Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity
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Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity. / Dimas, Antigone S; Lagou, Vasiliki; Barker, Adam; Knowles, Joshua W; Mägi, Reedik; Hivert, Marie-France; Benazzo, Andrea; Rybin, Denis; Jackson, Anne U; Stringham, Heather M; Song, Ci; Fischer-Rosinsky, Antje; Boesgaard, Trine Welløv; Grarup, Niels; Abbasi, Fahim A; Assimes, Themistocles L; Hao, Ke; Yang, Xia; Lecoeur, Cécile; Barroso, Inês; Bonnycastle, Lori L; Böttcher, Yvonne; Bumpstead, Suzannah; Chines, Peter S; Erdos, Michael R; Graessler, Jurgen; Kovacs, Peter; Morken, Mario A; Narisu, Narisu; Payne, Felicity; Stancakova, Alena; Swift, Amy J; Tönjes, Anke; Bornstein, Stefan R; Cauchi, Stéphane; Froguel, Philippe; Meyre, David; Schwarz, Peter E H; Häring, Hans-Ulrich; Smith, Ulf; Boehnke, Michael; Bergman, Richard N; Collins, Francis S; Mohlke, Karen L; Tuomilehto, Jaakko; Quertemous, Thomas; Lind, Lars; Hansen, Torben; Pedersen, Oluf; Walker, Mark; on behalf of the MAGIC investigators.
In: Diabetes, Vol. 63, No. 6, 02.12.2013, p. 2158-2171.Research output: Contribution to journal › Journal article › Research › peer-review
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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 -
ID: 91907390