lund Univ, Sweden.
    Bearoff, Frank
    Drexel Univ, PA 19104 USA.
    Blankenhorn, Elizabeth P.
    Drexel Univ, PA 19104 USA.
    Mordes, John P.
    Univ Massachusetts, MA 01655 USA.
    Persson, Martina
    Karolinska Univ Hosp, Sweden.
    Larsson, Helena Elding
    Lund Univ, Sweden.
    Forsander, Gun
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Ivarsson, Sten-Anders
    Lund Univ, Sweden.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Marcus, Claude
    Karolinska Inst, Sweden.
    Carlsson, Annelie
    Lund Univ, Sweden.
    Genetic Variation Within the HLA-DRA1 Gene Modulates Susceptibility to Type 1 Diabetes in HLA-DR3 Homozygotes2019In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 68, no 7, p. 1523-1527Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes (T1D) involves the interaction of multiple gene variants, environmental factors, and immunoregulatory dysfunction. Major T1D genetic risk loci encode HLA-DR and -DQ. Genetic heterogeneity and linkage disequilibrium in the highly polymorphic HLA region confound attempts to identify additional T1D susceptibility loci. To minimize HLA heterogeneity, T1D patients (N = 365) and control subjects (N = 668) homozygous for the HLA-DR3 high-risk haplotype were selected from multiple large T1D studies and examined to identify new T1D susceptibility loci using molecular inversion probe sequencing technology. We report that risk for T1D in HLA-DR3 homozygotes is increased significantly by a previously unreported haplotype of three single nucleotide polymorphisms (SNPs) within the first intron of HLA-DRA1. The homozygous risk haplotype has an odds ratio of 4.65 relative to the protective homozygous haplotype in our sample. Individually, these SNPs reportedly function as "expression quantitative trait loci," modulating HLA-DR and -DQ expression. From our analysis of available data, we conclude that the tri-SNP haplotype within HLA-DRA1 may modulate class II expression, suggesting that increased T1D risk could be attributable to regulated expression of class II genes. These findings could help clarify the role of HLA in T1D susceptibility and improve diabetes risk assessment, particularly in high-risk HLA-DR3 homozygous individuals.

  • 17.
    Badian, Reza A.
    et al.
    Oslo Univ Hosp, Norway.
    Ekman, Linnea
    Lund Univ, Sweden.
    Pripp, Are Hugo
    Oslo Univ Hosp, Norway.
    Utheim, Tor Paaske
    Oslo Univ Hosp, Norway; Sorlandet Hosp Arendal, Norway.
    Englund, Elisabet
    Lund Univ, Sweden.
    Dahlin, Lars
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Rolandsson, Olov
    Umea Univ, Sweden.
    Lagali, Neil
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Sorlandet Hosp Arendal, Norway.
    Comparison of Novel Wide-Field In Vivo Corneal Confocal Microscopy With Skin Biopsy for Assessing Peripheral Neuropathy in Type 2 Diabetes2023In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 72, no 7, p. 908-917Article in journal (Refereed)
    Abstract [en]

    Diabetic peripheral neuropathy (DPN) is a serious complication of diabetes, where skin biopsy assessing intraepidermal nerve fiber density (IENFD) plays an important diagnostic role. In vivo confocal microscopy (IVCM) of the corneal subbasal nerve plexus has been proposed as a noninvasive diagnostic modality for DPN. Direct comparisons of skin biopsy and IVCM in controlled cohorts are lacking, as IVCM relies on subjective selection of images depicting only 0.2% of the nerve plexus. We compared these diagnosticmodalities in a fixed-age cohort of 41 participants with type 2 diabetes and 36 healthy participants using machine algorithms to create wide-field image mosaics and quantify nerves in an area 37 times the size of prior studies to avoid human bias. In the same participants, and at the same time point, no correlation between IENFD and corneal nerve densitywas found. Corneal nerve density did not correlate with clinicalmeasures of DPN, including neuropathy symptom and disability scores, nerve conduction studies, or quantitative sensory tests. Our findings indicate that corneal and intraepidermal nerves likely mirror different aspects of nerve degeneration, where only intraepidermal nerves appear to reflect the clinical status of DPN, suggesting that scrutiny is warranted concerning methodologies of studies using corneal nerves to assess DPN.

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    fulltext
  • 18.
    Baldimtsi, Evangelia
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine and Geriatrics.
    Whiss, Per A
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology.
    Wahlberg, Jeanette
    Department of Medicine, Örebro University Hospital, Örebro, Sweden; Faculty of Medical Sciences, Örebro University, Örebro, Sweden.
    Systemic biomarkers of microvascular alterations in type 1 diabetes associated neuropathy and nephropathy - A prospective long-term follow-up study2023In: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, article id 108635Article in journal (Refereed)
    Abstract [en]

    Introduction

    This study aimed to investigate circulating biomarkers associated with the risk of developing diabetic peripheral neuropathy (DPN) and nephropathy in type 1 diabetes (T1D).

    Materials and methods

    Patients with childhood-onset T1D (n = 49, age 38.3 ± 3.8 yrs.) followed prospectively were evaluated after 30 years of diabetes duration. DPN was defined as an abnormality in nerve conduction tests. Matrix metalloproteinase-9 (MMP-9) and its tissue inhibitor TIMP-1, neutrophil gelatinase-associated lipocalin-2 (NGAL), soluble P-selectin (sP-selectin), estimated GFR (eGFR), micro/macroalbuminuria and routine biochemistry were assessed. For comparison, control subjects were included (n = 30, age 37.9 ± 5.5 yrs.).

    Results

    In all, twenty-five patients (51 %) were diagnosed with DPN, and nine patients (18 %) had nephropathy (five microalbuminuria and four macroalbuminuria). Patients with DPN had higher levels of TIMP-1 (p = 0.036) and sP-selectin (p = 0.005) than controls. Patients with DPN also displayed higher levels of TIMP-1 compared to patients without DPN (p = 0.035). Patients with macroalbuminuria had kidney disease stage 3 with lower eGFR, higher levels of TIMP-1 (p = 0.038), and NGAL (p = 0.002). In all patients, we found only weak negative correlations between eGFR and TIMP-1 (rho = −0.304, p = 0.040) and NGAL (rho = −0.277, p = 0.062, ns), respectively. MMP-9 was higher in patients with microalbuminuria (p = 0.021) compared with normoalbuminuric patients.

    Conclusions

    Our findings indicate that TIMP-1 and MMP-9, as well as sP-selectin and NGAL, are involved in microvascular complications in T1D. Monitoring and targeting these biomarkers may be a potential strategy for treating diabetic nephropathy and neuropathy.

  • 19.
    Bang, Peter
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Polak, Michel
    Hop Univ Necker Enfants Malad, France; France Univ Paris Cite, France.
    Bossowski, Artur
    Med Univ Bialystok, Poland.
    Maghnie, Mohamad
    IRCCS Ist Giannina Gaslini, Italy; Univ Genoa, Italy.
    Argente, Jesus
    Univ Nino Jesus, Spain; Univ Autonoma Madrid, Spain; Inst Salud Carlos III, Spain; IMDEA Food Inst, Spain.
    Ramon-Krauel, Marta
    Hosp St Joan De Deu, Spain; Inst Salud Carlos III, Spain.
    Sert, Caroline
    Ipsen Pharma, France.
    Perrot, Valerie
    Ipsen Pharma, France.
    Mazain, Sarah
    Ipsen Pharma, France.
    Woelfle, Joachim
    Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany; Friedrich Alexander Univ FAU Erlangen Nurnberg, Germany.
    Frequency and Predictive Factors of Hypoglycemia in Patients Treated With rhIGF-1: Data From the Eu-IGFD Registry2024In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 109, no 1, p. 46-56Article in journal (Refereed)
    Abstract [en]

    Context The European Increlex & REG; Growth Forum Database (Eu-IGFD) is an ongoing surveillance registry (NCT00903110) established to collect long-term safety and effectiveness data on the use of recombinant human insulin-like growth factor-1 (rhIGF-1, mecasermin, Increlex) for the treatment of children/adolescents with severe primary insulin-like growth factor-1 deficiency (SPIGFD).Objective This analysis of Eu-IGFD data aimed to identify the frequency and predictive factors for hypoglycemia adverse events (AEs) in children treated with rhIGF-1.Methods Data were collected from December 2008 to May 2021. Logistic regression was performed to identify predictive risk factors for treatment-induced hypoglycemia AEs. Odds ratios (ORs) are presented with 95% CIs for each factor.Results In total, 306 patients were enrolled in the registry; 84.6% were diagnosed with SPIGFD. Patients who experienced & GE; 1 hypoglycemia AE (n = 80) compared with those with no hypoglycemia AEs (n = 224) had a lower mean age at treatment start (8.7 years vs 9.8 years), a more frequent diagnosis of Laron syndrome (27.5% vs 10.3%), and a history of hypoglycemia (18.8% vs 4.5%). Prior history of hypoglycemia (OR 0.25; 95% CI: [0.11; 0.61]; P = .002) and Laron syndrome diagnosis (OR 0.36; 95% CI: [0.18; 0.72]; P = .004) predicted future hypoglycemia AEs. Total hypoglycemia AEs per patient per treatment year was 0.11 and total serious hypoglycemia AEs per patient per treatment year was 0.01.Conclusion Hypoglycemia occurs more frequently in patients with prior history of hypoglycemia and/or Laron syndrome compared with patients without these risk factors, and these patients should be carefully monitored for this AE throughout treatment.

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  • 20.
    Bang, Peter
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Polak, Michel
    Univ Paris, France.
    Perrot, Valerie
    Ipsen Pharma, France.
    Sert, Caroline
    Ipsen Pharma, France.
    Shaikh, Haris
    Ipsen Pharm, Wales.
    Woelfle, Joachim
    Friedrich Alexander Univ Erlangen Nurnberg, Germany.
    Pubertal Timing and Growth Dynamics in Children With Severe Primary IGF-1 Deficiency: Results From the European Increlex(R) Growth Forum Database Registry2022In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 13, article id 812568Article in journal (Refereed)
    Abstract [en]

    BackgroundPuberty is delayed in untreated children and adolescents with severe primary IGF-1 deficiency (SPIGFD); to date, it has not been reported whether recombinant human insulin-like growth factor-1 mecasermin (rhIGF-1) treatment affects this. Pubertal growth outcomes were extracted from the European Increlex(R) Growth Forum Database (Eu-IGFD) Registry (NCT00903110). MethodsThe Eu-IGFD Registry includes children and adolescents aged 2 to 18 years with growth failure associated with SPIGFD who are treated with rhIGF-1. Reported outcomes include: age at last registration of Tanner stage 1 and first registration of Tanner stage 2-5 (T2-T5; based on breast development for girls and genital development for boys, respectively); maximum height velocity during each Tanner stage; and pubertal peak height velocity (PPHV). Data cut-off was 13 May 2019. ResultsThis analysis included 213 patients (132 boys and 81 girls). Mean (SD) age at last registration of T1 and first registration of T5 was 13.0 (2.0) and 16.3 (1.6) years, respectively, in boys and 11.6 (1.8) and 14.7 (1.5) years, respectively, in girls. Among patients reaching the end of puberty (25 boys and 11 girls), mean (SD) height SDS increased from -3.7 (1.4) at baseline in the Eu-IGFD Registry to -2.6 (1.4) at T5 in boys and from -3.1 (1.1) to -2.3 (1.5) in girls. Maximum height velocity was observed during T2 in girls and T3 in boys. Median (range) PPHV was 8.0 (0.3-13.0) cm/year in boys and 6.8 (1.3-9.6) cm/year in girls and occurred most frequently during T2. Overall, the adverse events seen in this analysis were in line with the known safety profile of rhIGF-1. ConclusionChildren and adolescents treated with rhIGF-1 for SPIGFD with growth failure experienced an increase in height SDS in prepubertal years compared with baseline. Despite 1.5 years delay in pubertal start and a delayed and slightly lower PPHV, height SDS gain during puberty was maintained.

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  • 21.
    Bartoszek, Krzysztof
    et al.
    Linköping University, Department of Computer and Information Science, The Division of Statistics and Machine Learning. Linköping University, Faculty of Arts and Sciences.
    Okroj, Marcin
    Univ Gdansk, Poland; Med Univ Gdansk, Poland.
    Controversies around the statistical presentation of data on mRNA-COVID 19 vaccine safety in pregnant women2022In: Journal of Reproductive Immunology, ISSN 0165-0378, E-ISSN 1872-7603, Vol. 151, article id 103503Article in journal (Refereed)
    Abstract [en]

    The work entitled "Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons" published on April 21, 2021, in The New England Journal of Medicine, presented data collected from American surveillance systems and registries. However, problems with an unanimous interpretation of those results appeared in the public debate and citing articles. Some stated that the risk of miscarriage in vaccinated women was similar to historical values reported before the vaccines approval. The others stated that risk was highly above-normative in women vaccinated during the first and second trimesters. We found several problems with the statistical treatment/interpretation of the originally presented values: a substantial percentage (up to 95.6%) of missing data, an incorrect denominator used for risk estimation, and too short follow-up that disabled the evaluation of the studys endpoint in numerous participants. Eventually, the Authors published a corrigendum on September 8, 2021, and pointed to updated data. Herein, we explain the statistical controversies raised by the original presentation and stress that analyzing the trade-off between knowledge and confusion brought by the release of incomplete results of such a high social interest, should aid in solving the dilemma of whether to publish preliminary data or none.

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  • 22.
    Bauza-Thorbrügge, Marco
    et al.
    Univ Gothenburg, Sweden.
    Banke, Elin
    Univ Gothenburg, Sweden.
    Chanclon, Belen
    Univ Gothenburg, Sweden.
    Peris, Eduard
    Univ Gothenburg, Sweden.
    Wu, Yanling
    Univ Gothenburg, Sweden.
    Musovic, Saliha
    Univ Gothenburg, Sweden.
    Jönsson, Cecilia
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Rorsman, Patrik
    Univ Gothenburg, Sweden; Univ Oxford, England.
    Olofsson, Charlotta S.
    Univ Gothenburg, Sweden.
    Asterholm, Ingrid Wernstedt
    Univ Gothenburg, Sweden.
    Adipocyte-specific ablation of the Ca2+pump SERCA2 impairs whole-body metabolic function and reveals the diverse metabolic flexibility of white and brown adipose tissue2022In: Molecular Metabolism, ISSN 2212-8778, Vol. 63, article id 101535Article in journal (Refereed)
    Abstract [en]

    Objective: Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) transports Ca2+ from the cytosol into the endoplasmic retitculum (ER) and is essential for appropriate regulation of intracellular Ca2+ homeostasis. The objective of this study was to test the hypothesis that SERCA pumps are involved in the regulation of white adipocyte hormone secretion and other aspects of adipose tissue function and that this control is disturbed in obesity-induced type-2 diabetes. Methods: SERCA expression was measured in isolated human and mouse adipocytes as well as in whole mouse adipose tissue by Western blot and RT-qPCR. To test the significance of SERCA2 in adipocyte functionality and whole-body metabolism, we generated adipocyte-specific SERCA2 knockout mice. The mice were metabolically phenotyped by glucose tolerance and tracer studies, histological analyses, measurements of glucose-stimulated insulin release in isolated islets, and gene/protein expression analyses. We also tested the effect of pharmacological SERCA inhibition and genetic SERCA2 ablation in cultured adipocytes. Intracellular and mitochondrial Ca2+ levels were recorded with dualwavelength ratio imaging and mitochondrial function was assessed by Seahorse technology. Results: We demonstrate that SERCA2 is downregulated in white adipocytes from patients with obesity and type-2 diabetes as well as in adipocytes from diet-induced obese mice. SERCA2-ablated adipocytes display disturbed Ca2+ homeostasis associated with upregulated ER stress markers and impaired hormone release. These adipocyte alterations are linked to mild lipodystrophy, reduced adiponectin levels, and impaired glucose tolerance. Interestingly, adipocyte-specific SERCA2 ablation leads to increased glucose uptake in white adipose tissue while the glucose uptake is reduced in brown adipose tissue. This dichotomous effect on glucose uptake is due to differently regulated mitochondrial function. In white adipocytes, SERCA2 deficiency triggers an adaptive increase in fibroblast growth factor 21 (FGF21), increased mitochondrial uncoupling protein 1 (UCP1) levels, and increased oxygen consumption rate (OCR). In contrast, brown SERCA2 null adipocytes display reduced OCR despite increased mitochondrial content and UCP1 levels compared to wild type controls. Conclusions: Our data suggest causal links between reduced white adipocyte SERCA2 levels, deranged adipocyte Ca2+ homeostasis, adipose tissue dysfunction and type-2 diabetes. (c) 2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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  • 23.
    Beam, Craig A.
    et al.
    Western Michigan University, MI 49008 USA.
    MacCallum, Colleen
    Western Michigan University, MI 49008 USA.
    Herold, Kevan C.
    Yale University, CT USA; Yale University, CT USA.
    Wherrett, Diane K.
    Hospital Sick Children, Canada; University of Toronto, Canada.
    Palmer, Jerry
    University of Washington, WA 98195 USA; VA Puget Sound Health Care Syst, WA USA.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    GAD vaccine reduces insulin loss in recently diagnosed type 1 diabetes: findings from a Bayesian meta-analysis2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no 1, p. 43-49Article in journal (Refereed)
    Abstract [en]

    GAD is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. Randomised controlled clinical trials of a GAD + alum vaccine in human participants have so far given conflicting results. In this study, we sought to see whether a clearer answer to the question of whether GAD65 has an effect on C-peptide could be reached by combining individual-level data from the randomised controlled trials using Bayesian meta-analysis to estimate the probability of a positive biological effect (a reduction in C-peptide loss compared with placebo approximately 1 year after the GAD vaccine). We estimate that there is a 98% probability that 20 mu g GAD with alum administered twice yields a positive biological effect. The effect is probably a 15-20% reduction in the loss of C-peptide at approximately 1 year after treatment. This translates to an annual expected loss of between -0.250 and -0.235 pmol/ml in treated patients compared with an expected 2 h AUC loss of -0.294 pmol/ml at 1 year for untreated newly diagnosed patients. The biological effect of this vaccination should be developed further in order to reach clinically desirable reductions in insulin loss in patients recently diagnosed with type 1 diabetes.

  • 24.
    Becerro-Rey, Laura
    et al.
    Univ Extremadura, Spain.
    Martin-Cano, Francisco Eduardo
    Univ Extremadura, Spain.
    Ferrusola, Cristina Ortega
    Univ Extremadura, Spain.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Gaitskell-Phillips, Gemma
    Univ Extremadura, Spain.
    da Silva-Alvarez, Eva
    Univ Extremadura, Spain.
    Silva-Rodriguez, Antonio
    Univ Extremadura, Spain.
    Gil, Maria Cruz
    Univ Extremadura, Spain.
    Pena, Fernando J.
    Univ Extremadura, Spain.
    Aging of stallion spermatozoa stored in vitro is delayed at 22C using a 67 mm glucose-10 mm pyruvate-based media2023In: Andrology, ISSN 2047-2919, E-ISSN 2047-2927Article in journal (Refereed)
    Abstract [en]

    Background: Most commerce of equine seminal doses is carried out using commercial extenders under refrigeration at 5 degrees C.Objectives: To determine if 10 mM pyruvate in a 67 mM glucose extender and storage at 22 degrees C could be the basis of an alternative storage method to cooling to 5 degrees C.Material and methods: Stallion ejaculates were extendedin: INRA96 (67 mM glucose, non-pyruvate control), modified Tyrodes (67 mM glucose-10 mM pyruvate), supplemented with 0, 10, 50, and 100 mu M itaconate. As itaconate was vehiculated in DMSO, a control vehicle was also included. Sperm motility, viability, mitochondrial membrane potential, and production of reactive oxygen species were measured after collection and again after 48 and 96 h of storage at 22 degrees C. To disclose molecular metabolic changes, spermatozoa were incubated up to 3 h in modified Tyrodes 67 mM glucose-10 mM pyruvate and modified Tyrodes 67 mM glucose, and metabolic analysis conducted.Results: After 96 h of storage aliquots stored in the control, INRA96 had a very poor total motility of 5.6% +/- 2.3%, while in the 67 mM glucose-10 mM pyruvate/10 mu M itaconate extender, total motility was 34.7% +/- 3.8% (p = 0.0066). After 96 h, viability was better in most pyruvate-based media, and the mitochondrial membrane potential in spermatozoa extended in INRA96 was relatively lower (p &lt; 0.0001). Metabolomics revealed that in the spermatozoa incubated in the high pyruvate media, there was an increase in the relative amounts of NAD(+), pyruvate, lactate, and ATP.Discussion and conclusions: Aliquots stored in a 67 mM glucose-10 mM pyruvatebased medium supplemented with 10 mu M itaconate, maintained a 35% total motility after 96 h of storage at 22 degrees C, which is considered the minimum acceptable motility for commercialization. Improvements may be related to the conversion of pyruvate to lactate and regeneration of NAD(+).

  • 25. Order onlineBuy this publication >>
    Bengtsson, Daniel
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Cushing’s disease and aggressive pituitary tumours: Aspects on epidemiology, treatment, and long-term follow-up2021Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis focuses on clinical and epidemiological aspects of aggressive pituitary tumours/carcinomas and Cushing’s disease. Pituitary carcinomas account for only 0.1-0.2% of the tumours originating from the anterior pituitary gland and are defined solely by the event of distant metastases, whereas aggressive pituitary tumours are defined by their clinical behaviour of rapid/progressive growth despite optimal treatment with surgery, radiotherapy and medical agents. The prognosis for individuals with aggressive tumours/carcinomas has been poor with few treatment options. However, case reports indicated better outcomes after treatment with the alkylating agent temozolomide. In study I and III, we investigated 24 patients (16 aggressive tumours and 8 carcinomas) given treatment with temozolomide. We found an initial response rate (tumour regression ≥30%) in 10/21 evaluable patients, with complete regression in two carcinomas. Favourable response was associated with low tumour expression of the DNA repair protein MGMT; in responders median 9% (range 5-20%) vs non-responders median 93% (50-100%). Our results also indicated a longer survival in patients with low MGMT. Out of 11 patients with MGMT >10%, nine died with an estimated median survival of 26 months (95% CI 14-38), whereas only 1/6 patients with lower MGMT died from tumour progression during a follow-up of median 83 months (range 12-161).

    One of the patients in study I and III had a corticotroph pituitary carcinoma and in addition, Lynch syndrome (LS), a hereditary cancer-predisposing syndrome caused by germline mutations in DNA mismatch repair (MMR) genes and primarily associated with colon and endometrial carcinomas. In study II, we investigated the characteristics of the pituitary carcinoma and found loss of MSH2 and MSH6 protein expression, consistent with the patient’s germline mutation in MSH2. This was the first published case of a pituitary tumour associated with LS. In addition, we identified all known Swedish patients with LS (n=910) and searched for diagnostic codes consistent with a pituitary tumour in the Swedish national patient register. We found in total three patients with clinically relevant pituitary tumours, the reported prevalence in the background population is around 1:1000.

    The last two studies in the thesis focused on Cushing’s disease (CD), i.e. an ACTH-secreting pituitary tumour resulting in excess levels of cortisol. CD is associated with multiple comorbidities and increased mortality. The reversibility of comorbidities and mortality risk after remission of cortisol levels have been under debate. Study IV examined psychiatric consequences of CD, measured by the use of psychotropic drugs. 179 patients with CD and a quadrupled matched control group were followed from diagnosis and at 5- and 10-year follow-up. We found that use of antidepressants remained at around 25% of patients with CD, regardless of remission status, at diagnosis and follow-up, whereas drugs for somatic comorbidities decreased. Use of antidepressants, sleeping pills and anxiolytics was higher in patients with CD compared to controls at diagnosis and 5-year follow-up. A cross-sectional analysis of 76 patients in sustained biochemical remission for median 9.3 years showed that 25% were taking antidepressants, a significantly higher use than controls, OR 2.0 (95% CI 1.1-3.8). In addition, patients with CD had a higher use of psychotropic drugs, already in the 5-year period before diagnosis.

    Study V investigated mortality and causes of death in 371 patients with CD, compared to a quadrupled matched control group. Follow-up was median 10.6 years (IQR 5.7-18.2) after time of diagnosis. Overall mortality was increased in patients with CD, HR 2.1 (95% CI 1.5-2.8) and remained elevated for patients in remission at last follow-up (n=303), HR 1.5 (1.02-2.2). For patients not in remission (n=31), HR was 5.6 (2.7-11.6). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death in patients with CD.

     

    Main conclusions of the thesis:

    • Temozolomide improves outcome in patients with aggressive pituitary tumours/carcinomas and a low MGMT expression in the tumour predicts a favourable outcome. As additional therapies evolve, MGMT may help to tailor the treatment.
    • Germline mutations in MMR genes may contribute to the development and clinical course of pituitary tumours and may be a novel cause of hereditary pituitary tumours.
    • Patients with Cushing’s disease have a high use of psychotropic drugs that remains elevated despite achievement of biochemical remission, suggesting persisting negative effects on mental health and highlighting the need for long-term monitoring of psychiatric symptoms. In addition, psychiatric symptoms may be early and important signs of CD.
    • Efforts to achieve biochemical remission are crucial to reduce mortality in CD. However, patients in remission still have an increased mortality compared to controls. This underscores the need for life-long monitoring and treatment of associated comorbidities in patients with CD.
    List of papers
    1. Long-term outcome and MGMT as a predictive marker in 24 patients with atypical pituitary adenomas and pituitary carcinomas given treatment with temozolomide
    Open this publication in new window or tab >>Long-term outcome and MGMT as a predictive marker in 24 patients with atypical pituitary adenomas and pituitary carcinomas given treatment with temozolomide
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    2015 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 4, p. 1689-1698Article in journal (Refereed) Published
    Abstract [en]

    CONTEXT/OBJECTIVE: Locally aggressive pituitary tumors (LAPT) and pituitary carcinomas respond poorly to conventional therapy and cytotoxic drugs. Temozolomide (TMZ) is an oral alkylating drug with good tolerability, approved for treatment of malignant gliomas. The experience of its use in pituitary tumors is limited. DESIGN AND SETTING: We report on 24 patients with aggressive pituitary tumors (16 LAPTs, 8 carcinomas) treated with TMZ for a median of 6 months (range 1-23). Follow-up ranged from 4 to 91 months with a median of 32.5 months. 19/24 tumors were hormone secreting (PRL 9, ACTH 4, GH 4, GH/PRL 2). Ki-67 was 2-50% in LAPTs, and 5-80% in carcinomas. MAIN OUTCOME: Response to TMZ and the association with tumor expression of O6-methylguanine DNA methyltransferase (MGMT), MLH1, MSH2, and MSH6, examined by immunohistochemistry. RESULTS: Complete tumor regression occurred in two carcinomas and persisted at follow-up after 48 and 91 months, respectively. Partial regress of tumor mass ranging from 35% to 80% occurred in 5 LAPTs and 2 carcinomas. Another patient with LAPT had a 71% decrease in prolactin levels without change in tumor volume. Three LAPTs could not be evaluated. Median MGMT staining was 9% (5-20%) in responders vs 93% (50-100%) in nonresponders. Loss of MSH2 and MSH 6 was observed in a single patient who had a rapid development of resistance to TMZ. CONCLUSIONS: This study shows that TMZ is a valuable treatment option for patients with uncontrolled pituitary tumors. The data suggest that tumoral MGMT staining below 50% is associated with a high likelihood of treatment response.

    Place, publisher, year, edition, pages
    Oxford University Press, 2015
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:liu:diva-174710 (URN)10.1210/jc.2014-4350 (DOI)000353361500081 ()25646794 (PubMedID)2-s2.0-84927609324 (Scopus ID)
    Note

    Funding agencies: This work was supported by grants from Lund University, and the Arvid Nilsson Fund.

    Available from: 2021-03-31 Created: 2021-03-31 Last updated: 2021-04-07Bibliographically approved
    2. Corticotroph Pituitary Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort
    Open this publication in new window or tab >>Corticotroph Pituitary Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort
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    2017 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 11, p. 3928-3932Article in journal (Refereed) Published
    Abstract [en]

    Context: Lynch syndrome (LS) is a cancer-predisposing syndrome caused by germline mutations in genes involved in DNA mismatch repair (MMR). Patients are at high risk for several types of cancer, but pituitary tumors have not previously been reported. Case: A 51-year-old man with LS (MSH2 mutation) and a history of colon carcinoma presented with severe Cushing disease and a locally aggressive pituitary tumor. The tumor harbored a mutation consistent with the patients germline mutation and displayed defect MMR function. Sixteen months later, the tumor had developed into a carcinoma with widespread liver metastases. The patient prompted us to perform a nationwide study in LS. Nationwide Study: A diagnosis consistent with a pituitary tumor was sought for in the Swedish National Patient Registry. In 910 patients with LS, representing all known cases in Sweden, another two clinically relevant pituitary tumors were found: an invasive nonsecreting macroadenoma and a microprolactinoma (i.e., in total three tumors vs. one expected). Conclusion: Germline mutations in MMR genes may contribute to the development and/or the clinical course of pituitary tumors. Because tumors with MMR mutations are susceptible to treatment with immune checkpoint inhibitors, we suggest to actively ask for a family history of LS in the workup of patients with aggressive pituitary tumors.

    Place, publisher, year, edition, pages
    OXFORD UNIV PRESS INC, 2017
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-143246 (URN)10.1210/jc.2017-01401 (DOI)000414558500005 ()28938458 (PubMedID)
    Note

    Funding Agencies|Medical Research Council of Southeast Sweden; Eber and Ingrid Kinnemo foundation; Anna and Sven Lundbergs Stiftelse, Lund University

    Available from: 2017-11-27 Created: 2017-11-27 Last updated: 2021-04-07
    3. Tumoral MGMT content predicts survival in patients with aggressive pituitary tumors and pituitary carcinomas given treatment with temozolomide
    Open this publication in new window or tab >>Tumoral MGMT content predicts survival in patients with aggressive pituitary tumors and pituitary carcinomas given treatment with temozolomide
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    2018 (English)In: Endocrine, ISSN 1355-008X, E-ISSN 1559-0100, Vol. 62, no 3, p. 737-739Article in journal, Letter (Other academic) Published
    Abstract [en]

    n/a

    Place, publisher, year, edition, pages
    Humana Press, 2018
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:liu:diva-153516 (URN)10.1007/s12020-018-1751-9 (DOI)000451950800029 ()30246233 (PubMedID)2-s2.0-85053657322 (Scopus ID)
    Note

    Funding Agencies|Skane University Hospital, Region Skane, Sweden; Medical Research Council of Southeast Sweden

    Available from: 2019-01-02 Created: 2019-01-02 Last updated: 2023-08-28Bibliographically approved
    4. Psychotropic drugs in patients with Cushing's disease before diagnosis and at long-term follow-up - a nationwide study.
    Open this publication in new window or tab >>Psychotropic drugs in patients with Cushing's disease before diagnosis and at long-term follow-up - a nationwide study.
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    2021 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, article id dgab079Article in journal (Refereed) Published
    Abstract [en]

    CONTEXT: Psychiatric symptoms are common in Cushing's disease (CD) and seem only partly reversible following treatment.

    OBJECTIVE: To investigate drug dispenses associated to psychiatric morbidity in CD patients before treatment and during long-term follow-up.

    DESIGN: Nationwide longitudinal register-based study.

    SETTING: University Hospitals in Sweden.

    SUBJECTS: CD patients diagnosed between 1990 and 2018 (N=372) were identified in the Swedish Pituitary Register. Longitudinal data was collected from 5 years before, at diagnosis and during follow-up. Four matched controls per patient were included. Cross-sectional subgroup analysis of 76 patients in sustained remission was also performed.

    MAIN OUTCOME MEASURES: Data from the Swedish Prescribed Drug Register and the Patient Register.

    RESULTS: In the 5-year period before, and at diagnosis, use of antidepressants (OR 2.2[95%CI 1.3-3.7] and 2.3[1.6-3.5]), anxiolytics (2.9[1.6-5.3] and 3.9[2.3-6.6]) and sleeping pills (2.1[1.2-3.7] and 3.8[2.4-5.9]) was more common in CD than controls. ORs remained elevated at 5-year follow-up for antidepressants (2.4[1.5-3.9]) and sleeping pills (3.1[1.9-5.3]). Proportions of CD patients using antidepressants (26%) and sleeping pills (22%) were unchanged at diagnosis and 5-year follow-up, whereas drugs for hypertension and diabetes decreased. Patients in sustained remission for median 9.3 years (IQR 8.1-10.4) had higher use of antidepressants (OR 2.0[1.1-3.8]) and sleeping pills (2.4[1.3-4.7]), but not of drugs for hypertension.

    CONCLUSIONS: Increased use of psychotropic drugs in CD was observed before diagnosis and remained elevated regardless of remission status, suggesting persisting negative effects on mental health. The study highlights the importance of early diagnosis of CD, and the need for long-term monitoring of mental health.

    Place, publisher, year, edition, pages
    Oxford University Press, 2021
    Keywords
    Cushing’s syndrome, depression, hypercortisolism, neuropsychiatry, sleeping disorder
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:liu:diva-174801 (URN)10.1210/clinem/dgab079 (DOI)000658237600042 ()33567076 (PubMedID)
    Note

    Funding: Medical Research Council of Southeast SwedenUK Research & Innovation (UKRI)Medical Research Council UK (MRC); Swedish government; county councils; ALF [ALFGBG-771841, ALFGBG-936463]; Skane University Hospital

    Available from: 2021-04-05 Created: 2021-04-05 Last updated: 2021-12-28
    5. Increased Mortality Persists after Treatment of Cushing’s Disease: A Matched Nationwide Cohort Study
    Open this publication in new window or tab >>Increased Mortality Persists after Treatment of Cushing’s Disease: A Matched Nationwide Cohort Study
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    2022 (English)In: Journal of the Endocrine Society, E-ISSN 2472-1972, Vol. 6, no 6Article in journal (Refereed) Published
    Abstract [en]

    Context: Whether biochemical remission normalizes life expectancy in Cushings disease (CD) patients remains unclear. Previous studies evaluating mortality in CD are limited by using the expected number of deaths in the background population instead of the actual number in matched controls. Objective and setting: To study mortality by time-to-event analysis in an unselected nationwide CD patient cohort. Design and participants: Longitudinal data from the Swedish Pituitary Register of 371 patients diagnosed with CD from 1991 to 2018 and information from the Swedish Cause of Death Register were evaluated. Four controls per patient (n = 1484) matched at the diagnosis date by age, sex, and residential area were included. Main outcome measures: Mortality and causes of death. Results: The median diagnosis age was 44 years (interquartile range 32-56), and the median follow-up was 10.6 years (5.7-18.0). At the 1-, 5-, 10-, 15-, and 20-year follow-ups, the remission rates were 80%, 92%, 96%, 91%, and 97%, respectively. Overall mortality was increased in CD patients compared with matched controls [hazard ratio (HR) 2.1 (95% CI 1.5-2.8)1. The HRs were 1.5 (1.02-2.2) for patients in remission at the last follow-up In = 303), 1.7 (1.03-2.8) for those in remission after a single pituitary surgery In = 177), and 5.6 (2.7-11.6) for those not in remission (n = 31). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death. Conclusions: Mortality was increased in CD patients despite biochemical remission compared to matched controls. The study highlights the importance of careful comorbidity monitoring, regardless of remission status.

    Place, publisher, year, edition, pages
    Oxford University Press, 2022
    Keywords
    Cushing, hypercortisolism, mortality, remission, hazard ratio, epidemiology
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-184600 (URN)10.1210/jendso/bvac045 (DOI)000786709700001 ()35480633 (PubMedID)
    Note

    Funding agencies: Medical Research Council of Southeast SwedenUK Research & Innovation (UKRI)Medical Research Council UK (MRC) [FORSS-930862]

    Available from: 2022-04-26 Created: 2022-04-26 Last updated: 2022-05-12Bibliographically approved
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  • 26.
    Bengtsson, Daniel
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Daa Schrøder, Henrik
    Department of Pathology (H.D.S.) Odense, Denmark.
    Andersen, Marianne
    Department of Endocrinology (M.A.), Odense University Hospital, University of Southern Denmark, Odense, Denmark.
    Maiter, Dominique
    Department of Endocrinology and Nutrition (D.M.), Cliniques Universitaires St-Luc, Université Catholique de Louvain, Brussels, Belgium.
    Berinder, Katarina
    Department of Endocrinology, Metabolism and Diabetology (K.B., C.H., M.P.), Karolinska University Hospital, Stockholm, Sweden.
    Feldt Rasmussen, Ulla
    Department of Medical Endocrinology and Metabolism (U.F.R, Å.K.R), Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    Krogh Rasmussen, Åse
    Department of Medical Endocrinology and Metabolism (U.F.R, Å.K.R), Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    Johannsson, Gudmundur
    Department of Endocrinology (G.J., O.R.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Hoybye, Charlotte
    Department of Endocrinology, Metabolism and Diabetology (K.B., C.H., M.P.), Karolinska University Hospital, Stockholm, Sweden.
    van der Lely, Aart Jan
    Department of Medicine, Division of Endocrinology (A.J.v.d.L.), Erasmus University MC, Rotterdam, The Netherlands.
    Petersson, Maria
    Department of Endocrinology, Metabolism and Diabetology (K.B., C.H., M.P.), Karolinska University Hospital, Stockholm, Sweden.
    Ragnarsson, Oskar
    Department of Endocrinology (G.J., O.R.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg; Sahlgrenska University Hospital, Gothenburg, Sweden.
    Burman, Pia
    Department of Endocrinology (D.B., P.B.), Skane University Hospital, Malmö, Sweden.
    Long-term outcome and MGMT as a predictive marker in 24 patients with atypical pituitary adenomas and pituitary carcinomas given treatment with temozolomide2015In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 4, p. 1689-1698Article in journal (Refereed)
    Abstract [en]

    CONTEXT/OBJECTIVE: Locally aggressive pituitary tumors (LAPT) and pituitary carcinomas respond poorly to conventional therapy and cytotoxic drugs. Temozolomide (TMZ) is an oral alkylating drug with good tolerability, approved for treatment of malignant gliomas. The experience of its use in pituitary tumors is limited. DESIGN AND SETTING: We report on 24 patients with aggressive pituitary tumors (16 LAPTs, 8 carcinomas) treated with TMZ for a median of 6 months (range 1-23). Follow-up ranged from 4 to 91 months with a median of 32.5 months. 19/24 tumors were hormone secreting (PRL 9, ACTH 4, GH 4, GH/PRL 2). Ki-67 was 2-50% in LAPTs, and 5-80% in carcinomas. MAIN OUTCOME: Response to TMZ and the association with tumor expression of O6-methylguanine DNA methyltransferase (MGMT), MLH1, MSH2, and MSH6, examined by immunohistochemistry. RESULTS: Complete tumor regression occurred in two carcinomas and persisted at follow-up after 48 and 91 months, respectively. Partial regress of tumor mass ranging from 35% to 80% occurred in 5 LAPTs and 2 carcinomas. Another patient with LAPT had a 71% decrease in prolactin levels without change in tumor volume. Three LAPTs could not be evaluated. Median MGMT staining was 9% (5-20%) in responders vs 93% (50-100%) in nonresponders. Loss of MSH2 and MSH 6 was observed in a single patient who had a rapid development of resistance to TMZ. CONCLUSIONS: This study shows that TMZ is a valuable treatment option for patients with uncontrolled pituitary tumors. The data suggest that tumoral MGMT staining below 50% is associated with a high likelihood of treatment response.

  • 27.
    Bengtsson, Daniel
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Department of Internal Medicine, Kalmar, Region of Kalmar County , Kalmar, Sweden.
    Ragnarsson, Oskar
    Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden; Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Berinder, Katarina
    Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Dahlqvist, Per
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Edén Engström, Britt
    Department of Medical Sciences, Endocrinology and Mineral Metabolism, Uppsala University, Uppsala, Sweden; Department of Endocrinology and Diabetes, Uppsala University Hospital, Uppsala, Sweden.
    Ekman, Bertil
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology.
    Höybye, Charlotte
    Department of Endocrinology, Karolinska University Hospital , Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Burman, Pia
    Department of Endocrinology, Skåne University Hospital, University of Lund, Malmö, Sweden.
    Wahlberg, Jeanette
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology.
    Psychotropic drugs in patients with Cushing's disease before diagnosis and at long-term follow-up - a nationwide study.2021In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, article id dgab079Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Psychiatric symptoms are common in Cushing's disease (CD) and seem only partly reversible following treatment.

    OBJECTIVE: To investigate drug dispenses associated to psychiatric morbidity in CD patients before treatment and during long-term follow-up.

    DESIGN: Nationwide longitudinal register-based study.

    SETTING: University Hospitals in Sweden.

    SUBJECTS: CD patients diagnosed between 1990 and 2018 (N=372) were identified in the Swedish Pituitary Register. Longitudinal data was collected from 5 years before, at diagnosis and during follow-up. Four matched controls per patient were included. Cross-sectional subgroup analysis of 76 patients in sustained remission was also performed.

    MAIN OUTCOME MEASURES: Data from the Swedish Prescribed Drug Register and the Patient Register.

    RESULTS: In the 5-year period before, and at diagnosis, use of antidepressants (OR 2.2[95%CI 1.3-3.7] and 2.3[1.6-3.5]), anxiolytics (2.9[1.6-5.3] and 3.9[2.3-6.6]) and sleeping pills (2.1[1.2-3.7] and 3.8[2.4-5.9]) was more common in CD than controls. ORs remained elevated at 5-year follow-up for antidepressants (2.4[1.5-3.9]) and sleeping pills (3.1[1.9-5.3]). Proportions of CD patients using antidepressants (26%) and sleeping pills (22%) were unchanged at diagnosis and 5-year follow-up, whereas drugs for hypertension and diabetes decreased. Patients in sustained remission for median 9.3 years (IQR 8.1-10.4) had higher use of antidepressants (OR 2.0[1.1-3.8]) and sleeping pills (2.4[1.3-4.7]), but not of drugs for hypertension.

    CONCLUSIONS: Increased use of psychotropic drugs in CD was observed before diagnosis and remained elevated regardless of remission status, suggesting persisting negative effects on mental health. The study highlights the importance of early diagnosis of CD, and the need for long-term monitoring of mental health.

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  • 28.
    Bengtsson, Daniel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Council, Kalmar, Sweden.
    Schroder, H. D.
    Department of Pathology, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
    Berinder, K.
    Department of Molecular Medicine and Surgery, Patient Area Endocrinology and Nephrology, Inflammation and Infection Theme, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Maiter, D.
    Department of Endocrinology and Nutrition, Cliniques Universitaires St-Luc, Université Catholique de Louvain, Brussels, Belgium.
    Hoybye, C.
    Department of Molecular Medicine and Surgery, Patient Area Endocrinology and Nephrology, Inflammation and Infection Theme, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Ragnarsson, O.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Feldt-Rasmussen, U.
    Department of Medical Endocrinology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    Rasmussen, A. Krogh
    Department of Medical Endocrinology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    van der Lely, A.
    Department of Medicine, Division of Endocrinology, Erasmus University, Rotterdam, The Netherlands.
    Petersson, M.
    Department of Molecular Medicine and Surgery, Patient Area Endocrinology and Nephrology, Inflammation and Infection Theme, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Johannsson, G.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Andersen, M.
    Department of Endocrinology, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
    Burman, P.
    Department of Endocrinology, Skåne University Hospital, University of Lund, Malmö, Sweden.
    Tumoral MGMT content predicts survival in patients with aggressive pituitary tumors and pituitary carcinomas given treatment with temozolomide2018In: Endocrine, ISSN 1355-008X, E-ISSN 1559-0100, Vol. 62, no 3, p. 737-739Article in journal (Other academic)
    Abstract [en]

    n/a

  • 29.
    Bennet, Louise
    et al.
    Lund Univ, Sweden.
    Udumyan, Ruzan
    Orebro Univ, Sweden.
    Östgren, Carl Johan
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Ekholmen.
    Rolandsson, Olov
    Umea Univ, Sweden.
    Jansson, Stefan P. O.
    Orebro Univ, Sweden; Uppsala Univ, Sweden.
    Wandell, Per
    Karolinska Inst, Sweden.
    Mortality in first- and second-generation immigrants to Sweden diagnosed with type 2 diabetes: a 10 year nationwide cohort study2021In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 64, p. 95-108Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Non-Western immigrants to Europe are at high risk for type 2 diabetes. In this nationwide study including incident cases of type 2 diabetes, the aim was to compare all-cause mortality (ACM) and cause-specific mortality (CSM) rates in first- and second-generation immigrants with native Swedes. Methods People living in Sweden diagnosed with new-onset pharmacologically treated type 2 diabetes between 2006 and 2012 were identified through the Swedish Prescribed Drug Register. They were followed until 31 December 2016 for ACM and until 31 December 2012 for CSM. Analyses were adjusted for age at diagnosis, sex, socioeconomic status, education, treatment and region. Associations were assessed using Cox regression analysis. Results In total, 138,085 individuals were diagnosed with type 2 diabetes between 2006 and 2012 and fulfilled inclusion criteria. Of these, 102,163 (74.0%) were native Swedes, 28,819 (20.9%) were first-generation immigrants and 7103 (5.1%) were second-generation immigrants with either one or both parents born outside Sweden. First-generation immigrants had lower ACM rate (HR 0.80 [95% CI 0.76, 0.84]) compared with native Swedes. The mortality rates were particularly low in people born in non-Western regions (0.46 [0.42, 0.50]; the Middle East, 0.41 [0.36, 0.47]; Asia, 0.53 [0.43, 0.66]; Africa, 0.47 [0.38, 0.59]; and Latin America, 0.53 [0.42, 0.68]). ACM rates decreased with older age at migration and shorter stay in Sweden. Compared with native Swedes, first-generation immigrants with &lt;= 24 years in Sweden (0.55 [0.51, 0.60]) displayed lower ACM rates than those spending &gt;24 years in Sweden (0.92 [0.87, 0.97]). Second-generation immigrants did not have better survival rates than native Swedes but rather displayed higher ACM rates for people with both parents born abroad (1.28 [1.05, 1.56]). Conclusions/interpretation In people with type 2 diabetes, the lower mortality rate in first-generation non-Western immigrants compared with native Swedes was reduced over time and was equalised in second-generation immigrants. These findings suggest that acculturation to Western culture may impact ACM and CSM in immigrants with type 2 diabetes but further investigation is needed.

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  • 30.
    Bernfort, Lars
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences.
    Husberg, Magnus
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences.
    Wiréhn, Ann-Britt
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Regionledningskontoret, Forskningsstrategiska enheten.
    Rosenqvist, Ulf
    Region Östergötland, Local Health Care Services in West Östergötland, Department of Medical Specialist in Motala.
    Gustavsson, Staffan
    Boehringer Ingelheim AB, Sweden.
    Karlsdotter, Kristina
    Boehringer Ingelheim AB, Sweden.
    Levin, Lars-Åke
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences.
    Disease Burden and Healthcare Costs for T2D Patients With and Without Established Cardiovascular Disease in Sweden: A Retrospective Cohort Study2020In: Diabetes Therapy, ISSN 1869-6953, E-ISSN 1869-6961, Vol. 11, no 7, p. 1537-1549Article in journal (Refereed)
    Abstract [en]

    IntroductionType 2 diabetes (T2D) is a complex chronic disease with an increasing prevalence worldwide. It is commonly associated with complications, such as cardiovascular disease (CVD). Patients with both T2D and established CVD are exposed to increased risk of further cardiovascular events, which means increased healthcare costs and impairments to quality of life and survival. To determine the added burden of CVD for T2D patients, we have analyzed the consumption and costs of healthcare and mortality in two T2D patient cohorts, with and without established CVD, respectively, during a 5-year follow-up in a Swedish region.MethodsPatients with T2D on 1 January 2012 were identified using the administrative database of Region ostergotland and the Swedish National Diabetes Register. Established CVD was defined as the presence of a CVD-related healthcare visit in the period 2002-2011. Identified T2D patients were then followed retrospectively for 5 years (2012-2016) and data collected on utilization of healthcare resources, healthcare costs, and survival. Data pertinent to the study were retrieved from regional databases and national registries.ResultsOn the index date (1 January 2012) there were 19,731 patients with T2D (prevalence 4.5%) in Region ostergotland, of whom 5490 had established CVD. Those patients with established CVD were older, more often men, and had longer diabetes duration and worse kidney function than those without. Compared to T2D patients without CVD, those with CVD had a significantly higher healthcare consumption, experienced higher costs, and had lower survival during the follow-up.ConclusionThis study confirms that established CVD is common among patients with T2D (approximately 30%). Established CVD has negative effects on the utilization of healthcare resources, healthcare costs, and mortality. It is therefore very important to improve the treatment strategy of this patient group.

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  • 31.
    Bernfort, Lars
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences.
    Husberg, Magnus
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences.
    Wiréhn, Ann-Britt
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Regionledningskontoret, Forskningsstrategiska enheten.
    Rosenqvist, Ulf
    Region Östergötland, Local Health Care Services in West Östergötland, Department of Medical Specialist in Motala.
    Gustavsson, Staffan
    Boehringer Ingelheim AB, Sweden.
    Karlsdotter, Kristina
    Boehringer Ingelheim AB, Sweden.
    Levin, Lars-Åke
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences.
    Implementation of Empagliflozin in Patients with Diabetes Mellitus Type 2 and Established Cardiovascular Disease: Estimation of 5-Year Survival and Costs in Sweden2020In: Diabetes Therapy, ISSN 1869-6953, E-ISSN 1869-6961, Vol. 11, p. 2921-2930Article in journal (Refereed)
    Abstract [en]

    Introduction

    Cardiovascular disease (CVD) affects approximately 30% of patients with diabetes mellitus type 2 (T2D) and leads to increased morbidity, decreased survival and increased healthcare utilization. The aim of this study was to estimate the impact of treating these patients with the sodium–glucose cotransporter 2 (SGLT2) inhibitor empagliflozin on survival and healthcare utilization.

    Methods

    Actual survival and healthcare utilization data from a 5-year retrospective cohort study on patients with T2D and CVD in the Region of Östergötland, Sweden were used as a starting point. Actual data were adjusted in accordance with risk reductions for mortality and CV events related to empagliflozin treatment as reported in the EMPA-REG OUTCOME study.

    Results

    Applying the risk reductions related to empagliflozin treatment on the cohort of patients with T2D and CVD in Östergötland resulted in an increase in 5-year survival of 96 days per patient and reduced costs for healthcare and drugs other than empagliflozin. Including the cost of empagliflozin, treatment led to an increased net cost per patient of approximately SEK 18,000 over 5 years.

    Conclusion

    Empagliflozin treatment would reduce mortality and healthcare utilization in the patient group. The treatment strategy should be considered cost-effective, supporting a broad implementation of empagliflozin for patients with T2D and established CVD, in line with current national and international guidelines.

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  • 32.
    Birkebaek, N. H.
    et al.
    Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.
    Drivvoll, A K
    Norwegian Childhood Diabetes Registry, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Aakeson, K.
    Department of Pediatrics, County Hospital Ryhov, Jönköping, Sweden.
    Bjarnason, R.
    Medical Center, Landspitali University Hospital, Reykjavik, Iceland; Department of Pediatrics, University of Iceland, Reykjavik, Iceland.
    Johansen, A.
    Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Samuelsson, Ulf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Skrivarhaug, T.
    Norwegian Childhood Diabetes Registry, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Thorsson, A. V.
    Medical Center, Landspitali University Hospital, Reykjavik, Iceland; Department of Pediatrics, University of Iceland, Reykjavik, Iceland.
    Svensson, J.
    Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Children and Adolescents, Copenhagen University Hospital, Herlev, Denmark.
    Incidence of severe hypoglycemia in children with type 1 diabetes in the Nordic countries in the period 2008-2012: association with hemoglobin A 1c and treatment modality2017In: BMJ Open Diabetes Research & Care, ISSN 2052-4897, Vol. 5, no 1, article id e000377Article in journal (Refereed)
    Abstract [en]

    Treatment of type 1 diabetes has been intensified aiming at normalizing blood glucose, which may increase the risk of severe hypoglycemia (SH). We aimed to compare the incidence of SH events in the four Nordic countries Denmark, Iceland, Norway and Sweden, and to assess the influence of hemoglobin A1c (HbA1c) and treatment modalities on the frequency of SH; particularly, to explore if a HbA1c target =6.7% (50 mmol/mol) is feasible.

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  • 33.
    Birkebaek, N. H.
    et al.
    Aarhus Univ, Denmark.
    Kahlert, J.
    Aarhus Univ Hosp, Denmark.
    Bjarnason, R.
    Landspitali Univ Hosp, Iceland; Univ Iceland, Iceland.
    Drivvoll, A. K.
    Oslo Univ Hosp, Norway.
    Johansen, A.
    Rigshosp, Denmark.
    Konradsdottir, E.
    Landspitali Univ Hosp, Iceland; Univ Iceland, Iceland.
    Pundziute-Lycka, A.
    Queen Silvia Childrens Hosp, Sweden.
    Samuelsson, Ulf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Skrivarhaug, T.
    Oslo Univ Hosp, Norway.
    Svensson, J.
    Univ Copenhagen, Denmark.
    Body mass index standard deviation score and obesity in children with type 1 diabetes in the Nordic countries. HbA(1c) and other predictors of increasing BMISDS2018In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 19, no 7, p. 1198-1205Article in journal (Refereed)
    Abstract [en]

    Background: Intensified insulin therapy may increase body weight and cause obesity. This study compared body mass index standard deviation score (BMISDS) and obesity rate in children with type 1 diabetes (T1D) in Denmark, Iceland, Norway and Sweden, and uncovered predictors for increasing BMISDS. Methods: Data registered in the Nordic national childhood diabetes databases during the period 2008-2012 on children below 15 years with T1D for more than 3 months were compiled, including information on gender, age, diabetes duration, hemoglobin A(1c) (HbA(1c)), insulin dose, severe hypoglycemia (SH), treatment modality, height and weight. The Swedish reference chart for BMI was used for calculating BMISDS. Results: Totally, 11025 children (48% females) (30994 registrations) were included. Medians by the last recorded examination were: age, 13.5 years; diabetes duration, 4.3 years; HbA(1c), 7.9% (63 mmol/mol); insulin dose, 0.8 IU/kg/d and BMISDS, 0.70. Obesity rate was 18.5%. Adjusted mean BMISDS (BMISDS adj) was inversely related to HbA(1c) and directly to diabetes duration. Higher BMISDS adj was found in those with an insulin dose above 0.6 IU/kg/d, and in girls above 10 years. Pump users had higher BMISDS adj than pen users, and patients with registered SH had higher BMISDS adj than patients without SH (both P amp;lt; .001). Conclusion: Obesity rate in children with T1D in the Nordic countries is high, however, with country differences. Low HbA(1c), long diabetes duration, higher insulin dose, pump treatment and experiencing a SH predicted higher BMISDS. Diabetes caregivers should balance the risk of obesity and the benefit of a very low HbA(1c).

  • 34.
    Birkebaek, Niels H.
    et al.
    Aarhus Univ Hosp, Denmark; Aarhus Univ Hosp, Denmark.
    Kamrath, Clemens
    Justus Liebig Univ, Germany.
    Grimsmann, Julia M.
    Ulm Univ, Germany; German Ctr Diabet Res DZD, Germany.
    Åkesson, Karin
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Cty Hosp Ryhov, Sweden.
    Cherubini, Valentino
    Salesi Hosp, Italy.
    Dovc, Klemen
    Univ Childrens Hosp, Slovenia; Univ Ljubljana, Slovenia.
    de Beaufort, Carine
    Ctr Hosp Luxembourg, Luxembourg.
    Alonso, Guy T.
    Univ Colorado, CO USA.
    Gregory, John W.
    Cardiff Univ, Wales.
    White, Mary
    Royal Childrens Hosp, Australia; Royal Childrens Hosp, Australia; Murdoch Childrens Res Inst, Australia; Univ Melbourne, Australia.
    Skrivarhaug, Torild
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Sumnik, Zdenek
    Charles Univ Prague, Czech Republic.
    Jefferies, Craig
    Starship Childrens Hlth, New Zealand; Univ Auckland, New Zealand.
    Hoertenhuber, Thomas
    Kepler Univ Clin, Austria.
    Haynes, Aveni
    Univ Western Australia, Australia.
    De Bock, Martin
    Univ Otago, New Zealand.
    Svensson, Jannet
    Steno Diabet Ctr Copenhagen, Denmark; Univ Copenhagen, Denmark.
    Warner, Justin T.
    Childrens Hosp Wales, Wales.
    Gani, Osman
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Gesuita, Rosaria
    Polytech Univ Marche, Italy.
    Schiaffini, Riccardo
    Bambino Gesu Pediat Hosp, Italy.
    Hanas, Ragnar
    NU Hosp Grp, Sweden; Univ Gothenburg, Sweden.
    Rewers, Arleta
    Univ Colorado, CO USA.
    Eckert, Alexander J.
    Ulm Univ, Germany; German Ctr Diabet Res DZD, Germany.
    Holl, Reinhard W.
    Ulm Univ, Germany; German Ctr Diabet Res DZD, Germany.
    Cinek, Ondrej
    Charles Univ Prague, Czech Republic.
    Impact of the COVID-19 pandemic on long-term trends in the prevalence of diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes: an international multicentre study based on data from 13 national diabetes registries2022In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 10, no 11, p. 786-794Article in journal (Refereed)
    Abstract [en]

    Background An increased prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes in children was observed in various diabetes centres worldwide during the COVID-19 pandemic. We aimed to evaluate trends in the prevalence of diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes before and during the COVID-19 pandemic, and to identify potential predictors of changes in diabetic ketoacidosis prevalence during the pandemic.Methods For this international multicentre study, we used data from 13 national diabetes registries (Australia, Austria, Czechia, Denmark, Germany, Italy, Luxembourg, New Zealand, Norway, Slovenia, Sweden, USA [Colorado], and Wales). The study population comprised 104 290 children and adolescents aged 6 months to younger than 18 years, who were diagnosed with type 1 diabetes between Jan 1, 2006, and Dec 31, 2021. The observed diabetic ketoacidosis prevalence in 2020 and 2021 was compared to predictions based on trends over the pre-pandemic years 2006-19. Associations between changes in diabetic ketoacidosis prevalence and the severity of the COVID-19 pandemic and containment measures were examined with excess all-cause mortality in the whole population and the Stringency Index from the Oxford COVID-19 Government Response Tracker.Findings 87 228 children and adolescents were diagnosed with type 1 diabetes between 2006 and 2019, 8209 were diagnosed in 2020, and 8853 were diagnosed in 2021. From 2006 to 2019, diabetic ketoacidosis at diagnosis of type 1 diabetes was present in 23 775 (27middot3%) of 87 228 individuals and the mean annual increase in the prevalence of diabetic ketoacidosis in the total cohort from 2006 to 2019 was 1middot6% (95% CI 1middot3 to 1middot9). The adjusted observed prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes was 39middot4% (95% CI 34middot0 to 45middot6) in 2020 and 38middot9% (33middot6 to 45middot0) in 2021, significantly higher than the predicted prevalence of 32middot5% (27middot8 to 37middot9) for 2020 and 33middot0% (28middot3 to 38middot5) for 2021 (p&lt;0middot0001 for both years). The prevalence of diabetic ketoacidosis was associated with the pandemic containment measures, with an estimated risk ratio of 1middot037 (95% CI 1middot024 to 1middot051; p&lt;0middot0001) per ten-unit increase in the Stringency Index for 2020 and 1middot028 (1middot009 to 1middot047; p=0middot0033) for 2021, but was not significantly associated with excess all-cause mortality.Interpretation During the COVID-19 pandemic, there was a marked exacerbation of the pre-existing increase in diabetic ketoacidosis prevalence at diagnosis of type 1 diabetes in children. This finding highlights the need for early and timely diagnosis of type 1 diabetes in children and adolescents.Funding German Federal Ministry for Education and Research, German Robert Koch Institute, German Diabetes Association, German Diabetes Foundation, Slovenian Research Agency, Welsh Government, Central Denmark Region, and Swedish Association of Local Authorities and Regions.Copyright (c) 2022 Elsevier Ltd. All rights reserved.

  • 35. Order onlineBuy this publication >>
    Bjarnegård, Niclas
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Aspects on wall properties of the brachial artery in man: with special reference to SLE and insulin-dependent diabetes mellitus2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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

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

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

    Keywords
    Brachial artery, Ageing, Gender, Echo-tracking, Distensibility, Stiffness
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13028 (URN)10.1016/S0301-5629(03)00052-8 (DOI)
    Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2017-03-27
    2. The effect of sympathetic stimulation on proximal brachial artery mechanics in humans: differential behaviour within the length of the brachial artery
    Open this publication in new window or tab >>The effect of sympathetic stimulation on proximal brachial artery mechanics in humans: differential behaviour within the length of the brachial artery
    2004 (English)In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 182, no 1, p. 21-27Article in journal (Refereed) Published
    Abstract [en]

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

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

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

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

    Keywords
    ageing, brachial artery, distensibility, lower body negative pressure, stiffness, sympathetic stimulation
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13029 (URN)10.1111/j.1365-201X.2004.01336.x (DOI)
    Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2018-05-24
    3. Increased aortic pulse wave velocity in middle-aged women with systemic lupus erythematosus
    Open this publication in new window or tab >>Increased aortic pulse wave velocity in middle-aged women with systemic lupus erythematosus
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    2006 (English)In: Lupus, ISSN 0961-2033, Vol. 15, no 10, p. 644-650Article in journal (Refereed) Published
    Abstract [en]

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

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

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

    Keywords
    arteries, blood pressure, elasticity, pulse, SLE, women
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13030 (URN)10.1177/0961203306071402 (DOI)
    Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2017-03-27
    4. Impaired endothelial independent vasodilatation in women with type 1 diabetes
    Open this publication in new window or tab >>Impaired endothelial independent vasodilatation in women with type 1 diabetes
    Show others...
    2008 (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13031 (URN)
    Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2017-03-27Bibliographically approved
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  • 36.
    Björklund, Anneli
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Acad Specialist Ctr, Sweden.
    Hals, Ingrid K.
    Trondheim Reg & Univ Hosp, Norway; Norwegian Univ Sci & Technol NTNU, Norway; Nord Trondelag Hosp Trust, Norway.
    Grill, Valdemar
    Trondheim Reg & Univ Hosp, Norway.
    Ludvigsson, Johnny
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Latent Autoimmune Diabetes in Adults: Background, Safety and Feasibility of an Ongoing Pilot Study With Intra-Lymphatic Injections of GAD-Alum and Oral Vitamin D2022In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 13, article id 926021Article in journal (Refereed)
    Abstract [en]

    BackgroundLatent Autoimmune Diabetes in Adults (LADA) constitutes around 10% of all diabetes. Many LADA patients gradually lose their insulin secretion and progress to insulin dependency. In a recent trial BALAD (Behandling Av LADa) early insulin treatment compared with sitagliptin failed to preserve insulin secretion, which deteriorated in individuals displaying high levels of antibodies to GAD (GADA). These findings prompted us to evaluate a treatment that directly affects autoimmunity. Intra-lymphatic GAD-alum treatment has shown encouraging results in Type 1 diabetes patients. We therefore tested the feasibility of such therapy in LADA-patients (the GADinLADA pilot study). Material and MethodsFourteen GADA-positive (&gt;190 RU/ml), insulin-independent patients 30-70 years old, with LADA diagnosed within &lt; 36 months were included in an open-label feasibility trial. They received an intra-nodal injection of 4 mu g GAD-alum at Day 1, 30 and 60 plus oral Vitamin D 2000 U/d from screening 30 days before (Day -30) for 4 months if the vitamin D serum levels were below 100 nmol/L (40 ng/ml). Primary objective is to evaluate safety and feasibility. Mixed Meal Tolerance Test and i.v. Glucagon Stimulation Test at baseline and after 5 and 12 months are used for estimation of beta cell function. Results will be compared with those of the recent BALAD study with comparable patient population. Immunological response is followed. ResultsPreliminary results show feasibility and safety, with almost stable beta cell function and metabolic control during follow-up so far (5 months). ConclusionsIntra-lymphatic GAD-alum treatment is an option to preserve beta cell function in LADA-patients. An ongoing trial in 14 LADA-patients show feasibility and safety. Clinical and immunological responses will determine how to proceed with future trials.

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  • 37.
    Björn, Anders
    Linköping University, Department of Mathematics, Mathematics and Applied Mathematics. Linköping University, Faculty of Science & Engineering.
    HbA1c according to different standards2016Other (Other (popular science, discussion, etc.))
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  • 38.
    Björn, Anders
    Linköping University, Department of Mathematics, Mathematics and Applied Mathematics. Linköping University, Faculty of Science & Engineering.
    HbA1c enligt olika standarder2016Other (Other (popular science, discussion, etc.))
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  • 39.
    Björn, Anders
    Linköping University, Department of Mathematics, Mathematics and Applied Mathematics. Linköping University, Faculty of Science & Engineering.
    HbA1c podle různých standardů;2016Other (Other (popular science, discussion, etc.))
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  • 40.
    Bolivar Malachias, Marcus Vinicius
    et al.
    Fundacao Educ Lucas Machado, Brazil.
    Wijkman, Magnus
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Bertoluci, Marcello Casaccia
    Univ Fed Rio Grande do Sul, Brazil; Hosp Clin Porto Alegre, Brazil.
    NT-proBNP as a predictor of death and cardiovascular events in patients with type 2 diabetes2022In: Diabetology and Metabolic Syndrome, ISSN 1758-5996, E-ISSN 1758-5996, Vol. 14, no 1, article id 64Article, review/survey (Refereed)
    Abstract [en]

    Existing risk prediction scores based on clinical and laboratory variables have been considered inaccurate in patients with Type 2 Diabetes Mellitus (T2DM). Circulating concentrations of natriuretic peptides have been used to aid in the diagnosis and to predict outcomes in heart failure. However, there is a growing body of evidence for the use of natriuretic peptides measurements, mainly N-terminal pro-B-type natriuretic peptide (NT-proBNP), as a tool in risk stratification for individuals with T2DM. Studies have demonstrated the ability of NT-proBNP to improve outcomes prediction when incorporated into multivariate models. More recently, evidence has emerged of the discriminatory power of NT-proBNP, demonstrating, as a single variable, a similar and even superior ability to multivariate risk models for the prediction of death and cardiovascular events in individuals with T2DM. Natriuretic peptides are synthesized and released from the myocardium as a counter-regulatory response to increased cardiac wall stress, sympathetic tone, and vasoconstriction, acting on various systems and affecting different biological processes. In this article, we present a review of the accumulated knowledge about these biomarkers, underscoring the strength of the evidence of their predictive ability for fatal and non-fatal outcomes. It is likely that, by influencing the functioning of many organs, these biomarkers integrate information from different systems. Although not yet recommended by guidelines, measurement of natriuretic peptides, and particularly NT-proBNP, should be strongly considered in the risk stratification of individuals with T2DM.

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  • 41.
    Brismar, T. B.
    et al.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Shams, S.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Berinder, K.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Berlin, M.
    Karolinska University Hospital, Sweden.
    Udden, J.
    Karolinska University Hospital, Sweden.
    Brismar, K.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Ringertz, Hans
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    GLUCOCORTICOIDS AND SARCOIDOSIS: A LONGITUDINAL STUDY ON THE EFFECTS ON CORTICAL AND TRABECULAR BONE2015In: Sarcoidosis Vasculitis and Diffuse Lung Diseases, ISSN 1124-0490, Vol. 32, no 1, p. 63-69Article in journal (Refereed)
    Abstract [en]

    Background: Glucocorticoid induced osteoporosis is a well-known side effect of glucocorticoid treatment. In sarcoidosis the impact on bone by glucocorticoid treatment is complex due to hormonal disturbances of calcium and vitamin-D, which by itself may cause bone loss. In this study we aimed to investigate the longitudinal impact of glucocorticoids on cortical and trabecular bone in patients with mild, recently diagnosed sarcoidosis.

    Methods: Ten patients (8 females; mean age 44 (+/- 13)) were studied during one year of glucocorticoid treatment. The assessment of mainly cortical to purely trabecular bone was made by dual X-ray absorptiometry (DXA) of the spine and hip, quantitative ultrasound of the calcaneus, and magnetic resonance relaxometry of the spine and calcaneus. Bone and hormonal measurements were performed at baseline, after 3, 6, and 12 months, and baseline, 3 weeks and 3 months, respectively.

    Results: DXA of the spine, decreased from baseline at 6 months (P=0.01). R2 of the calcaneus decreased with time (B: -3.6; P=0.03). In the females (n=8) there was a significant decrease in DXA of the spine when comparing 3 months and 6 months (P=0.03), and 3 months and 12 months (P=0.02) and a decrease in R2 of the calcaneus from baseline to 12 months (P=0.01). There was no change in hormonal levels.

    Conclusion: Treatment of initial mild sarcoidosis with dose tapered glucocorticoid therapy only mildly affects the final trabecular and cortical bone and hormone levels. Dose tapering is an important part in glucocorticoid therapy, likely contributing to the mild effects on bone observed in this study.

  • 42.
    Bruchfeld, Annette
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Nephrology. Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    The COVID-19 pandemic: consequences for nephrology2021In: Nature Reviews Nephrology, ISSN 1759-5061, E-ISSN 1759-507X, Vol. 17, p. 81-82Article in journal (Other academic)
    Abstract [en]

    The consequences of the COVID-19 pandemic have been devastating; however, evidence suggests that patients with, or at risk of, kidney disease are disproportionally affected. Patients on dialysis and kidney transplant recipients are at higher risk of adverse outcomes from COVID-19, whereas, conversely, patients with severe COVID-19 are at increased risk of acute kidney injury, with short-term and possibly long-term consequences for nephrological care.

  • 43.
    Bruzzaniti, Sara
    et al.
    CNR, Italy.
    Piemonte, Erica
    Univ Naples Federico II, Italy.
    Bruzzese, Dario
    Univ Napoli Federico II, Italy.
    Lepore, Maria Teresa
    CNR, Italy.
    Strollo, Rocky
    Univ Telemat San Raffaele Roma, Italy.
    Izzo, Lavinia
    Univ Naples Federico II, Italy.
    Di Candia, Francesca
    Univ Napoli Federico II, Italy.
    Franzese, Adriana
    Univ Napoli Federico II, Italy.
    Bifulco, Maurizio
    Univ Naples Federico II, Italy.
    Mozzillo, Enza
    Univ Napoli Federico II, Italy.
    Ludvigsson, Johnny
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Matarese, Giuseppe
    CNR, Italy; Univ Naples Federico II, Italy.
    Galgani, Mario
    CNR, Italy; Univ Naples Federico II, Italy.
    Progression of type 1 diabetes is associated with high levels of soluble PD-1 in islet autoantibody-positive children2024In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesisType 1 diabetes is an autoimmune disorder that is characterised by destruction of pancreatic beta cells by autoreactive T lymphocytes. Although islet autoantibodies (AAb) are an indicator of disease progression, specific immune biomarkers that can be used as target molecules to halt development of type 1 diabetes have not been discovered. Soluble immune checkpoint molecules (sICM) play a pivotal role in counteracting excessive lymphocyte responses, but their role in type 1 diabetes is unexplored. In this longitudinal study, we measured sICM levels in AAb-positive (AAb+) children to identify molecules related to type 1 diabetes progression.MethodsWe measured the levels of 14 sICM in the sera of AAb+ children (n=57) compared to those with recent-onset type 1 diabetes (n=79) and healthy children (n=44), obtained from two cohorts. AAb+ children were followed up and divided based on their progression to type 1 diabetes (AAbP) or not (AAbNP) (if they lost islet autoimmunity and did not develop disease in subsequent years). sICM were also measured in the sample taken at the visit closest to disease onset in AAbP children.ResultsWe found that AAb+ children had a distinct sICM profile compared with healthy children and those with recent-onset type 1 diabetes. In addition, AAb+ children who progressed to type 1 diabetes (AAbP) had higher sICM concentrations than non-progressors (AAbNP). Further, sICM levels decreased in AAbP children close to disease onset. Application of Cox regression models highlighted that high concentrations of soluble programmed cell death protein 1 (sPD-1) are associated with type 1 diabetes progression (HR 1.71; 95% CI 1.16, 2.51; p=0.007).Conclusions/interpretationThis study reveals an sICM profile that is dysregulated during the preclinical stage of type 1 diabetes, and identifies sPD-1 as a pathophysiologically-relevant molecule that is associated with disease progression, offering a potential target for early interventions in autoimmune diabetes.

  • 44.
    Bruzzaniti, Sara
    et al.
    CNR, Italy; Univ Napoli Federico II, Italy.
    Piemonte, Erica
    Univ Napoli Federico II, Italy.
    Mozzillo, Enza
    Univ Napoli Federico II, Italy.
    Bruzzese, Dario
    Univ Napoli Federico II, Italy.
    Lepore, Maria Teresa
    CNR, Italy.
    Carbone, Fortunata
    CNR, Italy; Fdn Santa Lucia, Italy.
    de Candia, Paola
    Univ Napoli Federico II, Italy.
    Strollo, Rocky
    Univ Campus Biomed Roma, Italy.
    Porcellini, Antonio
    Univ Napoli Federico II, Italy.
    Marigliano, Marco
    Univ Verona, Italy; Azienda Osped Univ Integrata Verona, Italy.
    Maffeis, Claudio
    Univ Verona, Italy; Azienda Osped Univ Integrata Verona, Italy.
    Bifulco, Maurizio
    Univ Napoli Federico II, Italy.
    Ludvigsson, Johnny
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Franzese, Adriana
    Univ Napoli Federico II, Italy.
    Matarese, Giuseppe
    CNR, Italy; Univ Napoli Federico II, Italy.
    Galgani, Mario
    CNR, Italy; Univ Napoli Federico II, Italy.
    High levels of blood circulating immune checkpoint molecules in children with new-onset type 1 diabetes are associated with the risk of developing an additional autoimmune disease2022In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 65, p. 1390-1397Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis We assessed the levels of blood circulating immune checkpoint molecules (ICMs) at diagnosis of type 1 diabetes, and determined their association with the risk of developing an additional autoimmune disorder over time. Methods Children with new-onset type 1 diabetes (n = 143), without biological and/or clinical signs of additional autoimmune disorders, and healthy children (n = 75) were enrolled, and blood circulating levels of 14 ICMs were measured. The children with type 1 diabetes were divided into two groups on the basis of the development of an additional autoimmune disease in the 5 years after diabetes onset. Differences in soluble ICM levels between the groups were assessed, and a Cox regression analysis was used to evaluate their association with the risk of development of an additional autoimmune disease over time. To validate the data, circulating ICMs were measured in an independent cohort of 60 children with new-onset type 1 diabetes stratified into two groups. Results We found that the levels of circulating ICMs were significantly higher in children with new-onset diabetes compared with healthy children. Further, we observed that children with type 1 diabetes who developed a second autoimmune disease over time (T1D-AAD(+) children) had higher levels of soluble ICMs than children with type 1 diabetes who did not (T1D-AAD(-) children). Cox regression models revealed that high circulating levels of CD137/4-1BB and PD-1 molecules at diabetes diagnosis were associated with the risk of developing an additional autoimmune disease in both type 1 diabetes cohorts. Conclusions/interpretation Our findings suggest that soluble CD137/4-1BB and PD-1 molecules may be used as prognostic biomarkers in children with type 1 diabetes, and may pave the way for novel immunological screening at diabetes onset, allowing early identification of children at higher risk of developing other autoimmune conditions over time.

  • 45.
    Bullock, Martyn
    et al.
    Royal North Shore Hosp, Australia; Univ Sydney, Australia.
    Lim, Grace
    Royal North Shore Hosp, Australia; Univ Sydney, Australia.
    Zhu, Ying
    Royal North Shore Hosp, Australia.
    Åberg, Helena
    Linköping University, Faculty of Medicine and Health Sciences. Royal North Shore Hosp, Australia.
    Kurdyukov, Sergey
    Univ Sydney, Australia.
    Clifton-Bligh, Roderick
    Royal North Shore Hosp, Australia; Univ Sydney, Australia.
    ETS Factor ETV5 Activates the Mutant Telomerase Reverse Transcriptase Promoter in Thyroid Cancer2019In: Thyroid, ISSN 1050-7256, E-ISSN 1557-9077, Vol. 29, no 11, p. 1623-1633Article in journal (Refereed)
    Abstract [en]

    Background: Co-occurrence of TERT (telomerase reverse transcriptase) promoter (TERTp) mutations with BRAF/RAS mutations is associated with significantly more aggressive thyroid cancer. TERTp mutations are hypothesized to generate de novo binding sites for ETS transcription factors, which are themselves activated by BRAF/RAS-stimulated MEK-ERK activity. To date, a detailed study of this mechanism has been limited to only a few cancer types, and we hypothesized that ETS factors involved in TERTp activation could vary between different cancers. Methodology: Here we sought to identify ETS factor(s) required for TERTp activation in thyroid cancer, using a combination of in silico analyses of TCGA data, and experimentation using in vitro thyroid cell models analyzed by quantitative reverse transcription-PCR, immunoprecipitation (IP), chromatin IP, and gene reporter assays. Results: We found that ETV5 was abundantly expressed in papillary thyroid cancers from the TCGA data set, and in thyroid cancer cell line models. Furthermore, ETV5 was found to preferentially bind to the -124 bp(T) TERTp allele and stimulate TERT transcription in thyroid cancer cells devoid of GA binding protein transcription factor (GABP) activity. We also found that ETV5 functionally cooperates with the transcription factor FOXE1 to further enhance TERTp activity, a mechanism that may at least partially explain why FOXE1 represents a significant genetic determinant of thyroid cancer risk. Conclusions: ETS factors that activate mutant TERTp vary between cancer types, and here we show for the first time that ETV5 demonstrates mutant allele-specific affinity for TERTp in thyroid cancer, a property that has previously only been attributable to GABP.

  • 46.
    Bybrant, Mara Cerqueiro
    et al.
    Karolinska Inst, Sweden.
    Uden, Elin
    Lund Univ, Sweden.
    Frederiksen, Filippa
    Karolinska Inst, Sweden.
    Gustafsson, Anna L.
    Hallands Hosp, Sweden.
    Arvidsson, Carl-Goran
    Vastmanlands Hosp, Sweden.
    Fureman, Anna-Lena
    Ostersund Hosp, Sweden.
    Forsander, Gun
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Larsson, Helena Elding
    Lund Univ, Sweden.
    Ivarsson, Sten A.
    Lund Univ, Sweden.
    Lindgren, Marie
    Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Norrköping. Lund Univ, Sweden.
    Ludvigsson, Johnny
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Marcus, Claude
    Karolinska Inst, Sweden.
    Lycka, Auste Pundziute
    Sahlgrens Univ Hosp, Sweden.
    Persson, Martina
    Karolinska Univ Hosp, Sweden.
    Samuelsson, Ulf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Sarnblad, Stefan
    Orebro Univ, Sweden.
    Akesson, Karin
    Ryhov Cty Hosp, Sweden; Jonkoping Univ, Sweden.
    Ortqvist, Eva
    Karolinska Inst, Sweden.
    Carlsson, Annelie
    Lund Univ, Sweden.
    Celiac disease can be predicted by high levels of tissue transglutaminase antibodies in children and adolescents with type 1 diabetes2021In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 22, no 3, p. 417-424Article in journal (Refereed)
    Abstract [en]

    Objectives Children with type 1 diabetes (T1D) are not included in guidelines regarding diagnosis criteria for celiac disease (CD) without a diagnostic biopsy, due to lack of data. We explored whether tissue transglutaminase antibodies (anti-tTG) that were &gt;= 10 times the upper limit of normal (10x ULN) predicted CD in T1D. Methods Data from the Swedish prospective Better Diabetes Diagnosis study was used, and 2035 children and adolescents with T1D diagnosed between 2005-2010 were included. Of these, 32 had been diagnosed with CD before T1D. The children without CD were repeatedly screened for CD using anti-tTG antibodies of immunoglobulin type A. In addition, their human leukocyte antigen (HLA) were genotyped. All children with positive anti-tTG were advised to undergo biopsy. Biopsies were performed on 119 children and graded using the Marsh-Oberhuber classification. Results All of the 60 children with anti-tTG &gt;= 10x ULN had CD verified by biopsies. The degree of mucosal damage correlated with anti-tTG levels. Among 2003 screened children, 6.9% had positive anti-tTG and 5.6% were confirmed CD. The overall CD prevalence, when including the 32 children with CD before T1D, was 7.0% (145/2035). All but one of the children diagnosed with CD had HLA-DQ2 and/or DQ8. Conclusions As all screened children and adolescents with T1D with tissue transglutaminase antibodies above 10 times the positive value 10x ULN had CD, we propose that the guidelines for diagnosing CD in screened children, when biopsies can be omitted, should also apply to children and adolescents with T1D as a noninvasive method.

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  • 47.
    Bélteky, Malin
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Milletich, Patricia L.
    Univ Florida, FL 32611 USA.
    Ahrens, Angelica P.
    Univ Florida, FL 32611 USA.
    Triplett, Eric W.
    Univ Florida, FL 32611 USA.
    Ludvigsson, Johnny
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Infant gut microbiome composition correlated with type 1 diabetes acquisition in the general population: the ABIS study2023In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis While autoantibodies are traditional markers for type 1 diabetes development, we identified gut microbial biomarkers in 1-year-old infants associated with future type 1 diabetes up to 20 years before diagnosis. Methods Infants enrolled in the longitudinal general population cohort All Babies In Southeast Sweden (ABIS) provided a stool sample at a mean age of 12.5 months. Samples (future type 1 diabetes, n=16; healthy controls, n=268) were subjected to 16S ribosomal RNA (rRNA) sequencing and quantitative PCR. Microbial differences at the taxonomic and core microbiome levels were assessed. PICRUSt was used to predict functional content from the 16S rRNA amplicons. Sixteen infants, with a future diagnosis of type 1 diabetes at a mean age of 13.3 +/- 5.4 years, and one hundred iterations of 32 matched control infants, who remained healthy up to 20 years of age, were analysed. Results Parasutterella and Eubacterium were more abundant in healthy control infants, while Porphyromonas was differentially more abundant in infants with future type 1 diabetes diagnosis. Ruminococcus was a strong determinant in differentiating both control infants and those with future type 1 diabetes using random forest analysis and had differing trends of abundance when comparing control infants and those with future type 1 diabetes. Flavonifractor and UBA1819 were the strongest factors for differentiating control infants, showing higher abundance in control infants compared with those with future type 1 diabetes. Alternatively, Alistipes (more abundant in control infants) and Fusicatenibacter (mixed abundance patterns when comparing case and control infants) were the strongest factors for differentiating future type 1 diabetes. Predicted gene content regarding butyrate production and pyruvate fermentation was differentially observed to be higher in healthy control infants. Conclusions/interpretation This investigation suggests that microbial biomarkers for type 1 diabetes may be present as early as 1 year of age, as reflected in the taxonomic and functional differences of the microbial communities. The possibility of preventing disease onset by altering or promoting a healthy gut microbiome is appealing. Data availability The forward and reverse 16S raw sequencing data generated in this study are available through the NCBI Sequence Read Archive under BioProject PRJNA875929. Associated sample metadata used for statistical comparison are available in the source data file. R codes used for statistical comparisons and figure generation are available at: https://github.com/PMilletich/T1D_Pipeline.

  • 48.
    Carlhäll, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Bladh, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Brynhildsen, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Claesson, Ing-Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Josefsson, Ann
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Sydsjö, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Blomberg, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Maternal obesity (Class I-III), gestational weight gain and maternal leptin levels during and after pregnancy: a prospective cohort study2016In: BMC Obesity, ISSN 2052-9538, Vol. 3, no 28Article in journal (Refereed)
    Abstract [en]

    Background

    Maternal obesity is accompanied by maternal and fetal complications during and after pregnancy. The risks seem to increase with degree of obesity. Leptin has been suggested to play a role in the development of obesity related complications. Whether maternal leptin levels differ between obese and morbidly obese women, during and after pregnancy, have to our knowledge not been previously described. Neither has the association between maternal leptin levels and gestational weight gain in obese women. The aim was to evaluate if maternal plasma leptin levels were associated with different degrees of maternal obesity and gestational weight gain.

    Methods

    Prospective cohort study including women categorized as obesity class I-III (n = 343) and divided into three gestational weight gain groups (n = 304). Maternal plasma leptin was measured at gestational week 15, 29 and 10 weeks postpartum. Maternal Body Mass Index (BMI) was calculated from early pregnancy weight. Gestational weight gain was calculated using maternal weight in delivery week minus early pregnancy weight. The mean value and confidence interval of plasma-leptin were analysed with a two-way ANOVA model. Interaction effect between BMI and gestational weight gain group was tested with a two-way ANOVA model.

    Results

    The mean maternal leptin concentrations were significantly higher in women with obesity class III compared to women in obesity class I, at all times when plasma leptin were measured. The mean leptin concentrations were also significantly higher in women with obesity class II compared to women in obesity class I, except in gestational week 29. There was no difference in mean levels of plasma leptin between the gestational weight gain groups. No significant interaction between BMI and gestational weight gain group was found.

    Conclusions

    Plasma leptin levels during and after pregnancy were associated with obesity class but not with degree of gestational weight gain. These results are in concordance with epidemiological findings where the risk of obstetric complications increases with increased maternal obesity class. The effect on obstetric outcome by degree of gestational weight gain is less pronounced than the adverse effects associated with maternal obesity.

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    Maternal obesity (Class I-III), gestational weight gain and maternal leptin levels during and after pregnancy: a prospective cohort study
  • 49.
    Carlsson, Annelie
    et al.
    Lund Univ, Sweden.
    Shepherd, Maggie
    Univ Exeter, England.
    Ellard, Sian
    Univ Exeter, England; Royal Devon and Exeter NHS Fdn Trust, England.
    Weedon, Michael
    Univ Exeter, England.
    Lernmark, Ake
    Lund Univ, Sweden.
    Forsander, Gun
    Sahlgrens Univ Hosp, Sweden; Univ Gothenburg, Sweden.
    Colclough, Kevin
    Royal Devon and Exeter NHS Fdn Trust, England.
    Brahimi, Qefsere
    Lund Univ, Sweden.
    Valtonen-Andre, Camilla
    Univ and Reg Labs Reg, Sweden.
    Ivarsson, Sten A.
    Lund Univ, Sweden.
    Elding Larsson, Helena
    Lund Univ, Sweden.
    Samuelsson, Ulf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Ortqvist, Eva
    Karolinska Inst, Sweden.
    Groop, Leif
    Univ Helsinki, Finland.
    Ludvigsson, Johnny
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Marcus, Claude
    Karolinska Inst, Sweden.
    Hattersley, Andrew T.
    Univ Exeter, England.
    Absence of Islet Autoantibodies and Modestly Raised Glucose Values at Diabetes Diagnosis Should Lead to Testing for MODY: Lessons From a 5-Year Pediatric Swedish National Cohort Study2020In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 43, no 1, p. 82-89Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE Identifying maturity-onset diabetes of the young (MODY) in pediatric populations close to diabetes diagnosis is difficult. Misdiagnosis and unnecessary insulin treatment are common. We aimed to identify the discriminatory clinical features at diabetes diagnosis of patients with glucokinase (GCK), hepatocyte nuclear factor-1A (HNF1A), and HNF4A MODY in the pediatric population.

    RESEARCH DESIGN AND METHODS Swedish patients (n = 3,933) aged 1–18 years, diagnosed with diabetes May 2005 to December 2010, were recruited from the national consecutive prospective cohort Better Diabetes Diagnosis. Clinical data, islet autoantibodies (GAD insulinoma antigen-2, zinc transporter 8, and insulin autoantibodies), HLA type, and C-peptide were collected at diagnosis. MODY was identified by sequencing GCKHNF1A, and HNF4A, through either routine clinical or research testing.

    RESULTS The minimal prevalence of MODY was 1.2%. Discriminatory factors for MODY at diagnosis included four islet autoantibody negativity (100% vs. 11% not-known MODY; P = 2 × 10−44), HbA1c (7.0% vs. 10.7% [53 vs. 93 mmol/mol]; P = 1 × 10−20), plasma glucose (11.7 vs. 26.7 mmol/L; P = 3 × 10−19), parental diabetes (63% vs. 12%; P = 1 × 10−15), and diabetic ketoacidosis (0% vs. 15%; P = 0.001). Testing 303 autoantibody-negative patients identified 46 patients with MODY (detection rate 15%). Limiting testing to the 73 islet autoantibody-negative patients with HbA1c <7.5% (58 mmol/mol) at diagnosis identified 36 out of 46 (78%) patients with MODY (detection rate 49%). On follow-up, the 46 patients with MODY had excellent glycemic control, with an HbA1c of 6.4% (47 mmol/mol), with 42 out of 46 (91%) patients not on insulin treatment.

    CONCLUSIONS At diagnosis of pediatric diabetes, absence of all islet autoantibodies and modest hyperglycemia (HbA1c <7.5% [58 mmol/mol]) should result in testing for GCK, HNF1A, and HNF4A MODY. Testing all 12% patients negative for four islet autoantibodies is an effective strategy for not missing MODY but will result in a lower detection rate. Identifying MODY results in excellent long-term glycemic control without insulin.

  • 50.
    Carlsson, Axel C.
    et al.
    Karolinska Inst, Sweden.
    Nowak, Christoph
    Karolinska Inst, Sweden.
    Lind, Lars
    Uppsala Univ, Sweden.
    Östgren, Carl Johan
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Ödeshög.
    Nyström, Fredrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Cityhälsan Centrum.
    Sundstrom, Johan
    Uppsala Univ, Sweden.
    Carrero, Juan Jesus
    Karolinska Inst, Sweden.
    Riserus, Ulf
    Uppsala Univ, Sweden.
    Ingelsson, Erik
    Stanford Univ, CA 94305 USA; Stanford Univ, CA 94305 USA; Stanford Univ, CA 94305 USA; Uppsala Univ, Sweden.
    Fall, Tove
    Uppsala Univ, Sweden.
    Arnlov, Johan
    Karolinska Inst, Sweden; Dalarna Univ, Sweden.
    Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes: a proteomics approach2020In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 125, no 1, p. 37-43Article in journal (Refereed)
    Abstract [en]

    Background: Diabetic kidney disease (DKD) is a leading risk factor for end-stage renal disease and is one of the most important risk factors for cardiovascular disease in patients with diabetes. It is possible that novel markers portraying the pathophysiological underpinning processes may be useful. Aim: To investigate the associations between 80 circulating proteins, measured by a proximity extension assay, and prevalent DKD and major adverse cardiovascular events (MACE) in type 2 diabetes. Methods: We randomly divided individuals with type 2 diabetes from three cohorts into a two-thirds discovery and one-third replication set (total n = 813, of whom 231 had DKD defined by estimated glomerular filtration rate amp;lt;60 mg/mL/1.73 m(2) and/or urinary albumin-creatinine ratio amp;gt;= 3 g/mol). Proteins associated with DKD were also assessed as predictors for incident major adverse cardiovascular events (MACE) in persons with DKD at baseline. Results: Four proteins were positively associated with DKD in models adjusted for age, sex, cardiovascular risk factors, glucose control, and diabetes medication: kidney injury molecule-1 (KIM-1, odds ratio [OR] per standard deviation increment, 1.65, 95% confidence interval [CI] 1.27-2.14); growth differentiation factor 15 (GDF-15, OR 1.40, 95% CI 1.16-1.69); myoglobin (OR 1.57, 95% CI 1.30-1.91), and matrix metalloproteinase 10 (MMP-10, OR 1.43, 95% CI 1.17-1.74). In patients with DKD, GDF-15 was significantly associated with increased risk of MACE after adjustments for baseline age, sex, microalbuminuria, and kidney function and (59 MACE events during 7 years follow-up, hazard ratio per standard deviation increase 1.43 [95% CI 1.03-1.98]) but not after further adjustments for cardiovascular risk factors. Conclusion: Our proteomics approach confirms and extends previous associations of higher circulating levels of GDF-15 with both micro- and macrovascular disease in patients with type 2 diabetes. Our data encourage additional studies evaluating the clinical utility of our findings.

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