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Dimas, A.S.* ; Lagou, V.* ; Barker, A.* ; Knowles, J.W.* ; Mägi, R.* ; Hivert, M.F.* ; Benazzo, A.* ; Rybin, D.* ; Jackson, A.U.* ; Stringham, H.M.* ; Song, C.* ; Fischer-Rosinsky, A.* ; Boesgaard, T.W.* ; Grarup, N.* ; Abbasi, F.A.* ; Assimes, T.L.* ; Hao, K.* ; Yang, X.* ; Lecoeur, C.* ; Barroso, I.* ; Bonnycastle, L.L.* ; Böttcher, Y.* ; Bumpstead, S.* ; Chines, P.S.* ; Erdos, M.R.* ; Graessler, J.* ; Kovacs, P.* ; Morken, M.A.* ; Narisu, N.* ; Payne, F.* ; Stancáková, A.* ; Swift, A.J.* ; Tönjes, A.* ; Bornstein, S.R.* ; Cauchi, S.* ; Froguel, P.* ; Meyre, D.* ; Schwarz, P.E.* ; Häring, H.-U. ; Smith, U.* ; Boehnke, M.* ; Bergman, R.N.* ; Collins, F.S.* ; Mohlke, K.L.* ; Tuomilehto, J.* ; Quertemous, T.* ; Lind, L.* ; Hansen, T.* ; Pedersen, O.* ; Walker, M.* ; Pfeiffer, A.F.* ; Spranger, J.* ; Stumvoll, M.* ; Meigs, J.B.* ; Wareham, N.J.* ; Kuusisto, J.* ; Laakso, M.* ; Langenberg, C.* ; Dupuis, J.* ; Watanabe, R.M.* ; Florez, J.C* ; Ingelsson, E.* ; McCarthy, M.I.* ; Prokopenko, I.* ; MAGIC Investigators (Grallert, H. ; Gieger, C. ; Meisinger, C. ; Thorand, B. ; Wichmann, H.-E. ; Illig, T.)

Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.

Diabetes 63, 2158-2171 (2013)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci and indices of proinsulin processing, insulin secretion and insulin sensitivity. We included data from up to 58,614 non-diabetic subjects with basal measures, and 17,327 with dynamic measures. We employed additive genetic models with adjustment for sex, age and BMI, followed by fixed-effects inverse variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (including TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without detectable change in fasting glucose. The final group contained twenty risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Beta-cell Function; Scale Association Analysis; Body-mass Index; Insulin Sensitivity; Proinsulin Levels; Common Variant; Tcf7l2 Gene; Glucose; Genome; Loci
ISSN (print) / ISBN 0012-1797
e-ISSN 1939-327X
Journal Diabetes
Quellenangaben Volume: 63, Issue: 6, Pages: 2158-2171 Article Number: , Supplement: ,
Publisher American Diabetes Association
Publishing Place Alexandria, VA.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) CCG Biomarker for the subclassification of T2DM (KKG-KDB)
Institute of Human Genetics (IHG)
Institute of Epidemiology II (EPI2)
Research Unit Molecular Epidemiology (AME)
Institute of Epidemiology (EPI)
Institute of Genetic Epidemiology (IGE)
German Center for Diabetes Reseach (DZD)
Institute of Diabetes Research and Metabolic Diseases (IDM)