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  • 1.
    Brunner, G. A.
    et al.
    Department of Internal Medicine, Karl-Franzens University, Graz, Austria.
    Balent, B.
    Department of Internal Medicine, Karl-Franzens University, Graz, Austria.
    Ellmerer, M.
    Department of Internal Medicine, Karl-Franzens University, Graz, Austria.
    Schaupp, L.
    Department of Internal Medicine, Karl-Franzens University, Graz, Austria.
    Siebenhofer, A.
    Department of Internal Medicine, Karl-Franzens University, Graz, Austria.
    Jendle, Johan
    Novo Nordisk A/S, Copenhagen, Denmark.
    Okikawa, J.
    Aradigm Corp., Hayward, California, USA.
    Pieber, T. R.
    Department of Internal Medicine, Karl-Franzens University, Graz, Austria.
    Dose-response relation of liquid aerosol inhaled insulin in type I diabetic patients.2001In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 44, no 3, p. 305-308Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: The AERx insulin Diabetes Management system (AERx iDMS) is a liquid aerosol device that enables insulin to be administered to the peripheral parts of the lung. This study aimed to compare the pharmacokinetic and pharmacodynamic properties of insulin which is inhaled using AERx iDMS with insulin which is subcutaneously administered.

    METHODS: In total, 18 C-peptide negative patients with Type I (insulin-dependent) diabetes mellitus participated in this randomised, open-label, 5-period crossover trial. Human regular insulin was administered subcutaneously (0.12 U/kg body weight) or inhaled by means of the AERx iDMS (dosages 0.3, 0.6, 1.2, and 1.8 U/kg body weight). Thereafter plasma glucose was kept constant at 7.2 mmol/l for a 10-h period (glucose clamp technique).

    RESULTS: Inhaled insulin provided a dose-response relation that was close to linear for both pharmacokinetic (AUC-Ins(0-10 h); Cmax-Ins) and pharmacodynamic (AUC-GIR(0-10 h); GIRmax) parameters. Time to maximum insulin concentration (Tmax-Ins) and time to maximum glucose infusion rate (TGIRmax) were shorter with inhaled insulin than with subcutaneous administration. The pharmacodynamic system efficiency of inhaled insulin (AUC-GIR(0-6 h) was 12.7% (95% C.I.: 10.2-15.6).

    CONCLUSION/INTERPRETATION: The inhalation of soluble human insulin using the AERx iDMS is feasible and provides a clear dose response. Further long-term studies are required to investigate safety aspects, HbA1c values, incidence of hypoglycaemic events and the quality of life.

  • 2.
    de Mello, V. D. F.
    et al.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Lankinen, M.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland; VTT Technical Research Centre of Finland, Espoo, Finland.
    Schwab, U.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland; Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland.
    Kolehmainen, M.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Lehto, S.
    Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland.
    Seppänen-Laakso, T.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Pulkkinen, L.
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Uusitupa, M
    Department of Clinical Nutrition/Food and Health Research Centre, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Erkkilä, A. T.
    Department of Public Health, School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
    Link between plasma ceramides, inflammation and insulin resistance: association with serum IL-6 concentration in patients with coronary heart disease2009In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, no 12, p. 2612-2615Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: Ceramides and IL-6 have a role in immune-inflammatory responses and cardiovascular diseases, and are suggested to be involved in insulin and glucose metabolism. We sought to assess the associations of circulating levels of IL-6, TNF-alpha and high-sensitivity C reactive protein (hsCRP), which are inflammatory markers related to insulin resistance (IR), with the plasma lipid metabolites ceramides and diacylglycerols (DAG) in patients with CHD.

    METHODS: Cross-sectional analyses were carried out on data from 33 patients with CHD. Serum levels of the inflammatory markers and plasma lipid metabolites (lipidomics approach performed by ultra-performance liquid chromatography coupled to electrospray ionisation MS) were measured at the same time point as insulin resistance (IR) (HOMA-IR index).

    RESULTS: Serum circulating levels of IL-6 were strongly correlated with plasma ceramide concentrations (r = 0.59, p < 0.001). Adjustments for serum TNF-alpha or hsCRP levels, smoking, BMI, age, sex or HOMA-IR did not change the results (p < 0.001). After adjustments for the effect of serum inflammatory markers (TNF-alpha or hsCRP), HOMA-IR and BMI the correlation between plasma DAG and serum IL-6 (r = 0.33) was also significant (p < 0.03). In a linear regression model, circulating levels of both ceramides and TNF-alpha had a significant independent influence on circulating levels of IL-6, altogether accounting for 41% of its variation (p < 0.001).

    CONCLUSIONS/INTERPRETATION: Our results strongly suggest that the link between ceramides, IR and inflammation is related to the inflammatory marker IL-6. Ceramides may contribute to the induction of inflammation involved in IR states that frequently coexist with CHD.

  • 3.
    Ekelund, Ulf
    et al.
    Örebro University, School of Health and Medical Sciences.
    Anderssen, Sigmund
    Froberg, Karsten
    Sardinha, Luis B.
    Andersen, Lars Bo
    Brage, Sören
    Independent associations of physical activity and cardiorespiratory fitness with metabolic risk factors in children: the European youth heart study2007In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 50, no 9, p. 1832-1840Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: High levels of cardiorespiratory fitness (CRF) and physical activity (PA) are associated with a favourable metabolic risk profile. However, there has been no thorough exploration of the independent contributions of cardiorespiratory fitness and subcomponents of activity (total PA, time spent sedentary, and time spent in light, moderate and vigorous intensity PA) to metabolic risk factors in children and the relative importance of these factors. METHODS: We performed a population-based, cross-sectional study in 9- to 10- and 15- to 16-year-old boys and girls from three regions of Europe (n = 1709). We examined the independent associations of subcomponents of PA and CRF with metabolic risk factors (waist circumference, BP, fasting glucose, insulin, triacylglycerol and HDL-cholesterol levels). Clustered metabolic risk was expressed as a continuously distributed score calculated as the average of the standardised values of the six subcomponents. RESULTS: CRF (standardised beta = -0.09, 95% CI -0.12, -0.06), total PA (standardised beta = -0.08, 95% CI -0.10, -0.05) and all other subcomponents of PA were significantly associated with clustered metabolic risk. After excluding waist circumference from the summary score and further adjustment for waist circumference as a confounding factor, the magnitude of the association between CRF and clustered metabolic risk was attenuated (standardised beta = -0.05, 95% CI -0.08, -0.02), whereas the association with total PA was unchanged (standardised beta = -0.08 95% CI -0.10, -0.05). CONCLUSIONS/INTERPRETATION: PA and CRF are separately and independently associated with individual and clustered metabolic risk factors in children. The association between CRF and clustered risk is partly mediated or confounded by adiposity, whereas the association between activity and clustered risk is independent of adiposity. Our results suggest that fitness and activity affect metabolic risk through different pathways.

  • 4.
    Fraser, Abigail
    et al.
    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Lung and Allergy Unit, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Långström, Niklas
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lawlor, Debbie A
    MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
    Maternal diabetes in pregnancy and offspring cognitive ability: sibling study with 723,775 men from 579,857 families2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no 1, p. 102-109Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: The aim of this study was to investigate the association between maternal diabetes in pregnancy and offspring cognitive ability and also to assess whether the association was due to intrauterine mechanisms or shared familial characteristics.

    METHODS: We linked national registers and conducted a prospective cohort study of singleton Swedish-born men to explore associations between maternal pregnancy diabetes and educational achievement at age 16 years, the age of completing compulsory education in Sweden (n = 391,545 men from 337,174 families, graduating in 1988-1997 and n = 326,033 men from 282,079 families, graduating in 1998-2009), and intelligence quotient (IQ) at the mandatory conscription examination at 18 years of age (n = 664,871 from 543,203 families).

    RESULTS: Among non-siblings, maternal diabetes in pregnancy was associated with lower offspring cognitive ability even after adjustment for maternal age at birth, parity, education, early-pregnancy BMI, offspring birth year, gestational age and birthweight. For example, in non-siblings, the IQ of men whose mothers had diabetes in their pregnancy was on average 1.36 points lower (95% CI -2.12, -0.60) than men whose mothers did not have diabetes. In comparison, we found no such association within sibships (mean difference 1.70; 95% CI -1.80, 5.21).

    CONCLUSIONS/INTERPRETATION: The association between maternal diabetes in pregnancy and offspring cognitive outcomes is likely explained by shared familial characteristics and not by an intrauterine mechanism.

  • 5.
    Jansson, Stefan P. O.
    et al.
    Örebro University, Department of Clinical Medicine.
    Andersson, D. K. G.
    Svärdsudd, K.
    Prevalence and incidence rate of diabetes mellitus in a Swedish community during 30 years of follow-up2007In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 50, no 4, p. 703-710Article in journal (Refereed)
    Abstract [en]

    Increasing diabetes prevalence has been reported in most European countries in the last 20 years. In this study we report on the development of prevalence and incidence of diabetes from 1972 to 2001 in Laxa, a rural community in central Sweden. A diabetes register was established at the primary healthcare centre (PHCC) in Laxa, beginning in 1972 and based on data from clinical records at the PHCC, nearby hospitals and private practitioners in the area. In addition, case-finding procedures involving 85% of the residents aged 35 to 79 years old was performed from 1983 onwards. During the study period a total of 776 new diabetes cases was found, 36 type 1 diabetes mellitus and 740 type 2 diabetes mellitus. The age-standardised incidence rates for type 1 diabetes mellitus and type 2 diabetes mellitus were 0.15 and 3.03 cases per 1,000 population, respectively. No increase in incidence over time was detected for either forms of diabetes. Age-standardised prevalence for women and men increased from 28.3 and 25.9, respectively, per 1,000 in 1972 to 45 and 46.3 per 1,000 in 1988 (p < 0.0001), thereafter falling to a mean of 43.5 per 1,000 for women, while men had a mean of 44.9 per 1,000 for the rest of the study period. The prevalence of diabetes mellitus in Laxa is high, but has not increased during the last 13 years. The incidence rate was relatively stable over the whole 30-year period.

  • 6.
    Jendle, Johan
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Endocrine and Diabetes Center, University of Örebro, Örebro, Sweden.
    Blonde, L.
    Ochsner Medical Center, New Orleans LA, USA.
    Rosenstock, J.
    Dallas Diabetes and Endocrine Center, Dallas, USA.
    Woo, V.
    University of Manitoba, Winnipeg, Canada.
    Gross, J.
    Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
    Jiang, H.
    Eli Lilly and Company, Indianapolis, USA.
    Milicevic, Z.
    Eli Lilly and Company, Vienna, Austria.
    Better glycaemic control and less weight gain with once weekly dulaglutide vs bedtime insulin glargine, both combined with thrice daily lispro, in type 2 diabetes (AWARD-4)2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no Suppl 1, p. S23-S24Article in journal (Other academic)
    Abstract [en]

    Background and aims: This 52 week, parallel-arm, open-label, phase 3 study compared two doses of the once weekly GLP-1 receptor agonist dulaglutide (DU) versus bedtime insulin glargine, all combined with pre-meal insulin lispro with or without metformin, in patients with type 2 diabetes mellitus inadequately controlled on conventional insulin therapy. Insulin glargine and insulin lispro were titrated to attempt to reach glycaemic targets.

    Materials and methods: Patients (N = 884; mean baseline characteristics: age 59.4 years; duration of diabetes 12.7 years; HbA1c 8.5%; body weight 91.1 kg; BMI 32.5 kg/m2; total daily insulin dose 56 U) were randomised (1:1:1) to once weekly DU 1.5 mg, DU 0.75 mg, or bedtime insulin glargine titrated-to-target. The primary objective was to compare the change in HbA1c from baseline of DU 1.5 mg with insulin glargine at 26 weeks for noninferiority (margin 0.4%) and if met, then superiority was tested.

    Results: At 26 and 52 weeks, both DU doses were statistically superior to insulin glargine for HbA1c change from baseline. Insulin glargine was associ-ated with greater fasting serum glucose reduction compared with both DU doses. The mean prandial insulin doses at 26 weeks were 93 U for DU 1.5 mg, 97 U for DU 0.75 mg, and 68 U for insulin glargine. The insulin glargine dose was 65 U. Similar insulin doses were observed at 52 weeks. Body weight decreased with DU 1.5 mg and increased with DU 0.75 mg and insulin glar-gine at 52 weeks. The rate of documented symptomatic hypoglycaemia (≤3.9 mmol/L) at 52 weeks was 31.0, 35.0,and 39.9 events/patient/year for DU 1.5 mg, DU 0.75 mg, and insulin glargine, respectively. The number of severe hypoglycaemia events was 11 for DU 1.5 mg, 15 for DU 0.75 mg, and 22 for insulin glargine. Nausea, diarrhoea, and vomiting were more common with DU 1.5 mg (25.8%, 16.6%, and 12.2%, respectively) and DU 0.75 mg (17.7%, 15.7%, and 10.6%) versus insulin glargine (3.4%, 6.1%, and 1.7%).

    Conclusion: DU compared to insulin glargine, both combined with insu-lin lispro, resulted in better glycaemic control, less body weight gain, no in-creased risk of hypoglycaemia, and more common reporting of gastrointes-tinal adverse events.

  • 7.
    Jendle, Johan
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Testa, M.
    TH Chan Sch Publ Hlth, Harvard Univ, Boston, USA.
    Martin, S.
    Eli Lilly and Company, Indianapolis, USA.
    Jiang, H.
    Eli Lilly and Company, Indianapolis, USA.
    Milicevic, Z.
    Eli Lilly and Company Regional Operations, Vienna, Austria.
    Continuous glucose monitoring in type 2 diabetes patients treated with once weekly dulaglutide or once daily glargine, both combined with insulin lispro (AWARD-4 substudy)2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, p. S38-S38Article in journal (Other academic)
  • 8.
    Kotronen, A.
    et al.
    Department of Medicine, Division of Diabetes, Helsinki University Central Hospital, Helsinki, Finland; Minerva Medical Research Institute, Helsinki, Finland.
    Velagapudi, V. R.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Yetukuri, L.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Westerbacka, J.
    Department of Medicine, Division of Diabetes, Helsinki University Central Hospital, Helsinki, Finland.
    Bergholm, R.
    Department of Medicine, Division of Diabetes, Helsinki University Central Hospital, Helsinki, Finland; Minerva Medical Research Institute, Helsinki, Finland.
    Ekroos, K.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Makkonen, J.
    Department of Medicine, Division of Diabetes, Helsinki University Central Hospital, Helsinki, Finland; Minerva Medical Research Institute, Helsinki, Finland.
    Taskinen, M.-R.
    Department of Medicine, Division of Diabetes, Helsinki University Central Hospital, Helsinki, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Yki-Järvinen, H.
    Department of Medicine, Division of Diabetes, Helsinki University Central Hospital, Helsinki, Finland.
    Serum saturated fatty acids containing triacylglycerols are better markers of insulin resistance than total serum triacylglycerol concentrations2009In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, no 4, p. 684-690Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: The weak relationship between insulin resistance and total serum triacylglycerols (TGs) could be in part due to heterogeneity of TG molecules and their distribution within different lipoproteins. We determined concentrations of individual TGs and the fatty acid composition of serum and major lipoprotein particles and analysed how changes in different TGs and fatty acid composition are related to features of insulin resistance and abdominal obesity.

    METHODS: We performed lipidomic analyses of all major lipoprotein fractions using two analytical platforms in 16 individuals, who exhibited a broad range of insulin sensitivity.

    RESULTS: We identified 45 different TGs in serum. Serum TGs containing saturated and monounsaturated fatty acids were positively, while TGs containing essential linoleic acid (18:2 n-6) were negatively correlated with HOMA-IR. Specific serum TGs that correlated positively with HOMA-IR were also significantly positively related to HOMA-IR when measured in very-low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs) and LDL, but not in HDL subfraction 2 (HDL(2)) or 3 (HDL(3)). Analyses of proportions of esterified fatty acids within lipoproteins revealed that palmitic acid (16:0) was positively related to HOMA-IR when measured in VLDL, IDL and LDL, but not in HDL(2) or HDL(3). Monounsaturated palmitoleic (16:1 n-7) and oleic (18:1 n-9) acids were positively related to HOMA-IR when measured in HDL(2) and HDL(3), but not in VLDL, IDL or LDL. Linoleic acid was negatively related to HOMA-IR in all lipoproteins.

    CONCLUSIONS/INTERPRETATION: Serum concentrations of specific TGs, such as TG(16:0/16:0/18:1) or TG(16:0/18:1/18:0), may be more precise markers of insulin resistance than total serum TG concentrations.

  • 9.
    Lamichhane, Santosh
    et al.
    Turku Bioscience, University of Turku and Åbo Akademi University, Turku, Finland.
    Kemppainen, Esko
    Turku Bioscience, University of Turku and Åbo Akademi University, Turku, Finland.
    Trošt, Kajetan
    Steno Diabetes Center Copenhagen, Gentofte, Denmark.
    Siljander, Heli
    Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program Unit, University of Helsinki, Helsinki, Finland.
    Hyöty, Heikki
    Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
    Ilonen, Jorma
    Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland; Clinical Microbiology, Turku University Hospital, Turku, Finland.
    Toppari, Jorma
    Institute of Biomedicine, Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland; Department of Pediatrics, Turku University Hospital, Turku, Finland.
    Veijola, Riitta
    Department of Pediatrics, PEDEGO Research Unit, Medical Research Centre, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland; Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Knip, Mikael
    Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program Unit, University of Helsinki, Helsinki, Finland; Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland; Folkhälsan Research Center, Helsinki, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience, University of Turku and Åbo Akademi University, Turku, Finland; .
    Circulating metabolites in progression to islet autoimmunity and type 1 diabetes2019In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, no 12, p. 2287-2297Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: Metabolic dysregulation may precede the onset of type 1 diabetes. However, these metabolic disturbances and their specific role in disease initiation remain poorly understood. In this study, we examined whether children who progress to type 1 diabetes have a circulatory polar metabolite profile distinct from that of children who later progress to islet autoimmunity but not type 1 diabetes and a matched control group.

    METHODS: We analysed polar metabolites from 415 longitudinal plasma samples in a prospective cohort of children in three study groups: those who progressed to type 1 diabetes; those who seroconverted to one islet autoantibody but not to type 1 diabetes; and an antibody-negative control group. Metabolites were measured using two-dimensional GC high-speed time of flight MS.

    RESULTS: In early infancy, progression to type 1 diabetes was associated with downregulated amino acids, sugar derivatives and fatty acids, including catabolites of microbial origin, compared with the control group. Methionine remained persistently upregulated in those progressing to type 1 diabetes compared with the control group and those who seroconverted to one islet autoantibody. The appearance of islet autoantibodies was associated with decreased glutamic and aspartic acids.

    CONCLUSIONS/INTERPRETATION: Our findings suggest that children who progress to type 1 diabetes have a unique metabolic profile, which is, however, altered with the appearance of islet autoantibodies. Our findings may assist with early prediction of the disease.

  • 10.
    Lind, Lars
    et al.
    Dept Med Sci, Uppsala Univ, Uppsala, Sweden.
    Zethelius, Björn
    Dept Publ Hlth Geriatr, Uppsala Univ, Uppsala, Sweden; Med Prod Agcy, Uppsala, Sweden.
    Salihovic, Samira
    Örebro University, School of Science and Technology. Dept Med Sci, Uppsala Univ, Uppsala, Sweden.
    van Bavel, Bert
    Örebro University, School of Science and Technology.
    Lind, P. Monica
    Dept Med Sci Occupat & Environm Med, Uppsala Univ, Uppsala, Sweden.
    Circulating levels of perfluoroalkyl substances and prevalent diabetes in the elderly2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no 3, p. 473-479Article in journal (Refereed)
    Abstract [en]

    Several environmental contaminants, such as polychlorinated biphenyls, dioxins, bisphenol A and phthalates, have been linked to diabetes. We therefore investigated whether other kinds of contaminants, perfluoroalkyl substances (PFAS), also called perfluorinated compounds (PFCs), are also associated with diabetes.

    The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study investigated 1,016 men and women aged 70 years. Seven PFAS were detected in almost all participant sera by ultra-high performance liquid chromatograph/tandem mass spectrometry. Diabetes was defined as use of hypoglycaemic agents or fasting glucose > 7.0 mmol/l.

    114 people had diabetes. In the linear analysis, no significant relationships were seen between the seven PFAS and prevalent diabetes. However, inclusion of the quadratic terms of the PFAS revealed a significant non-linear relationship between perfluorononanoic acid (PFNA) and diabetes, even after adjusting for multiple confounders (OR 1.96, 95% CI 1.19, 3.22, p = 0.008 for the linear term and OR 1.25, 95% CI 1.08, 1.44, p = 0.002 for the quadratic term). Perfluorooctanoic acid (PFOA) also showed such a relationship (p = 0.01). PFOA was related to the proinsulin/insulin ratio (a marker of insulin secretion), but none of the PFAS was related to the HOMA-IR (a marker of insulin resistance) following adjustment for multiple confounders.

    PFNA was related to prevalent diabetes in a non-monotonic fashion in this cross-sectional study, supporting the view that this perfluoroalkyl substance might influence glucose metabolism in humans at the level of exposure seen in the general elderly population.

  • 11.
    Lindblad, Per
    et al.
    Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden.
    Chow, W. H.
    National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, Maryland, USA.
    Chan, J.
    Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
    Bergström, A.
    Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden.
    Wolk, A.
    Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden.
    Gridley, G.
    National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, Maryland, USA.
    McLaughlin, J. K.
    International Epidemiology Institute, Rockville, Maryland, USA.
    Nyren, O.
    Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden.
    Adami, H. O.
    Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden.
    The role of diabetes mellitus in the aetiology of renal cell cancer1999In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 42, no 1, p. 107-12Article in journal (Refereed)
    Abstract [en]

    To investigate the relation between diabetes mellitus and the risk of renal cell cancer we carried out a population-based retrospective cohort study. Patients identified in the Swedish Inpatient Register who were discharged from hospitals with a diagnosis of diabetes mellitus between 1965 and 1983 formed a cohort of 153852 patients (80005 women and 73847 men). The cohort members were followed up to 1989 by record linkage to three nation-wide registries. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were computed using age-specific sex-specific and period-specific incidence and mortality rates derived from the entire Swedish population. After exclusion of the first year of observation, a total of 267 incidences of renal cell cancer (ICD-7:180.0) occurred in diabetic patients compared with the 182.4 that had been expected. Increased risks were observed in both women (SIR = 1.7, 95% confidence interval, CI = 1.4-2.0) and men (SIR = 1.3; 95 % CI = 1.1-1.6) throughout the duration of follow-up (1-25 years). A higher risk was seen for kidney cancer (ICD-7:180) mortality (SMR = 1.9; 95% CI = 1.7-2.2, women; SMR 1.7, 95% CI = 1.4-1.9, men). In comparison with the general population, patients with diabetes mellitus have an increased risk of renal cell cancer.

  • 12.
    Lundman, P.
    et al.
    Department of Clinical Sciences, Karolinska Institutet, Stockholm, Sweden; Department of Cardiology, Danderyd University Hospital, Stockholm, Sweden.
    Karayiannides, S.
    Department of Clinical Sciences, Karolinska Institutet, Stockholm, Sweden; Department of Internal Medicine, Danderyd University Hospital, Stockholm, Sweden.
    Fröbert, Ole
    Örebro University, School of Medical Sciences. Department of Cardiology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    James, S.
    Department of Medical Sciences, Cardiology and Uppsala Clinical Research center, Uppsala University, Uppsala, Sweden.
    Lagerqvist, B.
    Department of Medical Sciences, Cardiology and Uppsala Clinical Research center, Uppsala University, Uppsala, Sweden.
    Norhammar, A.
    Cardiology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Higher one-year mortality in patients with diabetes and ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no Suppl. 1, p. S529-S530Article in journal (Other academic)
    Abstract [en]

    Background and aims: Patients with diabetes mellitus have a worse prognosis after acute coronary syndromes than patients without diabetes. Outcomes in patients with diabetes after ST-segment elevation myocar-dial infarction (STEMI) in the era of modern interventional treatment and antiplatelet therapy are less well studied. The aim is to characterise outcomes and complications in a contemporary population with diabetes and STEMI undergoing primary percutaneous coronary intervention (PCI).

    Materials and methods: In the registry-based randomised Thrombus Aspiration in ST-Elevation myocardial infarction in Scandinavia (TASTE) trial, 7244 patients with STEMI were randomised to undergo manual thrombus aspiration followed by PCI or to undergo PCI alone. Thrombus aspiration did not affect mortality at one year in the 1005 patients (13.9%) with diabetes [Hazard ratio (HR) 1.04; CI 0.69-1.58,p=0.839]. Therefore, all patients with diabetes, irrespective ofrandomisation in TASTE, were studied as one cohort. All patients were followed for incidence of all-cause mortality, myocardial infarction or stent thrombosis until one year after index event. HRs were calculated using a Cox proportional hazard regression model adjusted for comorbidities.

    Results: Patients with diabetes were older (mean age 67.6 vs 66.0 years, p<0.001), more often had a previous myocardial infarction (19.9 vs 10.3%, p<0.001) and undergone previous PCI (17.3 vs 8.4%, p<0.001). Thrombus grade did not differ between patients with and without diabetes (Grade 0 to Grade 5, p=0.909) and neither did the type of affected coronary vessel. Pharmacological cardiovascular treatment did not differ between groups, but the use of drug eluting stents was higher in patients with diabetes (59.0 vs 48.4%, p<0.001). After adjustment for comorbidities, diabetes independently increased the risk for mortality (HR 1.57; CI 1.23-2.00, p<0.001), but was not an independent risk factor for future myocardial infarction or stent thrombosis.

    Conclusion: Diabetes remained an adverse prognostic risk factor in this contemporary setting, resulting in increased one-year mortality in a large cohort of patients with STEMI treated with PCI. This was not influenced by thrombus aspiration and not explained by a higher thrombus burden or differences in cardiovascular medical therapy compared to patients without diabetes.

  • 13.
    Mollazadegan, Kaziwe
    et al.
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; St. Erik Eye Hospital, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Fored, Michael
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Lundberg, Sigrid
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ludvigsson, Johnny
    Div. of Pediatrics, Östergötland County Council, Linköping, Sweden; Pediatrics, Linköping University, Linköping, Sweden.
    Ekbom, Anders
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Montgomery, Scott M.
    Örebro University Hospital. Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Clinical Epidemiology and Biostatistics, Örebro University Hospital, Örebro, Sweden; Department of Epidemiology and Public Health, University College London, London, United Kingdom.
    Ludvigsson, Jonas F.
    Örebro University Hospital. Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Risk of renal disease in patients with both type 1 diabetes and coeliac disease2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no 7, p. 1339-1345Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Our aim was to study the risk of renal disease in patients with type 1 diabetes (T1D) and coexisting coeliac disease (CD).

    Methods: Individuals with T1D were defined as having a diagnosis of diabetes recorded at <= 30 years of age in the Swedish Patient Register between 1964 and 2009. Individuals with CD were identified through biopsy reports with villous atrophy (Marsh stage 3) from 28 pathology departments in Sweden between 1969 and 2008. We identified 954 patients with both T1D and CD. For each patient with T1D + CD, we selected five age- and sex-matched reference individuals with T1D only (n = 4,579). Cox regression was used to estimate the following risks: (1) chronic renal disease and (2) end-stage renal disease in patients with CD + T1D compared with T1D patients only.

    Results: Forty-one (4.3%) patients with CD + T1D and 143 (3.1%) patients with T1D only developed chronic renal disease. This corresponded to an HR of 1.43 for chronic renal disease (95% CI 0.94, 2.17) in patients with CD + T1D compared with T1D only. In addition, for end-stage renal disease there was a positive (albeit statistically non-significant) HR of 2.54 (95% CI 0.45, 14.2). For chronic renal disease, the excess risk was more pronounced after >10 years of CD (HR 2.03, 95% CI 1.08, 3.79). Risk estimates were similar when we restricted our cohort to the following T1D patients: (1) those who had an inpatient diagnosis of T1D; (2) those who had never received oral glucose-lowering medication; and (3) those who had not received their first diabetes diagnosis during pregnancy.

    Conclusions/interpretation: Overall this study found no excess risk of chronic renal disease in patients with T1D and CD. However, in a subanalysis we noted a positive association between longstanding CD and chronic renal disease in T1D.

  • 14.
    Naukkarinen, J.
    et al.
    Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Biomedicum Helsinki, Finland; FIMM, Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
    Heinonen, S.
    Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Biomedicum Helsinki, Finland.
    Hakkarainen, A.
    Helsinki Medical Imaging Center, University of Helsinki, Helsinki, Finland.
    Lundbom, J.
    Helsinki Medical Imaging Center, University of Helsinki, Helsinki, Finland.
    Vuolteenaho, K.
    The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland.
    Saarinen, L.
    Computational Systems Biology Laboratory, Genome-Scale Biology Research Program, Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
    Hautaniemi, S.
    Computational Systems Biology Laboratory, Genome-Scale Biology Research Program, Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
    Rodriguez, A.
    Metabolic Research Laboratory, Clinica Univ. de Navarra, University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Madrid, Spain.
    Frühbeck, G.
    Metabolic Research Laboratory, Clinica Univ. de Navarra, University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Madrid, Spain.
    Pajunen, P.
    Diabetes Prevention Unit,Division of Welfare andHealth Promotion, National Institute for Health and Welfare, Helsinki, Finland.
    Hyötyläinen, Tuulia
    Systems Biology and Bioinformatics, VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    Systems Biology and Bioinformatics, VTT Technical Research Centre of Finland, Espoo, Finland.
    Moilanen, E.
    The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland.
    Suomalainen, A.
    Research Program of Molecular Neurology and Department of Neurology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Lundbom, N.
    Helsinki Medical Imaging Center, University of Helsinki, Helsinki, Finland.
    Kaprio, J.
    FIMM, Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Finnish Twin Cohort Study, Hjelt Institute, University of Helsinki, Helsinki, Finland; Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.
    Rissanen, A.
    Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Biomedicum Helsinki, Finland.
    Pietiläinen, K. H.
    Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Biomedicum Helsinki, Finland; FIMM, Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Division of Endocrinology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
    Characterising metabolically healthy obesity in weight-discordant monozygotic twins2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no 1, p. 167-176Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Not all obese individuals display the metabolic disturbances commonly associated with excess fat accumulation. Mechanisms maintaining this ‘metabolically healthy obesity’ (MHO) are as yet unknown. We aimed to study different fat depots and transcriptional pathways in subcutaneous adipose tissue (SAT) as related to the MHO phenomenon.

    Methods: Sixteen rare young adult obesity-discordant monozygotic (MZ) twin pairs (intra-pair difference (∆) in BMI ≥3 kg/m2), aged 22.8–35.8 years, were examined for detailed characteristics of metabolic health (subcutaneous, intra-abdominal and liver fat [magnetic resonance imaging/spectroscopy]), OGTT, lipids, adipokines and C-reactive protein (CRP). Affymetrix U133 Plus 2.0 chips were used to analyse transcriptomics pathways related to mitochondrial function and inflammation in SAT.

    Results: Based on liver fat accumulation, two metabolically different subgroups emerged. In half (8/16) of the pairs (∆weight 17.1 ± 2.0 kg), the obese co-twin had significantly higher liver fat (∆718%), 78% increase in AUC insulin during OGTT and CRP, significantly more disturbance in the lipid profile and greater tendency for hypertension compared with the lean co-twin. In these obese co-twins, SAT expression of mitochondrial oxidative phosphorylation, branched-chain amino acid catabolism, fatty acid oxidation and adipocyte differentiation pathways were downregulated and chronic inflammation upregulated. In the other eight pairs (∆weight 17.4 ± 2.8 kg), the obese co-twin did not differ from the non-obese co-twin in liver fat (∆8%), insulin sensitivity, CRP, lipids, blood pressure or SAT transcriptomics.

    Conclusions/interpretation: Our results suggest that maintenance of high mitochondrial transcription and lack of inflammation in SAT are associated with low liver fat and MHO.

  • 15.
    Orešič, Matej
    et al.
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland.
    Kotronen, Anna
    Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland.
    Gopalacharyulu, Peddinti
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Arola, Johanna
    Department of Pathology, HUSLAB, University of Helsinki, Helsinki, Finland.
    Castillo, Sandra
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mattila, Ismo
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Hakkarainen, Antti
    Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland.
    Borra, Ronald J H
    Turku PET Centre, University of Turku, Turku, Finland; Medical Imaging Centre of Southwest Finland, Turku University Hospital, Turku, Finland.
    Honka, Miikka-Juhani
    Turku PET Centre, University of Turku, Turku, Finland.
    Verrijken, An
    Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
    Francque, Sven
    Department of Gastroenterology and Hepatology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
    Iozzo, Patricia
    Turku PET Centre, University of Turku, Turku, Finland; Institute of Clinical Physiology, National Research Council, Pisa, Italy.
    Leivonen, Marja
    Department of Surgery, Helsinki University Central Hospital, Vantaa, Finland.
    Jaser, Nabil
    Department of Surgery, Helsinki University Central Hospital, Vantaa, Finland.
    Juuti, Anne
    Department of Surgery, Helsinki University Central Hospital, Vantaa, Finland.
    Sørensen, Thorkild I A
    Institute of Preventive Medicine, Copenhagen University Hospitals, Copenhagen, Denmark.
    Nuutila, Pirjo
    Turku PET Centre, University of Turku, Turku, Finland.
    Van Gaal, Luc
    Medical Imaging Centre of Southwest Finland, Turku University Hospital, Turku, Finland.
    Yki-Järvinen, Hannele
    Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland.
    Prediction of non-alcoholic fatty-liver disease and liver fat content by serum molecular lipids2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, no 10, p. 2266-2274Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: We examined whether analysis of lipids by ultra-performance liquid chromatography (UPLC) coupled to MS allows the development of a laboratory test for non-alcoholic fatty-liver disease (NAFLD), and how a lipid-profile biomarker compares with the prediction of NAFLD and liver-fat content based on routinely available clinical and laboratory data.

    METHODS: We analysed the concentrations of molecular lipids by UPLC-MS in blood samples of 679 well-characterised individuals in whom liver-fat content was measured using proton magnetic resonance spectroscopy ((1)H-MRS) or liver biopsy. The participants were divided into biomarker-discovery (n = 287) and validation (n = 392) groups to build and validate the diagnostic models, respectively.

    RESULTS: Individuals with NAFLD had increased triacylglycerols with low carbon number and double-bond content while lysophosphatidylcholines and ether phospholipids were diminished in those with NAFLD. A serum-lipid signature comprising three molecular lipids ('lipid triplet') was developed to estimate the percentage of liver fat. It had a sensitivity of 69.1% and specificity of 73.8% when applied for diagnosis of NAFLD in the validation series. The usefulness of the lipid triplet was demonstrated in a weight-loss intervention study.

    CONCLUSIONS/INTERPRETATION: The liver-fat-biomarker signature based on molecular lipids may provide a non-invasive tool to diagnose NAFLD, in addition to highlighting lipid molecular pathways involved in the disease.

  • 16.
    Sen, Partho
    et al.
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Dickens, Alex M.
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    López-Bascón, María Asunción
    Department of Chemistry, Örebro University, Örebro, Sweden; Department of Analytical Chemistry, University of Córdoba, Córdoba, Spain; .
    Lindeman, Tuomas
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Kemppainen, Esko
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Lamichhane, Santosh
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Rönkkö, Tuukka
    Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Ilonen, Jorma
    Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland; Clinical Microbiology, Turku University Hospital, Turku, Finland.
    Toppari, Jorma
    Department of Pediatrics and Adolescent Medicine, Turku University Hospital, Turku, Finland; Institute of Biomedicine, Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland..
    Veijola, Riitta
    Department of Pediatrics, PEDEGO Research Unit, Medical Research Centre, University of Oulu, Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Hyöty, Heikki
    Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Knip, Mikael
    Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Tampere Centre for Child Health Research, Tampere University Hospital, Tampere, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
    Metabolic alterations in immune cells associate with progression to type 1 diabetes2020In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: Previous metabolomics studies suggest that type 1 diabetes is preceded by specific metabolic disturbances. The aim of this study was to investigate whether distinct metabolic patterns occur in peripheral blood mononuclear cells (PBMCs) of children who later develop pancreatic beta cell autoimmunity or overt type 1 diabetes.

    METHODS: In a longitudinal cohort setting, PBMC metabolomic analysis was applied in children who (1) progressed to type 1 diabetes (PT1D, n = 34), (2) seroconverted to ≥1 islet autoantibody without progressing to type 1 diabetes (P1Ab, n = 27) or (3) remained autoantibody negative during follow-up (CTRL, n = 10).

    RESULTS: During the first year of life, levels of most lipids and polar metabolites were lower in the PT1D and P1Ab groups compared with the CTRL group. Pathway over-representation analysis suggested alanine, aspartate, glutamate, glycerophospholipid and sphingolipid metabolism were over-represented in PT1D. Genome-scale metabolic models of PBMCs during type 1 diabetes progression were developed by using publicly available transcriptomics data and constrained with metabolomics data from our study. Metabolic modelling confirmed altered ceramide pathways, known to play an important role in immune regulation, as specifically associated with type 1 diabetes progression.

    CONCLUSIONS/INTERPRETATION: Our data suggest that systemic dysregulation of lipid metabolism, as observed in plasma, may impact the metabolism and function of immune cells during progression to overt type 1 diabetes.

    DATA AVAILABILITY: The GEMs for PBMCs have been submitted to BioModels (www.ebi.ac.uk/biomodels/), under accession number MODEL1905270001. The metabolomics datasets and the clinical metadata generated in this study were submitted to MetaboLights (https://www.ebi.ac.uk/metabolights/), under accession number MTBLS1015.

  • 17.
    Ylipaasto, Petri
    et al.
    Intestinal Viruses Unit, National Intestinal Viruses Unit, National Institute for Health and Welfare (THL), Helsinki, Finland.
    Smura, Teemu
    Intestinal Viruses Unit, National Institute for Health and Welfare (THL), Helsinki, Finland.
    Gopalacharyulu, Peddinti
    VTT Technical Research Center of Finland, Espoo, Finland.
    Paananen, Anja
    Intestinal Viruses Unit, National Institute for Health and Welfare (THL), Helsinki, Finland.
    Seppänen-Laakso, Tuulikki
    VTT Technical Research Center of Finland, Espoo, Finland.
    Kaijalainen, Svetlana
    Intestinal Viruses Unit, National Institute for Health and Welfare (THL), Helsinki, Finland.
    Ahlfors, Helena
    Division of Molecular Immunology, MRC National Institute for Medical Research, London, United Kingdom; Centre for Biotechnology, University of Turku, Turku, Finland.
    Korsgren, Olle
    Division of Clinical Immunology, Department of Oncology, Radiology, and Clinical Immunology, Uppsala University, Uppsala, Sweden.
    Lakey, Jonathan R. T.
    Department of Surgery, University of California, Irvine CA, United States.
    Lahesmaa, R.
    Centre for Biotechnology, University of Turku, Turku, Finland.
    Piemonti, Lorenzo
    Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milan, Italy.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Intestinal Viruses Unit, National Institute for Health and Welfare (THL), Helsinki, Finland.
    Galama, Jochem
    Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
    Roivainen, Merja M.
    Intestinal Viruses Unit, National Institute for Health and Welfare (THL), Helsinki, Finland.
    Enterovirus-induced gene expression profile is critical for human pancreatic islet destruction2012In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, no 12, p. 3273-3283Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: Virally induced inflammatory responses, beta cell destruction and release of beta cell autoantigens may lead to autoimmune reactions culminating in type 1 diabetes. Therefore, viral capability to induce beta cell death and the nature of virus-induced immune responses are among key determinants of diabetogenic viruses. We hypothesised that enterovirus infection induces a specific gene expression pattern that results in islet destruction and that such a host response pattern is not shared among all enterovirus infections but varies between virus strains.

    METHODS: The changes in global gene expression and secreted cytokine profiles induced by lytic or benign enterovirus infections were studied in primary human pancreatic islet using DNA microarrays and viral strains either isolated at the clinical onset of type 1 diabetes or capable of causing a diabetes-like condition in mice.

    RESULTS: The expression of pro-inflammatory cytokine genes (IL-1-α, IL-1-β and TNF-α) that also mediate cytokine-induced beta cell dysfunction correlated with the lytic potential of a virus. Temporally increasing gene expression levels of double-stranded RNA recognition receptors, antiviral molecules, cytokines and chemokines were detected for all studied virus strains. Lytic coxsackievirus B5 (CBV-5)-DS infection also downregulated genes involved in glycolysis and insulin secretion.

    CONCLUSIONS/INTERPRETATION: The results suggest a distinct, virus-strain-specific, gene expression pattern leading to pancreatic islet destruction and pro-inflammatory effects after enterovirus infection. However, neither viral replication nor cytotoxic cytokine production alone are sufficient to induce necrotic cell death. More likely the combined effect of these and possibly cellular energy depletion lie behind the enterovirus-induced necrosis of islets.

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