期刊
DIABETES
卷 63, 期 6, 页码 2158-2171出版社
AMER DIABETES ASSOC
DOI: 10.2337/db13-0949
关键词
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资金
- European Community [HEALTH-F4-2007-201413, LSHM-CT-2004-512013]
- Wellcome Trust [WT098051, 098381]
- Cambridge Biomedical Research Centre of the U.K. National Institute for Health Research
- Medical Research Council Centre for Obesity and Related Metabolic Diseases
- National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]
- Affymetrix Inc. [N02-HL-6-4278]
- Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine
- Boston Medical Center
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01 DK-078616]
- NIDDK [K24 DK-080140]
- Doris Duke Charitable Foundation Clinical Scientist Development Award
- NIH [DK-069922, U54 DA021519, DK-062370, DK-072193, RR01066]
- National Human Genome Research Institute [1 Z01 HG000024]
- Agence Nationale de la Recherche
- Conseil Regional Nord-Pas de Calais/Fonds europeen de developpement economique et regional
- Academy of Finland [124243]
- Clinical Research Group [KFO218/1]
- Deutsche Forschungsgemeinschaft (DFG) [SP716/2-1]
- German Bundesministerium fur Bildung und Forschung (BMBF)
- Mallinckrodt General Clinical Research Program, National Center for Research Resources
- Swedish Research Council
- Swedish Heart-Lung Foundation
- Swedish Foundation for Strategic Research
- Royal Swedish Academy of Science
- Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention
- Care
- Danish Diabetes Association
- Danish Research Council
- European Union [QLG1-CT-2001-01252]
- AstraZeneca
- German Research Council [SF8-1052]
- German Diabetes Association
- Diabetes Hi Ifs
- Forschungsfonds Deutschland
- Boehringer Ingelheim Foundation
- BMBF [FKZ: 01E01001]
- European Commission under the Marie Curie Intra-European Fellowship
- European Foundation
- National Center for Research Resources, NIH [2 M01 RR000070]
- U.S. Public Health Service
- American Heart Association Fellow [10FTF3360005]
- Medical Research Council [G1002084, MC_U106179471, MC_UU_12015/1, G0701863] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10099, NF-SI-0512-10135] Funding Source: researchfish
- Novo Nordisk Fonden [NNF14OC0009795] Funding Source: researchfish
- MRC [G1002084, G0701863, MC_UU_12015/1] Funding Source: UKRI
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 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used 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 cluster (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 (TCF712, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 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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