Dimas, Antigone S2; Lagou, Vasiliki3; Barker, Adam3; Knowles, Joshua W3; Mägi, Reedik3; Hivert, Marie-France3; Benazzo, Andrea3; Rybin, Denis3; Jackson, Anne U3; Stringham, Heather M3; Song, Ci3; Fischer-Rosinsky, Antje3; Boesgaard, Trine Welløv3; Grarup, Niels4; Abbasi, Fahim A3; Assimes, Themistocles L3; Hao, Ke3; Yang, Xia3; Lecoeur, Cécile3; Barroso, Inês3; Bonnycastle, Lori L3; Böttcher, Yvonne3; Bumpstead, Suzannah3; Chines, Peter S3; Erdos, Michael R3; Graessler, Jurgen3; Kovacs, Peter3; Morken, Mario A3; Narisu, Narisu3; Payne, Felicity3; Stancakova, Alena3; Swift, Amy J3; Tönjes, Anke3; Bornstein, Stefan R3; Cauchi, Stéphane3; Froguel, Philippe3; Meyre, David3; Schwarz, Peter E H3; Häring, Hans-Ulrich3; Smith, Ulf3; Boehnke, Michael3; Bergman, Richard N3; Collins, Francis S3; Mohlke, Karen L3; Tuomilehto, Jaakko3; Quertemous, Thomas3; Lind, Lars3; Hansen, Torben4; Pedersen, Oluf4; Walker, Mark3; Pfeiffer, Andreas F H3; Spranger, Joachim3; Stumvoll, Michael3; Meigs, James B3; Wareham, Nicholas J3; Kuusisto, Johanna3; Laakso, Markku3; Langenberg, Claudia3; Dupuis, Josée3; Watanabe, Richard M3; Florez, Jose C3; Ingelsson, Erik3; McCarthy, Mark I3; Prokopenko, Inga3
1 Section for Metabolic Genetics, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, Københavns Universitet2 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.3 unknown4 Section for Metabolic Genetics, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, Københavns Universitet
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.