期刊
DIABETES
卷 63, 期 12, 页码 4378-4387出版社
AMER DIABETES ASSOC
DOI: 10.2337/db14-0319
关键词
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资金
- MRC [MC_U106179471, G0601261]
- Diabetes UK
- Wellcome Trust [098051, 083270/Z/07/Z]
- U.K. National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre
- MRC Centre for Obesity and Related Metabolic Disease
- Uppsala University
- Uppsala University Hospital
- Science for Life Laboratory, Uppsala
- Swedish Research Council [80576801, 70374401]
- European Union [QLG1-CT-2001-01252]
- EU FP6 program [LSHM_CT_2006_037197]
- Swedish Diabetes Association
- Swedish Heart-Lung Foundation
- Health Research Fund (FIS) of the Spanish Ministry of Health
- Murcia Regional Government [6236]
- German Cancer Aid
- German Ministry of Research
- Cancer Research UK
- Danish Cancer Society
- Compagnia di San Paolo
- Asturias Regional Government
- Vasterboten County Council
- Dutch Ministry of Public Health, Welfare, and Sports
- Netherlands Cancer Registry
- LK Research Funds
- Dutch Prevention Funds
- Dutch ZON (Zorg Onderzoek Nederland)
- World Cancer Research Fund
- Statistics Netherlands
- AIRE-ONLUS Ragusa
- AVIS-Ragusa
- Sicilian Regional Government
- NL Agency [IGE05012]
- board of the UMC Utrecht
- U.K. NIHR Cambridge Biomedical Research Centre
- InterAct
- Imperial College Biomedical Research
- MRC [MC_UU_12015/5, G0600717, G0601261, MC_UU_12015/1, G0701863, G0500070, MC_UP_A100_1003] Funding Source: UKRI
- Wellcome Trust [083270/Z/07/Z] Funding Source: Wellcome Trust
- Cancer Research UK [16491] Funding Source: researchfish
- Diabetes UK [12/0004470] Funding Source: researchfish
- Medical Research Council [MC_UU_12015/1, G0600717, MC_UU_12012/5/B, G0600717B, MC_UU_12015/5, G0601261, G0500070, G0701863, MC_UP_A100_1003, MC_U106179471] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10135, NF-SI-0611-10099] Funding Source: researchfish
We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp- and oral glucose tolerance test-based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (beta in SDs per allele [95% CI], -0.03 [-0.04, -0.01]; P = 0.004). This score was associated with lower BMI (-0.01 [-0.01, -0.0]; P = 0.02) and gluteofemoral fat mass (-0.03 [-0.05,-0.02; P = 1.4x10(-6) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and gamma-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (P-interaction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (P-interaction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.
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