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  • 1. Albrechtsen, A.
    et al.
    Grarup, N.
    Li, Y.
    Sparso, T.
    Tian, G.
    Cao, H.
    Jiang, T.
    Kim, S. Y.
    Korneliussen, T.
    Li, Q.
    Nie, C.
    Wu, R.
    Skotte, L.
    Morris, A. P.
    Ladenvall, C.
    Cauchi, S.
    Stancakova, A.
    Andersen, G.
    Astrup, A.
    Banasik, K.
    Bennett, A. J.
    Bolund, L.
    Charpentier, G.
    Chen, Y.
    Dekker, J. M.
    Doney, A. S. F.
    Dorkhan, M.
    Forsen, T.
    Frayling, T. M.
    Groves, C. J.
    Gui, Y.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hattersley, A. T.
    He, K.
    Hitman, G. A.
    Holmkvist, J.
    Huang, S.
    Jiang, H.
    Jin, X.
    Justesen, J. M.
    Kristiansen, K.
    Kuusisto, J.
    Lajer, M.
    Lantieri, O.
    Li, W.
    Liang, H.
    Liao, Q.
    Liu, X.
    Ma, T.
    Ma, X.
    Manijak, M. P.
    Marre, M.
    Mokrosinski, J.
    Morris, A. D.
    Mu, B.
    Nielsen, A. A.
    Nijpels, G.
    Nilsson, P.
    Palmer, C. N. A.
    Rayner, N. W.
    Renstrom, F.
    Ribel-Madsen, R.
    Robertson, N.
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Rossing, P.
    Schwartz, T. W.
    Slagboom, P. E.
    Sterner, M.
    Tang, M.
    Tarnow, L.
    Tuomi, T.
    van't Riet, E.
    van Leeuwen, N.
    Varga, T. V.
    Vestmar, M. A.
    Walker, M.
    Wang, B.
    Wang, Y.
    Wu, H.
    Xi, F.
    Yengo, L.
    Yu, C.
    Zhang, X.
    Zhang, J.
    Zhang, Q.
    Zhang, W.
    Zheng, H.
    Zhou, Y.
    Altshuler, D.
    't Hart, L. M.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Balkau, B.
    Froguel, P.
    McCarthy, M. I.
    Laakso, M.
    Groop, L.
    Christensen, C.
    Brandslund, I.
    Lauritzen, T.
    Witte, D. R.
    Linneberg, A.
    Jorgensen, T.
    Hansen, T.
    Wang, J.
    Nielsen, R.
    Pedersen, O.
    Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, no 2, p. 298-310Article in journal (Refereed)
    Abstract [en]

    Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) > 1% with common metabolic phenotypes. The study comprised three stages. We performed medium-depth (8x) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI > 27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. Exome sequencing identified 70,182 polymorphisms with MAF > 1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 x 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 x 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 x 10(-10)). We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.

  • 2. Ali, Yusuf
    et al.
    Diez, Juan
    Selander, Lars
    Zheng, Xiaofeng
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.
    Berggren, Per-Olof
    The anterior chamber of the eye is a transplantation site that supports and enables visualisation of beta cell development in mice2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 5, p. 1007-1011Article in journal (Refereed)
    Abstract [en]

    In vivo imaging of the developing pancreas is challenging due to the inaccessibility of the tissue. To circumvent this, on embryonic day 10.5 (E10.5) we transplanted a mouse developing pancreatic bud into the anterior chamber of the eye (ACE) to determine whether the eye is a useful transplant site to support pancreas development. We transplanted an E10.5 dorsal pancreatic bud into the ACE of a syngeneic recipient mouse. Using a mouse insulin promoter-green fluorescent protein (MIP-GFP) mouse as the tissue donor, we non-invasively imaged the pancreatic bud as it develops at single beta cell resolution across time. The transplanted pancreatic bud rapidly engrafts and vascularises when transplanted into the ACE. The pancreatic progenitor cells differentiate into exocrine and endocrine cells, including cells expressing insulin, glucagon and somatostatin. The morphology of the transplanted pancreatic bud resembles that of the native developing pancreas. Beta cells within the transplanted pancreatic bud respond to glucose in a manner similar to that of native fetal beta cells and superior to that of in vitro developed beta cells. Unlike in vitro grown pancreatic explants, pancreatic tissue developing in the ACE is vascularised, providing the developing pancreatic tissue with a milieu resembling the native situation. Altogether, we show that the ACE is able to support growth, differentiation and function of a developing pancreatic bud across time in vivo.

  • 3. Allin, Kristine H.
    et al.
    Tremaroli, Valentina
    Caesar, Robert
    Jensen, Benjamin A. H.
    Damgaard, Mads T. F.
    Bahl, Martin I.
    Licht, Tine R.
    Hansen, Tue H.
    Nielsen, Trine
    Dantoft, Thomas M.
    Linneberg, Allan
    Jørgensen, Torben
    Vestergaard, Henrik
    Kristiansen, Karsten
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Hansen, Torben
    Bäckhed, Fredrik
    Pedersen, Oluf
    Aberrant intestinal microbiota in individuals with prediabetes2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 4, p. 810-820Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Individuals with type 2 diabetes have aberrant intestinal microbiota. However, recent studies suggest that metformin alters the composition and functional potential of gut microbiota, thereby interfering with the diabetes-related microbial signatures. We tested whether specific gut microbiota profiles are associated with prediabetes (defined as fasting plasma glucose of 6.1-7.0 mmol/l or HbA1c of 42-48 mmol/mol [6.0-6.5%]) and a range of clinical biomarkers of poor metabolic health.

    Methods: In the present case-control study, we analysed the gut microbiota of 134 Danish adults with prediabetes, overweight, insulin resistance, dyslipidaemia and low-grade inflammation and 134 age-and sex-matched individuals with normal glucose regulation.

    Results: We found that five bacterial genera and 36 operational taxonomic units (OTUs) were differentially abundant between individuals with prediabetes and those with normal glucose regulation. At the genus level, the abundance of Clostridium was decreased (mean log2 fold change -0.64 (SEM 0.23), p adj = 0.0497), whereas the abundances of Dorea, [Ruminococcus], Sutterella and Streptococcus were increased (mean log2 fold change 0.51 (SEM 0.12), p adj = 5 x 10-4; 0.51 (SEM 0.11), p adj = 1 x 10-4; 0.60 (SEM 0.21), p adj = 0.0497; and 0.92 (SEM0.21), p adj = 4 x 10-4, respectively). The two OTUs that differed the most were a member of the order Clostridiales (OTU 146564) and Akkermansia muciniphila, which both displayed lower abundance among individuals with prediabetes (mean log2 fold change -1.74 (SEM0.41), p adj = 2 x 10-3 and -1.65 (SEM0.34), p adj = 4 x 10-4, respectively). Faecal transfer from donors with prediabetes or screen-detected, drug-naive type 2 diabetes to germfree Swiss Webster or conventional C57BL/6 J mice did not induce impaired glucose regulation in recipient mice.

    Conclusions/interpretation: Collectively, our data show that individuals with prediabetes have aberrant intestinal microbiota characterised by a decreased abundance of the genus Clostridium and the mucin-degrading bacterium A. muciniphila. Our findings are comparable to observations in overt chronic diseases characterised by low-grade inflammation.

  • 4. Almby, K. E.
    et al.
    Abrahamsson, N.
    Lundqvist, M. H.
    Hammar, U.
    Thombare, K.
    Panagiotou, A.
    Karlsson, F. A.
    Sundbom, M.
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Eriksson, J. W.
    Effects of GLP-1 receptor activation on counterregulatory responses during hypoglycaemia after gastric bypass surgery: no evidence for GLP-1 as a counterregulatory hormone2019In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, p. S416-S416Article in journal (Other academic)
  • 5. Almby, K. E.
    et al.
    Abrahamsson, N.
    Lundqvist, M. H.
    Hammar, U.
    Thombare, K.
    Panagiotou, A.
    Karlsson, F. A.
    Sundbom, M.
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Eriksson, J. W.
    Effects of GLP-1 receptor activation on counterregulatory responses during hypoglycaemia after gastric bypass surgery: no evidence for GLP-1 as a counterregulatory hormone2019In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, p. S416-S416Article in journal (Refereed)
  • 6. Alssema, M
    et al.
    Vistisen, D
    Heymans, M W
    Nijpels, G
    Glümer, C
    Zimmet, P Z
    Shaw, J E
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stehouwer, C D A
    Tabák, A G
    Colagiuri, S
    Borch-Johnsen, K
    Dekker, J M
    Risk scores for predicting type 2 diabetes: using the optimal tool2011In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 54, no 9, p. 2468-2470Article in journal (Refereed)
  • 7. Alssema, M
    et al.
    Vistisen, D
    Heymans, MW
    Nijpels, G
    Glümer, C
    Zimmet, PZ
    Shaw, JE
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stehouwer, CDA
    Tabák, AG
    Colagiuri, S
    Borch-Johnsen, K
    Dekker, JM
    The evaluation of screening and early detection strategies for type 2 diabetes and impaired glucose tolerance (DETECT-2) update of the Finnish diabetes risk score for prediction of incident type 2 diabetes2011In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 54, no 5, p. 1004-1012Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: The Finnish diabetes risk questionnaire is a widely used, simple tool for identification of those at risk for drug-treated type 2 diabetes. We updated the risk questionnaire by using clinically diagnosed and screen-detected type 2 diabetes instead of drug-treated diabetes as an endpoint and by considering additional predictors.

    METHODS: Data from 18,301 participants in studies of the Evaluation of Screening and Early Detection Strategies for Type 2 Diabetes and Impaired Glucose Tolerance (DETECT-2) project with baseline and follow-up information on oral glucose tolerance status were included. Incidence of type 2 diabetes within 5 years was used as the outcome variable. Improvement in discrimination and classification of the logistic regression model was assessed by the area under the receiver-operating characteristic (ROC) curve and by the net reclassification improvement. Internal validation was by bootstrapping techniques.

    RESULTS: Of the 18,301 participants, 844 developed type 2 diabetes in a period of 5 years (4.6%). The Finnish risk score had an area under the ROC curve of 0.742 (95% CI 0.726-0.758). Re-estimation of the regression coefficients improved the area under the ROC curve to 0.766 (95% CI 0.750-0.783). Additional items such as male sex, smoking and family history of diabetes (parent, sibling or both) improved the area under the ROC curve and net reclassification. Bootstrapping showed good internal validity.

    CONCLUSIONS/INTERPRETATION: The predictive value of the original Finnish risk questionnaire could be improved by adding information on sex, smoking and family history of diabetes. The DETECT-2 update of the Finnish diabetes risk questionnaire is an adequate and robust predictor for future screen-detected and clinically diagnosed type 2 diabetes in Europid populations.

  • 8.
    Andersen, C. D.
    et al.
    Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Bennet, L.
    Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden.
    Nyström, Lennarth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Lindblad, U.
    Department of Primary Health Care, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Lindholm, E.
    Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Groop, L.
    Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Worse glycaemic control in LADA patients than in those with type 2 diabetes, despite a longer time on insulin therapy2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, no 2, p. 252-258Article in journal (Refereed)
    Abstract [en]

    Our aim was to study whether glycaemic control differs between individuals with latent autoimmune diabetes in adults (LADA) and patients with type 2 diabetes, and whether it is influenced by time on insulin therapy. We performed a retrospective study of 372 patients with LADA (205 men and 167 women; median age 54 years, range 35-80 years) from Swedish cohorts from SkAyenne (n = 272) and Vasterbotten (n = 100). Age- and sex-matched patients with type 2 diabetes were included as controls. Data on the use of oral hypoglycaemic agents (OHAs), insulin and insulin-OHA combination therapy was retrieved from the medical records. Poor glycaemic control was defined as HbA(1c) a parts per thousand yen7.0% (a parts per thousand yen53 mmol/mol) at follow-up. The individuals with LADA and with type 2 diabetes were followed for an average of 107 months. LADA patients were leaner than type 2 diabetes patients at diagnosis (BMI 27.7 vs 31.0 kg/m(2); p < 0.001) and follow-up (BMI 27.9 vs 30.2 kg/m(2); p < 0.001). Patients with LADA had been treated with insulin for longer than those with type 2 diabetes (53.3 vs 28.8 months; p < 0.001). There was no significant difference between the patient groups with regard to poor glycaemic control at diagnosis, but more patients with LADA (67.8%) than type 2 diabetes patients (53.0%; p < 0.001) had poor glycaemic control at follow-up. Patients with LADA had worse glycaemic control at follow-up compared with participants with type 2 diabetes (OR = 1.8, 95% CI 1.2, 2.7), adjusted for age at diagnosis, HbA(1c), BMI at diagnosis, follow-up time and duration of insulin treatment. Individuals with LADA have worse glycaemic control than patients with type 2 diabetes despite a longer time on insulin therapy.

  • 9. Andersen, Mette K.
    et al.
    Sterner, Maria
    Forsen, Tom
    Käräjämäki, Annemari
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Forsblom, Carol
    Groop, Per-Henrik
    Lahti, Kaj
    Nilsson, Peter M.
    Groop, Leif
    Tuomi, Tiinamaija
    Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no 9, p. 1859-1868Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Latent autoimmune diabetes in adults (LADA) is phenotypically a hybrid of type 1 and type 2 diabetes. Genetically LADA is poorly characterised but does share genetic predisposition with type 1 diabetes. We aimed to improve the genetic characterisation of LADA and hypothesised that type 2 diabetes-associated gene variants also predispose to LADA, and that the associations would be strongest in LADA patients with low levels of GAD autoantibodies (GADA). Methods We assessed 41 type 2 diabetes-associated gene variants in Finnish (phase I) and Swedish (phase II) patients with LADA (n=911) or type 1 diabetes (n=406), all diagnosed after the age of 35 years, as well as in non-diabetic control individuals 40 years or older (n=4,002). Results Variants in the ZMIZ1 (rs12571751, p=4.1 x 10(-5)) and TCF7L2 (rs7903146, p=5.8 x 10(-4)) loci were strongly associated with LADA. Variants in the KCNQ1 (rs2237895, p=0.0012), HHEX (rs1111875, p=0.0024 in Finns) and MTNR1B (rs10830963, p=0.0039) loci showed the strongest association in patients with low GADA, supporting the hypothesis that the disease in these patients is more like type 2 diabetes. In contrast, variants in the KLHDC5 (rs10842994, p=9.5 x 10(-4) in Finns), TP53INP1 (rs896854, p=0.005), CDKAL1 (rs7756992, p=7.0 x 10(-4); rs7754840, p=8.8 x 10(-4)) and PROX1 (rs340874, p=0.003) loci showed the strongest association in patients with high GADA. For type 1 diabetes, a strong association was seen for MTNR1B (rs10830963, p=3.2 x 10(-6)) and HNF1A (rs2650000, p=0.0012). Conclusions/interpretation LADA and adult-onset type 1 diabetes share genetic risk variants with type 2 diabetes, supporting the idea of a hybrid form of diabetes and distinguishing them from patients with classical young-onset type 1 diabetes.

  • 10. Bakhtadze, E
    et al.
    Borg, H
    Stenström, G
    Fernlund, P
    Arnqvist, H J
    Ekbom-Schnell, A
    Bolinder, J
    Eriksson, Jan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Gudbjörnsdottir, S
    Nyström, Lennarth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Groop, L C
    Sundkvist, G
    HLA-DQB1 genotypes, islet antibodies and beta cell function in the classification of recent-onset diabetes among young adults in the nationwide Diabetes Incidence Study in Sweden.2006In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 49, no 8, p. 1785-1794Article in journal (Refereed)
  • 11. Bendinelli, B.
    et al.
    Palli, D.
    Masala, G.
    Sharp, S. J.
    Schulze, M. B.
    Guevara, M.
    van der A, D. L.
    Sera, F.
    Amiano, P.
    Balkau, B.
    Barricarte, A.
    Boeing, H.
    Crowe, F. L.
    Dahm, C. C.
    Dalmeijer, G.
    de Lauzon-Guillain, B.
    Egeberg, R.
    Fagherazzi, G.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden.
    Krogh, V.
    Huerta, J. M.
    Jakszyn, P.
    Khaw, K. T.
    Li, K.
    Mattiello, A.
    Nilsson, P. M.
    Overvad, K.
    Ricceri, F.
    Rodríguez-Suárez, L.
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Sánchez, M. J.
    Slimani, N.
    Sluijs, I.
    Spijkerman, A. M. W.
    Teucher, B.
    Tjonneland, A.
    Tumino, R.
    van den Berg, S. W.
    Forouhi, N. G.
    Langenberg, C.
    Feskens, E. J. M.
    Riboli, E.
    Wareham, N. J.
    Association between dietary meat consumption and incident type 2 diabetes: the EPIC-InterAct study2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, no 1, p. 47-59Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: A diet rich in meat has been reported to contribute to the risk of type 2 diabetes. The present study aims to investigate the association between meat consumption and incident type 2 diabetes in the EPIC-InterAct study, a large prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

    Methods: During 11.7 years of follow-up, 12,403 incident cases of type 2 diabetes were identified among 340,234 adults from eight European countries. A centre-stratified random subsample of 16,835 individuals was selected in order to perform a case-cohort design. Prentice-weighted Cox regression analyses were used to estimate HR and 95% CI for incident diabetes according to meat consumption.

    Results: Overall, multivariate analyses showed significant positive associations with incident type 2 diabetes for increasing consumption of total meat (50 g increments: HR 1.08; 95% CI 1.05, 1.12), red meat (HR 1.08; 95% CI 1.03, 1.13) and processed meat (HR 1.12; 95% CI 1.05, 1.19), and a borderline positive association with meat iron intake. Effect modifications by sex and class of BMI were observed. In men, the results of the overall analyses were confirmed. In women, the association with total and red meat persisted, although attenuated, while an association with poultry consumption also emerged (HR 1.20; 95% CI 1.07, 1.34). These associations were not evident among obese participants.

    Conclusions/interpretation: This prospective study confirms a positive association between high consumption of total and red meat and incident type 2 diabetes in a large cohort of European adults.

  • 12.
    Bergman, Marie-Louise
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Penha-Gonçalves, Carlos
    Gulbenkian Institute for Science, Oeiras, Portugal, PT.
    Lejon, Kristina
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Low rate of proliferation in immature thymocytes of the non-obese diabetic mouse maps to the Idd6 diabetes susceptibility region2001In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 44, no 8, p. 1054-1061Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: The non-obese diabetic (NOD) mouse spontaneously develops T-cell-dependent autoimmune diabetes. This mouse strain has a number of immune dysfunctions related to T-cell development but so far there are no available data on the proliferation of NOD immature thymocytes. We therefore studied the thymocyte proliferation in the NOD mouse in discrete stages of T-cell development.

    Methods: We depleted thymocytes in vivo and analysed thymocyte proliferation during the thymus recovery from depletion. We used co-segregation analysis and quantitative loci trait analysis to investigate the genetic control of proliferation impairments in NOD thymocytes.

    Results: Immature thymocytes of female NOD mice proliferate with a relatively low rate compared to non-autoimmune C57Bl/6 mice. This aberrant proliferation was most pronounced in CD4 /loCD8+ cells differentiating from the CD4CD8 to the CD4+CD8+ stage. A genetic mapping study using an F2 intercross between the NOD and the C57BL/6 strains showed that a major locus controlling this trait is linked to the insulin-dependent diabetes susceptibility locus Idd6.

    Conclusion/interpretation: Our results suggest that impairment of proliferation of immature thymocytes is one possible mechanism through which the Idd6 locus contributes to the pathogenesis of diabetes.

  • 13.
    Brito, Ema C
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Vimaleswaran, K S
    Brage, S
    Andersen, L B
    Sardinha, L B
    Wareham, N J
    Ekelund, U
    Loos, R J F
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    PPARGC1A sequence variation and cardiovascular risk-factor levels: a study of the main genetic effects and gene x environment interactions in children from the European youth heart study2009In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, no 4, p. 609-613Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: The PPARGC1A gene coactivates multiple nuclear transcription factors involved in cellular energy metabolism and vascular stasis. In the present study, we genotyped 35 tagging polymorphisms to capture all common PPARGC1A nucleotide sequence variations and tested for association with metabolic and cardiovascular traits in 2,101 Danish and Estonian boys and girls from the European Youth Heart Study, a multicentre school-based cross-sectional cohort study. METHODS: Fasting plasma glucose concentrations, anthropometric variables and blood pressure were measured. Habitual physical activity and aerobic fitness were objectively assessed using uniaxial accelerometry and a maximal aerobic exercise stress test on a bicycle ergometer, respectively. RESULTS: In adjusted models, nominally significant associations were observed for BMI (rs10018239, p = 0.039), waist circumference (rs7656250, p = 0.012; rs8192678 [Gly482Ser], p = 0.015; rs3755863, p = 0.02; rs10018239, beta = -0.01 cm per minor allele copy, p = 0.043), systolic blood pressure (rs2970869, p = 0.018) and fasting glucose concentrations (rs11724368, p = 0.045). Stronger associations were observed for aerobic fitness (rs7656250, p = 0.005; rs13117172, p = 0.008) and fasting glucose concentrations (rs7657071, p = 0.002). None remained significant after correcting for the number of statistical comparisons. We proceeded by testing for gene x physical activity interactions for the polymorphisms that showed nominal evidence of association in the main effect models. None of these tests was statistically significant. CONCLUSIONS/INTERPRETATION: Variants at PPARGC1A may influence several metabolic traits in this European paediatric cohort. However, variation at PPARGC1A is unlikely to have a major impact on cardiovascular or metabolic health in these children.

  • 14.
    Dahlquist, Gisela
    Department of Paediatrics, Sachs' Children's Hospital, Stockholm.
    Epidemiological and ethical consiluations on trials with immunotherapy in pre-type 1 (insulin-dependent) diabetes mellitus1991In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 34, no 7, p. 536-Article in journal (Refereed)
  • 15.
    Dahlquist, Gisela
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Gothefors, Leif
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    The cumulative incidence of childhood diabetes mellitus in Sweden unaffected by BCG-vaccination.1995In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 38, no 7, p. 873-4Article in journal (Refereed)
  • 16.
    Dahlquist, Gisela
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Källén, B
    School performance in children with type 1 diabetes: a population-based register study2007In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 50, no 5, p. 957-964Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: We examined the school marks of diabetic children in Sweden at the time of leaving compulsory education. Marks were examined in comparison with non-diabetic children and with special regard to age at onset of diabetes.

    SUBJECTS AND METHODS: The study involved 5,159 children who developed diabetes between 1 July 1977 and 1 July 2000, and 1,330,968 non-diabetic children. We linked the nationwide Swedish Childhood Diabetes Register to the Swedish School-Mark Register, which contains school marks for all children in Sweden at the time of leaving compulsory education (usually at 16 years old). Adjustment was made for potential confounders such as year of birth, maternal age, parity and educational level.

    RESULTS: The mean of all numerical school marks for diabetic children was slightly but statistically significantly lower than those of the referent children (3.15 +/- 0.01 [mean + SD] vs 3.23, p < 0.001). The lowest mean score was among children with diabetes diagnosis before the age of 2 years (2.97 +/- 0.09 vs 3.08-3.17 in the older age groups, p = 0.10). When individual subjects were studied (sports, mathematics, English and Swedish), a more complex picture emerged. In four subjects (mathematics, English, Swedish and sports) the risk of a diabetic child not getting a school mark or not passing was increased; in sports and English the diabetic children had significantly reduced odds of getting a high mark.

    CONCLUSIONS/INTERPRETATION: Despite a well-developed diabetes care system, we have not succeeded in preventing the disease from affecting school achievements. Among children with a young age at onset and therefore longer duration, the negative effects tend to be greater.

  • 17. Dawed, Adem Y.
    et al.
    Ali, Ashfaq
    Zhou, Kaixin
    Pearson, Ewan R.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, USA.
    Evidence-based prioritisation and enrichment of genes interacting with metformin in type 2 diabetes2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no 11, p. 2231-2239Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: There is an extensive body of literature suggesting the involvement of multiple loci in regulating the action of metformin; most findings lack replication, without which distinguishing true-positive from false-positive findings is difficult. To address this, we undertook evidence-based, multiple data integration to determine the validity of published evidence. Methods: We (1) built a database of published data on gene-metformin interactions using an automated text-mining approach (n = 5963 publications), (2) generated evidence scores for each reported locus, (3) from which a rank-ordered gene set was generated, and (4) determined the extent to which this gene set was enriched for glycaemic response through replication analyses in a well-powered independent genome-wide association study (GWAS) dataset from the Genetics of Diabetes and Audit Research Tayside Study (GoDARTS). Results: From the literature search, seven genes were identified that are related to the clinical outcomes of metformin. Fifteen genes were linked with either metformin pharmacokinetics or pharmacodynamics, and the expression profiles of a further 51 genes were found to be responsive to metformin. Gene-set enrichment analysis consisting of the three sets and two more composite sets derived from the above three showed no significant enrichment in four of the gene sets. However, we detected significant enrichment of genes in the least prioritised category (a gene set in which their expression is affected by metformin) with glycaemic response to metformin (p = 0.03). This gene set includes novel candidate genes such as SLC2A4 (p = 3.24 x 10(-04)) and G6PC (p = 4.77 x 10(-04)). Conclusions/interpretation: We have described a semi-automated text-mining and evidence-scoring algorithm that facilitates the organisation and extraction of useful information about gene-drug interactions. We further validated the output of this algorithm in a drug-response GWAS dataset, providing novel candidate loci for gene-metformin interactions.

  • 18. Donnelly, Louise A.
    et al.
    Zhou, Kaixin
    Doney, Alex S. F.
    Jennison, Chris
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Department of Clinical Science, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, USA.
    Pearson, Ewan R.
    Rates of glycaemic deterioration in a real-world population with type 2 diabetes2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 3, p. 607-615Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: There is considerable variability in how diabetes progresses after diagnosis. Progression modelling has largely focused on 'time to failure' methods, yet determining a 'coefficient of failure' has many advantages. We derived a rate of glycaemic deterioration in type 2 diabetes, using a large real-world cohort, and aimed to investigate the clinical, biochemical, pharmacological and immunological variables associated with fast and slow rates of glycaemic deterioration. Methods: An observational cohort study was performed using the electronic medical records from participants in the Genetics of Diabetes Audit and Research in Tayside Study (GoDARTS). A model was derived based on an individual's observed HbA(1c) measures from the first eligible HbA(1c) after the diagnosis of diabetes through to the study end (defined as insulin initiation, death, leaving the area or end of follow-up). Each HbA(1c) measure was time-dependently adjusted for the effects of non-insulin glucose-lowering drugs, changes in BMI and corticosteroid use. GAD antibody (GADA) positivity was defined as GAD titres above the 97.5th centile of the population distribution. Results: The mean (95% CI) glycaemic deterioration for type 2 diabetes and GADA-positive individuals was 1.4 (1.3, 1.4) and 2.8 (2.4, 3.3) mmol/mol HbA(1c) per year, respectively. A younger age of diagnosis, lower HDL-cholesterol concentration, higher BMI and earlier calendar year of diabetes diagnosis were independently associated with higher rates of glycaemic deterioration in individuals with type 2 diabetes. The rate of deterioration in those diagnosed at over 70 years of age was very low, with 66% having a rate of deterioration of less than 1.1 mmol/mol HbA(1c) per year, and only 1.5% progressing more rapidly than 4.4 mmol/mol HbA(1c) per year. Conclusions/interpretation: We have developed a novel approach for modelling the progression of diabetes in observational data across multiple drug combinations. This approach highlights how glycaemic deterioration in those diagnosed at over 70 years of age is minimal, supporting a stratified approach to diabetes management.

  • 19. Ekelund, U.
    et al.
    Palla, L.
    Brage, S.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Lund University, Malmö, Sweden.
    Peters, T.
    Balkau, B.
    Diaz, M. J. T.
    Huerta, J. M.
    Agnoli, C.
    Arriola, L.
    Ardanaz, E.
    Boeing, H.
    Clavel-Chapelon, F.
    Crowe, F.
    Fagherazzi, G.
    Groop, L.
    Hainaut, P.
    Johnsen, N. Fons
    Kaaks, R.
    Khaw, K. T.
    Key, T. J.
    de Lauzon-Guillain, B.
    May, A.
    Monninkhof, E.
    Navarro, C.
    Nilsson, P.
    Ostergaard, J. Nautrup
    Norat, T.
    Overvad, K.
    Palli, D.
    Panico, S.
    Redondo, M. L.
    Ricceri, F.
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Romaguera, D.
    Romieu, I.
    Sanchez Perez, M. J.
    Slimani, N.
    Spijkerman, A.
    Teucher, B.
    Tjonneland, A.
    Travier, N.
    Tumino, R.
    Vos, W.
    Vigl, M.
    Sharp, S.
    Langenberg, C.
    Forouhi, N.
    Riboli, E.
    Feskens, E.
    Wareham, N. J.
    Physical activity reduces the risk of incident type 2 diabetes in general and in abdominally lean and obese men and women: the EPIC-InterAct Study2012In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, no 7, p. 1944-1952Article in journal (Refereed)
    Abstract [en]

    We examined the independent and combined associations of physical activity and obesity with incident type 2 diabetes in men and women. The InterAct case-cohort study consists of 12,403 incident type 2 diabetes cases and a randomly selected subcohort of 16,154 individuals, drawn from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. Physical activity was assessed by a four-category index. Obesity was measured by BMI and waist circumference (WC). Associations between physical activity, obesity and case-ascertained incident type 2 diabetes were analysed by Cox regression after adjusting for educational level, smoking status, alcohol consumption and energy intake. In combined analyses, individuals were stratified according to physical activity level, BMI and WC. A one-category difference in physical activity (equivalent to approximately 460 and 365 kJ/day in men and women, respectively) was independently associated with a 13% (HR 0.87, 95% CI 0.80, 0.94) and 7% (HR 0.93, 95% CI 0.89, 0.98) relative reduction in the risk of type 2 diabetes in men and women, respectively. Lower levels of physical activity were associated with an increased risk of diabetes across all strata of BMI. Comparing inactive with active individuals, the HRs were 1.44 (95% CI 1.11, 1.87) and 1.38 (95% CI 1.17, 1.62) in abdominally lean and obese inactive men, respectively, and 1.57 (95% CI 1.19, 2.07) and 1.19 (95% CI 1.01, 1.39) in abdominally lean and obese inactive women, respectively. Physical activity is associated with a reduction in the risk of developing type 2 diabetes across BMI categories in men and women, as well as in abdominally lean and obese men and women.

  • 20.
    Eliasson, Mats
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lundblad, Dan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    The disparity between long-term survival in patients with and without diabetes following a first myocardial infarction did not change between 1989 and 2006: an analysis of 6,776 patients in the Northern Sweden MONICA Study2011In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 54, no 10, p. 2538-2543Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Long-term survival after myocardial infarction(MI) has improved in the population, but data ondiabetic patients is lacking. We analysed survival for up to18 years after a first MI in patients with or without diabetes

    Methods: The Northern Sweden MONICA MyocardialInfarction Registry was linked to the Cause-of-DeathRegistry for a total of 6,776 patients, 25–64 years of age,with a first MI during 1989–2006. Prehospital deaths wereincluded. Follow-up ended on 30 August 2008.

    Results: Sixteen per cent had diabetes. Median follow-uptime was 6.8 years, and the study included 50,667 patientyears.One third of the non-diabetic patients died vs half ofthe diabetic patients. Median survival for non-diabetic menwas 227 months and for diabetic men 123 months.Corresponding figures for the non-diabetic and diabeticwomen were 222 and 81 months respectively. Men withdiabetes had an age-adjusted HR for all-cause mortality of 1.56 (95% CI 1.39, 1.79) vs men without diabetes. Mortality risk was higher among diabetic women, HR1.97 (1.62, 2.39) (diabetes × sex interaction, p=0.03). Survival increased for three consecutive cohorts and washigher in non-diabetic patients for all durations of follow-upand in all three cohorts. The interaction of diabetes x cohortwas not significant over time (p=0.5) and HRs did notdiffer either.

    Conclusions/interpretation Long-term survival after a firstMI is markedly lower in diabetic patients, especially amongwomen, over an 18-year observation time. Althoughsurvival has improved in diabetic patients, the effect ofdiabetes upon mortality has not diminished.

  • 21.
    Eriksson, Marie
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Van Rompaye, Bart
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Differences in cardiovascular risk factors and socioeconomic status do not explain the increased risk of death after a first stroke in diabetic patients: results from the Swedish Stroke Register2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, no 10, p. 2181-2186Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: This study compared survival rates and causes of death after stroke in diabetic and non-diabetic patients in Sweden. We hypothesised that differences in cardiovascular risk factors, acute stroke management or socioeconomic status (SES) could explain the higher risk of death after stroke in diabetic patients. METHODS: The study included 155,806 first-ever stroke patients from the Swedish Stroke Register between 2001 and 2009. Individual patient information on SES was retrieved from Statistics Sweden. Survival was followed until 2010 (532,140 person-years) with a median follow-up time of 35 months. Multiple Cox regression was used to analyse survival adjusting for differences in background characteristics, in-hospital treatment, SES and year of stroke. Causes of death were analysed using cause-specific proportional hazard models. RESULTS: The risk of death after stroke increased in diabetic patients (HR 1.28, 95% CI 1.25, 1.31), and this risk was greater in younger patients and in women. Differences in background characteristics, cardiovascular risk factors, in-hospital treatment and SES did not explain the increased risk of death after stroke (HR 1.35, 95% CI 1.32, 1.37) after adjustments. Diabetic patients had an increased probability of dying from cerebrovascular disease and even higher probabilities of dying from other circulatory causes and all other causes except cancer. CONCLUSIONS/INTERPRETATION: Differences in cardiovascular risk factors, acute stroke management and SES do not explain the lower survival after stroke in diabetic compared with non-diabetic patients. Diabetic patients are at higher risk of dying from cardiovascular causes and all other causes of death, other than cancer.

  • 22. Feldman, Adina L.
    et al.
    Griffin, Simon J.
    Fhärm, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Norberg, Margareta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Wennberg, Patrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Screening for type 2 diabetes: do screen-detected cases fare better?2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no 11, p. 2200-2209Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: We aimed to investigate whether diabetes cases detected through screening have better health outcomes than clinically detected cases in a population-based cohort of adults who were eligible to be screened for diabetes at 10 year intervals.

    METHODS: The Västerbotten Intervention Programme is a community- and individual-based public health programme in Västerbotten County, Sweden. Residents are invited to clinical examinations that include screening for diabetes by OGTTs at age 30, 40, 50 and 60 years (individuals eligible for screening, n = 142,037). Between 1992 and 2013, we identified 1024 screen-detected cases and 8642 clinically detected cases of diabetes using registry data. Clinically detected individuals were either prior screening participants (n = 4506) or people who did not participate in screening (non-participants, n = 4136). Study individuals with diabetes were followed from date of detection until end of follow-up, emigration, death or incident cardiovascular disease (CVD), renal disease or retinopathy event, and compared using Cox proportional hazard regression adjusted for calendar time, age at detection, year of detection, sex and socioeconomic status.

    RESULTS: The average age at diabetes diagnosis was 4.6 years lower for screen-detected individuals compared with clinically detected individuals. Overall, those who were clinically detected had worse health outcomes than those who were screen-detected (HR for all-cause mortality 2.07 [95% CI 1.63, 2.62]). Compared with screen-detected study individuals, all-cause mortality was higher for clinically detected individuals who were screening non-participants (HR 2.31 [95% CI 1.82, 2.94]) than for those clinically detected who were prior screening participants (HR 1.70 [95% CI 1.32, 2.18]). Estimates followed a similar pattern for CVD, renal disease and retinopathy.

    CONCLUSIONS/INTERPRETATION: Individuals with screen-detected diabetes were diagnosed earlier and appeared to fare better than those who were clinically detected with regard to all-cause mortality, CVD, renal disease and retinopathy. How much of these associations can be explained by earlier treatment because of screening rather than healthy user bias, lead time bias and length time bias warrants further investigation.

  • 23. Florez, J
    et al.
    Jablonski, K
    McAteer, J
    Sandhu, M
    Wareham, N
    Barroso, I
    Franks, Paul
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Altshuler, D
    Knowler, W
    Testing of diabetes-associated WFS1 polymorphisms in the Diabetes Prevention Program2007In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 51, no 3, p. 451-457Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) is caused by mutations in the WFS1 gene. Recently, single nucleotide polymorphisms (SNPs) in WFS1 have been reproducibly associated with type 2 diabetes. We therefore examined the effects of these variants on diabetes incidence and response to interventions in the Diabetes Prevention Program (DPP), in which a lifestyle intervention or metformin treatment was compared with placebo.

    Methods: We genotyped the WFS1 SNPs rs10010131, rs752854 and rs734312 (H611R) in 3,548 DPP participants and performed Cox regression analysis using genotype, intervention and their interactions as predictors of diabetes incidence. We also evaluated the effect of these SNPs on insulin resistance and beta cell function at 1 year.

    Results: Although none of the three SNPs was associated with diabetes incidence in the overall cohort, white homozygotes for the previously reported protective alleles appeared less likely to develop diabetes in the lifestyle arm. Examination of the publicly available Diabetes Genetics Initiative genome-wide association dataset revealed that rs10012946, which is in strong linkage disequilibrium with the three WFS1 SNPs (r 2 = 0.88–1.0), was associated with type 2 diabetes (allelic odds ratio 0.85, 95% CI 0.75–0.97, p = 0.026). In the DPP, we noted a trend towards increased insulin secretion in carriers of the protective variants, although for most SNPs this was seen as compensatory for the diminished insulin sensitivity.

    Conclusions/interpretation: The previously reported protective effect of select WFS1 alleles may be magnified by a lifestyle intervention. These variants appear to confer an improvement in beta cell function.

  • 24. Fontaine-Bisson, B
    et al.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Payne, F
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Barroso, I
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Evaluating the discriminative power of multi-trait genetic risk scores for type 2 diabetes in a northern Swedish population.2010In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 53, no 10, p. 2155-2162Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: We determined whether single nucleotide polymorphisms (SNPs) previously associated with diabetogenic traits improve the discriminative power of a type 2 diabetes genetic risk score. METHODS: Participants (n = 2,751) were genotyped for 73 SNPs previously associated with type 2 diabetes, fasting glucose/insulin concentrations, obesity or lipid levels, from which five genetic risk scores (one for each of the four traits and one combining all SNPs) were computed. Type 2 diabetes patients and non-diabetic controls (n = 1,327/1,424) were identified using medical records in addition to an independent oral glucose tolerance test. RESULTS: Model 1, including only SNPs associated with type 2 diabetes, had a discriminative power of 0.591 (p < 1.00 x 10(-20) vs null model) as estimated by the area under the receiver operator characteristic curve (ROC AUC). Model 2, including only fasting glucose/insulin SNPs, had a significantly higher discriminative power than the null model (ROC AUC 0.543; p = 9.38 x 10(-6) vs null model), but lower discriminative power than model 1 (p = 5.92 x 10(-5)). Model 3, with only lipid-associated SNPs, had significantly higher discriminative power than the null model (ROC AUC 0.565; p = 1.44 x 10(-9)) and was not statistically different from model 1 (p = 0.083). The ROC AUC of model 4, which included only obesity SNPs, was 0.557 (p = 2.30 x 10(-7) vs null model) and smaller than model 1 (p = 0.025). Finally, the model including all SNPs yielded a significant improvement in discriminative power compared with the null model (p < 1.0 x 10(-20)) and model 1 (p = 1.32 x 10(-5)); its ROC AUC was 0.626. CONCLUSIONS/INTERPRETATION: Adding SNPs previously associated with fasting glucose, insulin, lipids or obesity to a genetic risk score for type 2 diabetes significantly increases the power to discriminate between people with and without clinically manifest type 2 diabetes compared with a model including only conventional type 2 diabetes loci.

  • 25.
    Franks, P. W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Genetic risk scores ascertained in early adulthood and the prediction of type 2 diabetes later in life2012In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, no 10, p. 2555-2558Article in journal (Other academic)
    Abstract [en]

    It is hoped that information garnered from studies on population genetics will one day be translated into a form in which it meaningfully improves the prediction, prevention or treatment of type 2 diabetes. Type 2 diabetes genetics researchers have made extraordinary progress in identifying common genetic variants that are associated with type 2 diabetes, which has shed light on the biological pathways in which molecular defects that cause the disease likely reside. However, the expectation that genetic discoveries will aid the prevention or treatment of type 2 diabetes has not, so far, been fulfilled. In a paper published in this edition of the journal, Vassy and colleagues (DOI: 10.1007/s00125-012-2637-7) test the hypothesis that the predictive accuracy of established genetic risk markers for type 2 diabetes varies by age, with the predictive accuracy being greatest in younger cohorts. The authors found no substantive support for this hypothesis. However, a number of interesting questions are raised by their study concerning why risk alleles for a given genotype may differ in younger and older cohorts and why prospective cohort studies may yield results that are inconsistent with those derived from cross-sectional studies; this commentary discusses these points.

  • 26.
    Franks, Paul
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Christophi, Costas A.
    Jablonski, Kathleen A.
    Billings, Liana K.
    Delahanty, Linda M.
    Horton, Edward S.
    Knowler, William C.
    Florez, Jose C.
    Common variation at PPARGC1A/B and change in body composition and metabolic traits following preventive interventions: the Diabetes Prevention Program2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no 3, p. 485-490Article in journal (Refereed)
    Abstract [en]

    PPARGC1A and PPARGCB encode transcriptional coactivators that regulate numerous metabolic processes. We tested associations and treatment (i.e. metformin or lifestyle modification) interactions with metabolic traits in the Diabetes Prevention Program, a randomised controlled trial in persons at high risk of type 2 diabetes. We used Tagger software to select 75 PPARGCA1 and 94 PPARGC1B tag single-nucleotide polymorphisms (SNPs) for analysis. These SNPs were tested for associations with relevant cardiometabolic quantitative traits using generalised linear models. Aggregate genetic effects were tested using the sequence kernel association test. In aggregate, PPARGC1A variation was strongly associated with baseline triacylglycerol concentrations (p = 2.9 x 10(-30)), BMI (p = 2.0 x 10(-5)) and visceral adiposity (p = 1.9 x 10(-4)), as well as with changes in triacylglycerol concentrations (p = 1.7 x 10(-5)) and BMI (p = 9.9 x 10(-5)) from baseline to 1 year. PPARGC1B variation was only associated with baseline subcutaneous adiposity (p = 0.01). In individual SNP analyses, Gly482Ser (rs8192678, PPARGC1A) was associated with accumulation of subcutaneous adiposity and worsening insulin resistance at 1 year (both p < 0.05), while rs2970852 (PPARGC1A) modified the effects of metformin on triacylglycerol levels (p (interaction) = 0.04). These findings provide several novel and other confirmatory insights into the role of PPARGC1A variation with respect to diabetes-related metabolic traits. Trial registration ClinicalTrials.gov NCT00004992.

  • 27.
    Franks, Paul W.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Lund Univ, Ctr Diabet, Genet & Mol Epidemiol Unit, Malmo, Sweden.
    Chen, Y.
    Estampador, A.
    Keller, M.
    Poveda, A.
    Dalla-Riva, J.
    Renstrom, F.
    Kurbasic, A.
    Varga, T. V.
    Gene-diet interaction analysis, fine mapping and genomic annotation of the FADS1-2-3 gene cluster reveals regulatory potential in diabetes2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, p. S163-S163Article in journal (Other academic)
  • 28.
    Franks, Paul W
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Diabetes Prevention Program Coordinating Center, The Biostatistics Center, George Washington University, 6110 Executive Blvd, Suite 750, Rockville, MD 20852, USA.
    Jablonski, KA
    Delahanty, LM
    McAteer, JB
    Kahn, SE
    Knowler, WC
    Florez, JC
    Assessing gene-treatment interactions at the FTO and INSIG2 loci on obesity-related traits in the Diabetes Prevention Program2008In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 51, no 12, p. 2214-2223Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: The single nucleotide polymorphism (SNP) rs9939609 in the fat mass and obesity associated gene (FTO) and the rs7566605 SNP located 10 kb upstream of the insulin-induced gene 2 gene (INSIG2) have been proposed as risk factors for common obesity.

    METHODS: We tested for genotype-treatment interactions on changes in obesity-related traits in the Diabetes Prevention Program (DPP). The DPP is a randomised controlled trial of 3,548 high-risk individuals from 27 participating centres throughout the USA who were originally randomised to receive metformin, troglitazone, intensive lifestyle modification or placebo to prevent the development of type 2 diabetes. Measures of adiposity from computed tomography were available in a subsample (n = 908). This report focuses on the baseline and 1 year results.

    RESULTS: The minor A allele at FTO rs9939609 was positively associated with baseline BMI (p = 0.003), but not with baseline adiposity or the change at 1 year in any anthropometric trait. For the INSIG2 rs7566605 genotype, the minor C allele was associated with more subcutaneous adiposity (second and third lumbar vertebrae [L2/3]) at baseline (p = 0.04). During follow-up, CC homozygotes lost more weight than G allele carriers (p = 0.009). In an additive model, we observed nominally significant gene-lifestyle interactions on weight change (p = 0.02) and subcutaneous (L2/3 [p = 0.01] and L4/5 [p = 0.03]) and visceral (L2/3 [p = 0.02]) adipose areas. No statistical evidence of association with physical activity energy expenditure or energy intake was observed for either genotype.

    CONCLUSIONS/INTERPRETATION: Within the DPP study population, common variants in FTO and INSIG2 are nominally associated with quantitative measures of obesity, directly and possibly by interacting with metformin or lifestyle intervention.

  • 29.
    Franks, Paul W.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA ; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Clinical Research Centre, Lund University.
    Poveda, Alaitz
    Lifestyle and precision diabetes medicine: will genomics help optimise the prediction, prevention and treatment of type 2 diabetes through lifestyle therapy?2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no 5, p. 784-792Article in journal (Refereed)
    Abstract [en]

    Precision diabetes medicine, the optimisation of therapy using patient-level biomarker data, has stimulated enormous interest throughout society as it provides hope of more effective, less costly and safer ways of preventing, treating, and perhaps even curing the disease. While precision diabetes medicine is often framed in the context of pharmacotherapy, using biomarkers to personalise lifestyle recommendations, intended to lower type 2 diabetes risk or to slow progression, is also conceivable. There are at least four ways in which this might work: (1) by helping to predict a person's susceptibility to adverse lifestyle exposures; (2) by facilitating the stratification of type 2 diabetes into subclasses, some of which may be prevented or treated optimally with specific lifestyle interventions; (3) by aiding the discovery of prognostic biomarkers that help guide timing and intensity of lifestyle interventions; (4) by predicting treatment response. In this review we overview the rationale for precision diabetes medicine, specifically as it relates to lifestyle; we also scrutinise existing evidence, discuss the barriers germane to research in this field and consider how this work is likely to proceed.

  • 30. Goedecke, Julia H.
    et al.
    Keswell, Dheshnie
    Weinreich, Carsten
    Fan, Jia
    Hauksson, Jon
    Victor, Hendriena
    Utzschneider, Kristina
    Levitt, Naomi S.
    Lambert, Estelle V.
    Kahn, Steven E.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Univ Stellenbosch, Wallenberg Res Ctr, Stellenbosch Inst Adv Study STIAS, ZA-7600 Stellenbosch, South Africa.
    Ethnic differences in hepatic and systemic insulin sensitivity and their associated determinants in obese black and white South African women2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 11, p. 2647-2652Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis There is evidence to suggest that ectopic fat deposition in liver and skeletal muscle may differ between black and white women resulting in organ-specific differences in insulin sensitivity. Accordingly, the aim of the study was to examine ethnic differences in hepatic and peripheral insulin sensitivity, and the association with hepatic and skeletal muscle lipid content, and skeletal muscle gene expression. Methods In a cross-sectional study including 30 obese premenopausal black and white women, body composition (dual energy x-ray absorptiometry), liver fat and skeletal muscle (soleus and tibialis anterior) fat accumulation (proton-magnetic resonance spectroscopy), skeletal muscle gene expression, insulin sensitivity (two-step isotope labelled, hyperinsulinaemic-euglycaemic clamp with 10 mU m(-2) min(-1) and 40 mU m(-2) min(-1) insulin infusions), and serum adipokines were measured. Results We found that, although whole-body insulin sensitivity was not different, obese white women presented with lower hepatic insulin sensitivity than black women (% suppression of endogenous glucose production [% supp EGP], median [interquartile range (IQR)]: 17 [5-51] vs 56 [29-100] %, p = 0.002). While liver fat tended to be lower (p = 0.065) and skeletal muscle fat deposition tended to be higher (p = 0.074) in black compared with white women, associations with insulin sensitivity were only observed in black women (% supp EGP vs liver fat: r = -0.57, p < 0.05 and % supp EGP vs soleus fat: r = -0.56, p < 0.05). Conclusions/interpretation These findings may suggest that black women are more sensitive to the effects of ectopic lipid deposition than white women.

  • 31. Grote, V. A.
    et al.
    Rohrmann, S.
    Nieters, A.
    Dossus, L.
    Tjonneland, A.
    Halkjaer, J.
    Overvad, K.
    Fagherazzi, G.
    Boutron-Ruault, M. C.
    Morois, S.
    Teucher, B.
    Becker, S.
    Sluik, D.
    Boeing, H.
    Trichopoulou, A.
    Lagiou, P.
    Trichopoulos, D.
    Palli, D.
    Pala, V.
    Tumino, R.
    Vineis, P.
    Panico, S.
    Rodriguez, L.
    Duell, E. J.
    Molina-Montes, E.
    Dorronsoro, M.
    Huerta, J. M.
    Ardanaz, E.
    Jeurnink, S. M.
    Beulens, J. W. J.
    Peeters, P. H. M.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Ye, W.
    Lindkvist, B.
    Johansen, D.
    Khaw, K. T.
    Wareham, N.
    Allen, N.
    Crowe, F.
    Jenab, M.
    Romieu, I.
    Michaud, D. S.
    Riboli, E.
    Romaguera, D.
    Bueno-de-Mesquita, H. B.
    Kaaks, R.
    Diabetes mellitus, glycated haemoglobin and C-peptide levels in relation to pancreatic cancer risk: a study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort2011In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 54, no 12, p. 3037-3046Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: There has been long-standing debate about whether diabetes is a causal risk factor for pancreatic cancer or a consequence of tumour development. Prospective epidemiological studies have shown variable relationships between pancreatic cancer risk and blood markers of glucose and insulin metabolism, overall and as a function of lag times between marker measurements (blood donation) and date of tumour diagnosis.

    Methods: Pre-diagnostic levels of HbA(1c) and C-peptide were measured for 466 participants with pancreatic cancer and 466 individually matched controls within the European Prospective Investigation into Cancer and Nutrition. Conditional logistic regression models were used to estimate ORs for pancreatic cancer.

    Results: Pancreatic cancer risk gradually increased with increasing pre-diagnostic HbA(1c) levels up to an OR of 2.42 (95% CI 1.33, 4.39 highest [>= 6.5%, 48 mmol/mol] vs lowest [<= 5.4%, 36 mmol/mol] category), even for individuals with HbA(1c) levels within the non-diabetic range. C-peptide levels showed no significant relationship with pancreatic cancer risk, irrespective of fasting status. Analyses showed no clear trends towards increasing hyperglycaemia (as marked by HbA(1c) levels) or reduced pancreatic beta cell responsiveness (as marked by C-peptide levels) with decreasing time intervals from blood donation to cancer diagnosis.

    Conclusions/interpretation: Our data on HbA(1c) show that individuals who develop exocrine pancreatic cancer tend to have moderate increases in HbA(1c) levels, relatively independently of obesity and insulin resistance-the classic and major risk factors for type 2 diabetes. While there is no strong difference by lag time, more data are needed on this in order to reach a firm conclusion.

  • 32. Imagawa, A
    et al.
    Hanafusa, T
    Makino, H
    Miyagawa, J-I
    Juto, Per
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    High titres of IgA antibodies to enterovirus in fulminant type-1 diabetes.2005In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 48, no 2, p. 290-3Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: We have recently proposed that fulminant type-1 diabetes is a novel subtype of type-1 diabetes with abrupt onset of insulin-deficient hyperglycaemia without islet-related autoantibodies. The pathogenesis is still unknown, but flu-like symptoms are frequently observed before the onset of disease of this subtype. Enterovirus infection is a candidate environmental factor causing type-1 diabetes. The aim of this study was to determine whether enterovirus infection contributes to the development of fulminant type-1 diabetes. METHODS: We investigated 19 patients with recent-onset fulminant type-1 diabetes, 18 patients with recent-onset typical type-1A diabetes, and 19 healthy controls. IgM, IgG, and IgA subclasses of antibodies to enterovirus were determined by ELISA. RESULTS: IgA antibody titres to enterovirus were significantly higher in fulminant type-1 diabetes than in typical type-1A diabetes (p=0.033) and controls (p=0.0003). IgM antibodies to enterovirus were not detected in any subject. IgG titres were lower in autoimmune diabetes than fulminant type and controls (p=0.014 and 0.019, respectively). CONCLUSIONS/INTERPRETATION: High titres of enterovirus IgA antibodies in serum suggest recurrent enterovirus infection in fulminant type-1 diabetic patients, indicating higher susceptibility to enteroviral infections among them. Such infections might have pathogenetic importance in the triggering of fulminant type-1 diabetes.

  • 33. Jonsson, A
    et al.
    Renström, Frida
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Lyssenko, V
    Brito, Ema C
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Isomaa, B
    Berglund, G
    Nilsson, P M
    Groop, L
    Franks, Paul W
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Assessing the effect of interaction between an FTO variant (rs9939609) and physical activity on obesity in 15,925 Swedish and 2,511 Finnish adults.2009In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, no 7, p. 1334-1338Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: Recent reports have suggested that genotypes at the FTO locus interact with physical activity to modify levels of obesity-related traits. We tested this hypothesis in two non-diabetic population-based cohorts, the first from southern Sweden and the second from the Botnia region of western Finland. METHODS: In total 2,511 Finnish and 15,925 Swedish non-diabetic middle-aged adults were genotyped for the FTO rs9939609 variant. Physical activity was assessed by questionnaires and standard clinical procedures were conducted, including measures of height and weight and glucose regulation. Tests of gene x physical activity interaction were performed using linear interaction effects to determine whether the effect of this variant on BMI is modified by physical activity. RESULTS: The minor A allele at rs9939609 was associated with higher BMI in both cohorts, with the per allele difference in BMI being about 0.13 and 0.43 kg/m(2) in the Swedish and Finnish cohorts, respectively (p < 0.0001). The test of interaction between physical activity and the rs9939609 variant on BMI was not statistically significant after controlling for age and sex in either cohort (Sweden: p = 0.71, Finland: p = 0.18). CONCLUSIONS/INTERPRETATION: The present report does not support the notion that physical activity modifies the effects of the FTO rs9939609 variant on obesity risk in the non-diabetic Swedish or Finnish adults studied here.

  • 34. Katsogiannos, P.
    et al.
    Kamble, P. G.
    Hammar, U.
    Sundbom, M.
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Pereira, M. J.
    Eriksson, J. W.
    Early effects of RYGB on hormone regulation and autonomic nerve activity in patients with obesity and type 2 diabetes2019In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, p. S274-S274Article in journal (Other academic)
  • 35. Katsogiannos, P.
    et al.
    Kamble, P. G.
    Hammar, U.
    Sundbom, M.
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Pereira, M. J.
    Eriksson, J. W.
    Early effects of RYGB on hormone regulation and autonomic nerve activity in patients with obesity and type 2 diabetes2019In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, p. S274-S274Article in journal (Refereed)
  • 36. Keindl, M.
    et al.
    Fedotkina, A.
    du Plessis, E.
    Jain, R.
    Bergum, B.
    Falhammar, H.
    Nyström, T.
    Catrina, S. -B
    Groop, L.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Eliasson, B.
    Nilsson, P. M.
    Berg, T. J.
    Appel, S.
    Lyssenko, V.
    sIL-2R plasma levels as a potential marker for progression to vascular complications in patients with type 1 diabetes2019In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, p. S36-S36Article in journal (Other academic)
  • 37. Klüppelholz, Birgit
    et al.
    Thorand, Barbara
    Koenig, Wolfgang
    Gala, Tonia de las Heras
    Meisinger, Christa
    Huth, Cornelia
    Giani, Guido
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Roden, Michael
    Rathmann, Wolfgang
    Peters, Annette
    Herder, Christian
    Association of subclinical inflammation with deterioration of glycaemia before the diagnosis of type 2 diabetes: the KORA S4/F4 study2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 10, p. 2269-2277Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis The role of biomarkers of subclinical inflammation in the early deterioration of glycaemia before type 2 diabetes is largely unknown. We hypothesised that increased levels of circulating proinflammatory biomarkers and decreased circulating adiponectin would be associated with 7 year increases of HbA1c in non-diabetic individuals.

    Methods This study was based on individuals who participated in the prospective Cooperative Health Research in the Region of Augsburg (KORA) S4 survey (1999–2001) and the 7 year follow-up KORA F4 (2006–2008) survey. Individuals with type 2 diabetes at baseline or with a diagnosis of diabetes in the period between both surveys were excluded, which left a sample of 850 men and women. Multivariable linear regression analyses were performed to assess associations among baseline values of leucocyte count and levels of acute-phase proteins (high-sensitivity C-reactive protein [hsCRP], serum amyloid A [SAA] and fibrinogen), IL-6 and adiponectin with changes in HbA1c between baseline and follow-up.

    Results A high leucocyte count and high hsCRP, SAA and IL-6 levels were positively associated with changes in HbA1c after adjusting for age, sex, lifestyle factors and baseline HbA1c. In contrast, the adiponectin level was inversely associated with changes in HbA1c (p value between <0.0001 and 0.020). The associations of leucocyte count and levels of hsCRP and SAA with HbA1c changes remained significant after additional adjustment for waist circumference and circulating lipids at baseline and for the 7 year change in waist circumference (p value between 0.004 and 0.045).

  • 38. Koivula, R. W.
    et al.
    Grontved, A.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Wennberg, Patrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Ostergaard, L.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Renstrom, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Bicycling to work and primordial prevention of cardiovascular and type 2 diabetes risk: a cohort study from Northern Sweden2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, p. S150-S150, article id 298Article in journal (Refereed)
  • 39. Koivula, Robert W.
    et al.
    Forgie, Ian M.
    Kurbasic, Azra
    Vinuela, Ana
    Heggie, Alison
    Giordano, Giuseppe N.
    Hansen, Tue H.
    Hudson, Michelle
    Koopman, Anitra D. M.
    Rutters, Femke
    Siloaho, Maritta
    Allin, Kristine H.
    Brage, Soren
    Brorsson, Caroline A.
    Dawed, Adem Y.
    De Masi, Federico
    Groves, Christopher J.
    Kokkola, Tarja
    Mahajan, Anubha
    Perry, Mandy H.
    Rauh, Simone P.
    Ridderstrale, Martin
    Teare, Harriet J. A.
    Thomas, E. Louise
    Tura, Andrea
    Vestergaard, Henrik
    White, Tom
    Adamski, Jerzy
    Bell, Jimmy D.
    Beulens, Joline W.
    Brunak, Soren
    Dermitzakis, Emmanouil T.
    Froguel, Philippe
    Frost, Gary
    Gupta, Ramneek
    Hansen, Torben
    Hattersley, Andrew
    Jablonka, Bernd
    Kaye, Jane
    Laakso, Markku
    McDonald, Timothy J.
    Pedersen, Oluf
    Schwenk, Jochen M.
    Pavo, Imre
    Mari, Andrea
    McCarthy, Mark I.
    Ruetten, Hartmut
    Walker, Mark
    Pearson, Ewan
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Department of Clinical Sciences, Lund University Diabetes Centre, Genetic and Molecular Epidemiology Unit, CRC, Skåne University Hospital Malmö, Malmö, Sweden; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
    Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium2019In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, no 9, p. 1601-1615Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up).

    Methods: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at similar to 18 months (both cohorts) and at similar to 48 months (cohort 1) or similar to 36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe.

    Results: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean +/- SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m(2); fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m(2); fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l.

    Conclusions/interpretation: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.

  • 40. Koivula, Robert W.
    et al.
    Heggie, Alison
    Barnett, Anna
    Cederberg, Henna
    Hansen, Tue H.
    Koopman, Anitra D.
    Ridderstrale, Martin
    Rutters, Femke
    Vestergaard, Henrik
    Gupta, Ramneek
    Herrgard, Sanna
    Heymans, Martijn W.
    Perry, Mandy H.
    Rauh, Simone
    Siloaho, Maritta
    Teare, Harriet J. A.
    Thorand, Barbara
    Bell, Jimmy
    Brunak, Soren
    Frost, Gary
    Jablonka, Bernd
    Mari, Andrea
    McDonald, Tim J.
    Dekker, Jacqueline M.
    Hansen, Torben
    Hattersley, Andrew
    Laakso, Markku
    Pedersen, Oluf
    Koivisto, Veikko
    Ruetten, Hartmut
    Walker, Mark
    Pearson, Ewan
    Franks, Paul
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: rationale and design of the epidemiological studies within the IMI DIRECT Consortium2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no 6, p. 1132-1142Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS:

    The DIRECT (Diabetes Research on Patient Stratification) Study is part of a European Union Framework 7 Innovative Medicines Initiative project, a joint undertaking between four industry and 21 academic partners throughout Europe. The Consortium aims to discover and validate biomarkers that: (1) predict the rate of glycaemic deterioration before and after type 2 diabetes onset; (2) predict the response to diabetes therapies; and (3) help stratify type 2 diabetes into clearly definable disease subclasses that can be treated more effectively than without stratification. This paper describes two new prospective cohort studies conducted as part of DIRECT.

    METHODS:

    Prediabetic participants (target sample size 2,200-2,700) and patients with newly diagnosed type 2 diabetes (target sample size ~1,000) are undergoing detailed metabolic phenotyping at baseline and 18 months and 36 months later. Abdominal, pancreatic and liver fat is assessed using MRI. Insulin secretion and action are assessed using frequently sampled OGTTs in non-diabetic participants, and frequently sampled mixed-meal tolerance tests in patients with type 2 diabetes. Biosamples include venous blood, faeces, urine and nail clippings, which, among other biochemical analyses, will be characterised at genetic, transcriptomic, metabolomic, proteomic and metagenomic levels. Lifestyle is assessed using high-resolution triaxial accelerometry, 24 h diet record, and food habit questionnaires.

    CONCLUSIONS/INTERPRETATION:

    DIRECT will yield an unprecedented array of biomaterials and data. This resource, available through managed access to scientists within and outside the Consortium, will facilitate the development of new treatments and therapeutic strategies for the prevention and management of type 2 diabetes

  • 41. Kroeger, Janine
    et al.
    Schulze, Matthias B
    Romaguera, Dora
    Guevara, Marcela
    Buijsse, Brian
    Boeing, Heiner
    Beulens, Joline WJ
    Feskens, Edith JM
    Amiano, Pilar
    Ardanaz, Eva
    Agnoli, Claudia
    Buckland, Genevieve
    Clavel-Chapelon, Francoise
    Dahm, Christina C
    Fagherazzi, Guy
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Kaaks, Rudolf
    Key, Timothy J
    Khaw, Kay Tee
    Lajous, Martin
    Mattiello, Amalia
    Menendez Garcia, Virginia
    Navarro, Carmen
    Nilsson, Peter M
    Overvad, Kim
    Palli, Domenico
    Ricceri, Fulvio
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Sanchez, Maria-Jose
    Slimani, Nadia
    Spijkerman, Annemieke MW
    Tjonneland, Anne
    Tumino, Rosario
    van der A, Daphne L
    Langenberg, Claudia
    Sharp, Stephen J
    Forouhi, Nita G
    Riboli, Elio
    Wareham, Nicholas J
    Adherence to predefined dietary patterns and incident type 2 diabetes in European populations: EPIC-InterAct Study2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no 2, p. 321-333Article in journal (Refereed)
    Abstract [en]

    Few studies have investigated the relationship between predefined dietary patterns and type 2 diabetes incidence; little is known about the generalisability of these associations. We aimed to assess the association between predefined dietary patterns and type 2 diabetes risk in European populations. From among a case-cohort of 12,403 incident diabetes cases and 16,154 subcohort members nested within the prospective European Prospective Investigation into Cancer and Nutrition study, we used data on 9,682 cases and 12,595 subcohort participants from seven countries. Habitual dietary intake was assessed at baseline with country-specific dietary questionnaires. Two diet-quality scores (alternative Healthy Eating Index [aHEI], Dietary Approaches to Stop Hypertension [DASH] score) and three reduced rank regression (RRR)-derived dietary-pattern scores were constructed. Country-specific HRs were calculated and combined using a random-effects meta-analysis. After multivariable adjustment, including body size, the aHEI and DASH scores were not significantly associated with diabetes, although for the aHEI there was a tendency towards an inverse association in countries with higher mean age. We observed inverse associations of the three RRR-derived dietary-pattern scores with diabetes: HRs (95% CIs) for a 1-SD difference were 0.91 (0.86, 0.96), 0.92 (0.84, 1.01) and 0.87 (0.82, 0.92). Random-effects meta-analyses revealed heterogeneity between countries that was explainable by differences in the age of participants or the distribution of dietary intake. Adherence to specific RRR-derived dietary patterns, commonly characterised by high intake of fruits or vegetables and low intake of processed meat, sugar-sweetened beverages and refined grains, may lower type 2 diabetes risk.

  • 42. Langenberg, C.
    et al.
    Sharp, S.
    Forouhi, N. G.
    Franks, Paul
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Schulze, M. B.
    Kerrison, N.
    Ekelund, U.
    Barroso, I.
    Panico, S.
    Tormo, M. J.
    Spranger, J.
    Griffin, S.
    van der Schouw, Y. T.
    Amiano, P.
    Ardanaz, E.
    Arriola, L.
    Balkau, B.
    Barricarte, A.
    Beulens, J. W. J.
    Boeing, H.
    Bueno-de-Mesquita, H. B.
    Buijsse, B.
    Chirlaque Lopez, M. D.
    Clavel-Chapelon, F.
    Crowe, F. L.
    de Lauzon-Guillan, B.
    Deloukas, P.
    Dorronsoro, M.
    Drogan, D.
    Froguel, P.
    Gonzalez, C.
    Grioni, S.
    Groop, L.
    Groves, C.
    Hainaut, P.
    Halkjaer, J.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hansen, T.
    Huerta Castano, J. M.
    Kaaks, R.
    Key, T. J.
    Khaw, K. T.
    Koulman, A.
    Mattiello, A.
    Navarro, C.
    Nilsson, P.
    Norat, T.
    Overvad, K.
    Palla, L.
    Palli, D.
    Pedersen, O.
    Peeters, P. H.
    Quiros, J. R.
    Ramachandran, A.
    Rodriguez-Suarez, L.
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Romaguera, D.
    Romieu, I.
    Sacerdote, C.
    Sanchez, M. J.
    Sandbaek, A.
    Slimani, N.
    Sluijs, I.
    Spijkerman, A. M. W.
    Teucher, B.
    Tjonneland, A.
    Tumino, R.
    van der A, D. L.
    Verschuren, W. M. M.
    Tuomilehto, J.
    Feskens, E.
    McCarthy, M.
    Riboli, E.
    Wareham, N. J.
    Design and cohort description of the InterAct Project: an examination of the interaction of genetic and lifestyle factors on the incidence of type 2 diabetes in the EPIC Study2011In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 54, no 9, p. 2272-2282Article in journal (Refereed)
    Abstract [en]

    Studying gene-lifestyle interaction may help to identify lifestyle factors that modify genetic susceptibility and uncover genetic loci exerting important subgroup effects. Adequately powered studies with prospective, unbiased, standardised assessment of key behavioural factors for gene-lifestyle studies are lacking. This case-cohort study aims to investigate how genetic and potentially modifiable lifestyle and behavioural factors, particularly diet and physical activity, interact in their influence on the risk of developing type 2 diabetes. Incident cases of type 2 diabetes occurring in European Prospective Investigation into Cancer and Nutrition (EPIC) cohorts between 1991 and 2007 from eight of the ten EPIC countries were ascertained and verified. Prentice-weighted Cox regression and random-effects meta-analyses were used to investigate differences in diabetes incidence by age and sex. A total of 12,403 verified incident cases of type 2 diabetes occurred during 3.99 million person-years of follow-up of 340,234 EPIC participants eligible for InterAct. We defined a centre-stratified subcohort of 16,154 individuals for comparative analyses. Individuals with incident diabetes who were randomly selected into the subcohort (n = 778) were included as cases in the analyses. All prevalent diabetes cases were excluded from the study. InterAct cases were followed-up for an average of 6.9 years; 49.7% were men. Mean baseline age and age at diagnosis were 55.6 and 62.5 years, mean BMI and waist circumference values were 29.4 kg/m(2) and 102.7 cm in men, and 30.1 kg/m(2) and 92.8 cm in women, respectively. Risk of type 2 diabetes increased linearly with age, with an overall HR of 1.56 (95% CI 1.48-1.64) for a 10 year age difference, adjusted for sex. A male excess in the risk of incident diabetes was consistently observed across all countries, with a pooled HR of 1.51 (95% CI 1.39-1.64), adjusted for age. InterAct is a large, well-powered, prospective study that will inform our understanding of the interplay between genes and lifestyle factors on the risk of type 2 diabetes development.

  • 43. Li, Sherly X.
    et al.
    Imamura, Fumiaki
    Schulze, Matthias B.
    Zheng, Jusheng
    Ye, Zheng
    Agudo, Antonio
    Ardanaz, Eva
    Aune, Dagfinn
    Boeing, Heiner
    Dorronsoro, Miren
    Dow, Courtney
    Fagherazzi, Guy
    Grioni, Sara
    Gunter, Marc J.
    María Huerta, José
    Ibsen, Daniel B.
    Jakobsen, Marianne Uhre
    Kaaks, Rudolf
    Key, Timothy J.
    Khaw, Kay-Tee
    Kyrø, Cecilie
    Mancini, Francesca Romana
    Molina-Portillo, Elena
    Murphy, Neil
    Nilsson, Peter M.
    Onland-Moret, N. Charlotte
    Palli, Domenico
    Panico, Salvatore
    Poveda, Alaitz
    Umeå University, Faculty of Medicine, Department of Nursing. Department of Clinical Sciences, Clinical Research Center, Skåne University Hospital, Lund University, Malmö, Sweden.
    Ramón Quirós, J.
    Ricceri, Fulvio
    Sluijs, Ivonne
    Spijkerman, Annemieke M. W.
    Tjonneland, Anne
    Tumino, Rosario
    Winkvist, Anna
    Langenberg, Claudia
    Sharp, Stephen J.
    Riboli, Elio
    Scott, Robert A.
    Forouhi, Nita G.
    Wareham, Nicholas J.
    Interplay between genetic predisposition, macronutrient intake and type 2 diabetes incidence: analysis within EPIC-InterAct across eight European countries2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 6, p. 1325-1332Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Gene-macronutrient interactions may contribute to the development of type 2 diabetes but research evidence to date is inconclusive. We aimed to increase our understanding of the aetiology of type 2 diabetes by investigating potential interactions between genes and macronutrient intake and their association with the incidence of type 2 diabetes.

    Methods: We investigated the influence of interactions between genetic risk scores (GRSs) for type 2 diabetes, insulin resistance and BMI and macronutrient intake on the development of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a prospective case-cohort study across eight European countries (N = 21,900 with 9742 incident type 2 diabetes cases). Macronutrient intake was estimated from diets reported in questionnaires, including proportion of energy derived from total carbohydrate, protein, fat, plant and animal protein, saturated, monounsaturated and polyunsaturated fat and dietary fibre. Using multivariable-adjusted Cox regression, we estimated country-specific interaction results on the multiplicative scale, using random-effects meta-analysis. Secondary analysis used isocaloric macronutrient substitution.

    Results: No interactions were identified between any of the three GRSs and any macronutrient intake, with low-to-moderate heterogeneity between countries (I-2 range 0-51.6%). Results were similar using isocaloric macronutrient substitution analyses and when weighted and unweighted GRSs and individual SNPs were examined.

    Conclusions/interpretation: Genetic susceptibility to type 2 diabetes, insulin resistance and BMI did not modify the association between macronutrient intake and incident type 2 diabetes. This suggests that macronutrient intake recommendations to prevent type 2 diabetes do not need to account for differences in genetic predisposition to these three metabolic conditions.

  • 44.
    Lilja, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Julin, B.
    Stockholm, Sweden.
    Andersson, G.
    Stockholm, Sweden.
    Andersson, I. -L
    Nacka, Sweden.
    Axelsen, M.
    Nacka, Sweden.
    Ek, M.
    Stockholm, Sweden.
    Kristiansson, R.
    Uppsala, Sweden.
    Lekell, J.
    Uppsala, Sweden.
    Lindberg, A.
    Malmö, Sweden.
    Lindgren, P.
    Stockholm, Sweden.
    Löndahl, F.
    Stockholm, Sweden.
    Looström Muth, K.
    Gothenburg, Sweden.
    Svensson, A. -M
    Gothenburg, Sweden.
    Dahlström, T.
    Uppsala, Sweden.
    Determinants of HbA1c in patients with type 1 diabetes in seven Swedish county councils2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1 Abstr. 278, p. S140-S141Article in journal (Other academic)
    Abstract [en]

    Background and aims: In order to make fair comparisons between the results of different health care providers, proper consideration of the casemix of the populations they serve is important. HbA1c is often used as a metric to indicate the quality of diabetes care, it is therefore of value to determine what patient characteristics affect this outcome. As part of the ongoing National Collaboration for Value Based Reimbursement and Monitoring Systems, we therefore set out to investigate what factors are associated with HbA1c in a large retrospective cohort of persons with type 1 diabetes.

    Materials and methods: This was a retrospective register study where we analyzed persons 18 years or older, with a health care contact and a diagnosis of diabetes during 2010-11 in the administrative systems of seven Swedish county councils (Dalarna, Jämtland Härjedalen, Skåne, Stockholm, Uppsala, Västra Götaland and Östergötland), covering ~70% of the Swedish population and linked this data to data from the National Diabetes Register, socioeconomic data from Statistics Sweden and data on filled prescriptions from the Prescribed Drug Register. We estimated a random effect model on HbA1c after one year of follow-up, including socioeconomic, demographic and clinical factors.

    Results: Based on a complete case approach, 13 396 patients were analyzed. Women had on average higher HbA1c than men. Blood sugar control seemed to be better with higher age. Of the socioeconomic factors, higher education was associated with lower levels of HbA1c, as was being married. By contrast, we found no association between HbA1c and being born outside the EU.Ahistory (previous 2 years) of diabetes related complications were associated with higher levels of HbA1c, which is likely due to high levels of HbA1c being an indicator of what is causing the complications in the first place. The exception to this pattern was patients with renal failure.

    Conclusion: Apart from obvious demographic factors such as age and gender as well as disease history, educational and civil status are important factors to take into consideration when comparing obtained HbA1c levels between health care providers. This also raises the question of the need for additional focus on education directed towards these groups to facilitate improved diabetes management.

  • 45.
    Lind, Torbjörn
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Waernbaum, Ingeborg
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Berhan, Yonas
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Socioeconomic factors, rather than diabetes mellitus per se, contribute to an excessive use of antidepressants among young adults with childhood onset type 1 diabetes mellitus: a register-based study2012In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, no 3, p. 617-624Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: Mood disorders, including depression, are suggested to be prevalent in persons with type 1 diabetes and may negatively affect self-management and glycaemic control and increase the risk of diabetic complications. The aim of this study was to analyse the prevalence of antidepressant (AD) use in adults with childhood onset type 1 diabetes and to compare risk determinants for AD prescription among diabetic patients and a group of matched controls. METHODS: Young adults ≥18 years on 1 January 2006 with type 1 diabetes (n = 7,411) were retrieved from the population-based Swedish Childhood Diabetes Registry (SCDR) and compared with 30,043 age- and community-matched controls. Individual level data were collected from the Swedish National Drug Register (NDR), the Hospital Discharge Register (HDR) and the Labor Market Research database (LMR). RESULTS: ADs were prescribed to 9.5% and 6.8% of the type 1 diabetes and control subjects, respectively. Female sex, having received economic or other social support, or having a disability pension were the factors with the strongest association with AD prescription in both groups. Type 1 diabetes was associated with a 44% (OR 1.44, 95% CI 1.32, 1.58) higher risk of being prescribed ADs in crude analysis. When adjusting for potential confounders including sex, age and various socioeconomic risk factors, this risk increase was statistically non-significant (OR 1.11, 95% CI 0.99, 1.21). CONCLUSIONS/INTERPRETATION: The risk factor patterns for AD use are similar among type 1 diabetic patients and controls, and socioeconomic risk factors, rather than the diabetes per se, contribute to the increased risk of AD use in young adults with type 1 diabetes.

  • 46. Lyssenko, V.
    et al.
    Moller, C.
    Storm, P.
    Poon, W.
    Vikman, P.
    Groop, L.
    Rossing, P.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Eliasson, B.
    Brismar, K.
    Nilsson, P. M.
    How to survive type 1 diabetes: the prolong study2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no S1, p. S146-S146Article in journal (Other academic)
  • 47. Madsen, O D
    et al.
    Olsson, M L
    Bille, G
    Sundkvist, G
    Lernmark, A
    Dahlquist, Gisela
    Department of Pediatrics, Sachs' Children Hospital, Stockholm.
    Ludvigsson, J
    A two-colour immunofluorescence test with a monoclonal human proinsulin antibody improves the assay for islet cell antibodies1986In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 29, no 2, p. 115-118Article in journal (Refereed)
    Abstract [en]

    The conventional indirect immunofluorescence assay for islet cell antibodies was compared with a two-colour immunofluorescent assay to detect both islet cell antibodies with fluorescein isothiocyanate-labeled rabbit anti-human IgG and pancreatic B cells with a monoclonal human proinsulin antibody and Texas red-labeled sheep anti-mouse IgG. Determinations of end-point titres showed a correlation between the new two-colour immunofluorescent assay and the conventional indirect immunofluorescent assay in 1) selected sera positive for islet cell antibodies and insulin autoantibodies r s= 0.93 (p<0.01) or for islet cell antibodies alone r s=0.99 (p<0.005) and 2) sera from children or young adults with newly diagnosed Type 1 (insulin-dependent) diabetes r s=0.95 (p<0.0001). No interference between the monoclonal human proinsulin antibodies and islet cell antibodies with or without insulin autoantibodies or between the two second fluorescent antibodies was detected. It is concluded that the two-colour immunofluorescence assay is advantageous since a) it is possible to mix the reagents to avoid a more time-consuming and technically complicated assay, b) the presence of B cells can be confirmed in each section to permit detection of B cell cytoplasmic antibodies and c) microscopic evaluation is easier and more accurate, particulary in islet cell antibody negative samples.

  • 48. Medina, Anya
    et al.
    Parween, Saba
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ullsten, Sara
    Vishnu, Neelanjan
    Siu, Yuk Ting
    Quach, My
    Bennet, Hedvig
    Balhuizen, Alexander
    Åkesson, Lina
    Wierup, Nils
    Carlsson, Per Ola
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lernmark, Åke
    Fex, Malin
    Early deficits in insulin secretion, beta cell mass and islet blood perfusion precede onset of autoimmune type 1 diabetes in BioBreeding rats2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 4, p. 896-905Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Genetic studies show coupling of genes affecting beta cell function to type 1 diabetes, but hitherto no studies on whether beta cell dysfunction could precede insulitis and clinical onset of type 1 diabetes are available.

    Methods: We used 40-day-old BioBreeding (BB) DRLyp/Lyp rats (a model of spontaneous autoimmune type 1 diabetes) and diabetes-resistant DRLyp/+ and DR+/+ littermates (controls) to investigate beta cell function in vivo, and insulin and glucagon secretion in vitro. Beta cell mass was assessed by optical projection tomography (OPT) and morphometry. Additionally, measurements of intra-islet blood flow were performed using microsphere injections. We also assessed immune cell infiltration, cytokine expression in islets (by immunohistochemistry and qPCR), as well as islet Glut2 expression and ATP/ADP ratio to determine effects on glucose uptake and metabolism in beta cells.

    Results: DRLyp/Lyp rats were normoglycaemic and without traces of immune cell infiltrates. However, IVGTTs revealed a significant decrease in the acute insulin response to glucose compared with control rats (1685.3 +/- 121.3 vs 633.3 +/- 148.7; p < 0.0001). In agreement, insulin secretion was severely perturbed in isolated islets, and both first- and second-phase insulin release were lowered compared with control rats, while glucagon secretion was similar in both groups. Interestingly, after 5-7 days of culture of islets from DRLyp/Lyp rats in normal media, glucose-stimulated insulin secretion (GSIS) was improved; although, a significant decrease in GSIS was still evident compared with islets from control rats at this time (7393.9 +/- 1593.7 vs 4416.8 +/- 1230.5 pg islet-1 h-1; p < 0.0001). Compared with controls, OPT of whole pancreas from DRLyp/Lyp rats revealed significant reductions in medium (4.1 x 109 +/- 9.5 x 107 vs 3.8 x 109 +/- 5.8 x 107 μm3; p = 0.044) and small sized islets (1.6 x 109 +/- 5.1 x 107 vs 1.4 x 109 +/- 4.5 x 107 μm3; p = 0.035). Finally, we found lower intra-islet blood perfusion in vivo (113.1 +/- 16.8 vs 76.9 +/- 11.8 μl min-1 [g pancreas]-1; p = 0.023) and alterations in the beta cell ATP/ADP ratio in DRLyp/Lyp rats vs control rats.

    Conclusions/interpretation: The present study identifies a deterioration of beta cell function and mass, and intra-islet blood flow that precedes insulitis and diabetes development in animals prone to autoimmune type 1 diabetes. These underlying changes in islet function may be previously unrecognised factors of importance in type 1 diabetes development.

  • 49.
    Mollsten, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Svensson, M
    Berhan, Yonas
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Age at onset and sex influence the risk of developing end-stage renal disease in young patients with type 1 diabetes2009In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, p. S25-S26Article in journal (Refereed)
  • 50.
    Möllsten, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Jorsal, A
    Steno Diabetes Center, Gentofte, Denmark.
    Lajer, M
    Steno Diabetes Center, Gentofte, Denmark.
    Vionnet, N
    INSERM and Université Pierre et Marie Curie-Paris, UMR S 525, Paris, France.
    Tarnow, L
    Steno Diabetes Center, Gentofte, Denmark.
    The V16A polymorphism in SOD2 is associated with increased risk of diabetic nephropathy and cardiovascular disease in type 1 diabetes2009In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, no 12, p. 2590-2593Article in journal (Refereed)
    Abstract [en]

    The MnSOD V16A polymorphism is involved in the development of nephropathy caused by type 1 diabetes and seems to predict cardiovascular disease during follow-up.

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