TY - JOUR

T1 - Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity

AU - Dimas, Antigone S

AU - Lagou, Vasiliki

AU - Barker, Adam

AU - Knowles, Joshua W

AU - Mägi, Reedik

AU - Hivert, Marie-France

AU - Benazzo, Andrea

AU - Rybin, Denis

AU - Jackson, Anne U

AU - Stringham, Heather M

AU - Song, Ci

AU - Fischer-Rosinsky, Antje

AU - Boesgaard, Trine Welløv

AU - Grarup, Niels

AU - Abbasi, Fahim A

AU - Assimes, Themistocles L

AU - Hao, Ke

AU - Yang, Xia

AU - Lecoeur, Cécile

AU - Barroso, Inês

AU - Bonnycastle, Lori L

AU - Böttcher, Yvonne

AU - Bumpstead, Suzannah

AU - Chines, Peter S

AU - Erdos, Michael R

AU - Graessler, Jurgen

AU - Kovacs, Peter

AU - Morken, Mario A

AU - Narisu, Narisu

AU - Payne, Felicity

AU - Stancakova, Alena

AU - Swift, Amy J

AU - Tönjes, Anke

AU - Bornstein, Stefan R

AU - Cauchi, Stéphane

AU - Froguel, Philippe

AU - Meyre, David

AU - Schwarz, Peter E H

AU - Häring, Hans-Ulrich

AU - Smith, Ulf

AU - Boehnke, Michael

AU - Bergman, Richard N

AU - Collins, Francis S

AU - Mohlke, Karen L

AU - Tuomilehto, Jaakko

AU - Quertemous, Thomas

AU - Lind, Lars

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Walker, Mark

AU - on behalf of the MAGIC investigators

PY - 2013/12/2

Y1 - 2013/12/2

N2 - 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.

AB - 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.

U2 - 10.2337/db13-0949

DO - 10.2337/db13-0949

M3 - Journal article

C2 - 24296717

VL - 63

SP - 2158

EP - 2171

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 6

ER -