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- Title
Role of Type 2 Diabetes Susceptibility Variants in Insulin Sensitivity, Insulin Secretion, and Disposition Index.
- Authors
Elbein, Steven C.; Chu, Winston S.; Hua Wang; Das, Swapan K.; Gomes, Tina; Sharma, Neeraj; Kern, Philip A.; Rasouli, Neda
- Abstract
Prediabetic traits of insulin sensitivity (St), insulin secretion in response to IV glucose (AIR[sub g]), and β-cell compensation for S[sub I] (AIR[sub g]*S[sub I], disposition index or DI) are heritable in high risk families, but genetic variants accounting for the heritability have not been identified. Over 20 nonsynonymous single nucleotide polymorphisms (SNPs) or putative regulatory variants have been reported to be associated with type 2 diabetes (T2DM). We completed analysis of 16 variants in 15 genes in an ongoing survey of strong candidate SNPs for insulin action or insulin secretion, including well established T2DM genes KCNJ11 and PPARG. We examined 2 Caucasian cohorts of nondiabetic individuals who underwent frequently sampled intravenous glucose tolerance tests (FSIGT) with minimal model estimation of S[sub I] and determination of AIR[sub g] and calculation of DI. A cohort of 124 related individuals was ascertained from 26 high risk families of Northern European ancestry (Study 1). A second cohort of 341 unrelated individuals had variable family history, broader European ancestry, and a greater range of BMI (Study 2). SNPs were selected for single variants previously reported to be associated with T2DM or related Waits, and were typed by pyrosequencing. Analysis used a general linear model in which marginal means were compared after adjusting for age, gender, and BMI; Study 1 included family membership as a random factor. In study 1, KCNJ11 E23K was associated with decreased AIR[sub g] (p<0.02), and PPARG P12A with increased S[sub I] (p<0.05) consistent with expectations, but neither finding replicated in Study 2. Resistin (RETN) promoter -420 reduced S[sub I] (p<0.02), and TNFA promoter - 308 unexpectedly increased DI (p=0.005), but neither replicated in Study 2. The UCP2 untranslated insertion/deletion (InDel) reduced S[sub I] and DI (p<0.001) in Study 1 but not Study 2. In contrast, in Study 2 homozygosity for ADRB2 R16G` reducedAIR[sub g] (p<0.005) but not DI, and IRS1 G972R reduced S[sub I] by 30% (p<0.02) and increased AIR[sub g] (p<0.03), but did not change DI. No positive association replicated between Study 1 and Study 2, and IL6 promoter, ENPP1 K121Q, ADRB3 W64R, GCK promoter, FABP2 A54T, and 2 PPP1R3 variants were not associated in either study. Additional work is in progress. Currently known functional variants are unlikely to explain the heritability of prediabetic traits, particularly DI. High risk families may have unique risk factors, but small effect size may account for apparent heterogeneity. ADA-Funded Research
- Subjects
GENETICS of type 2 diabetes; GENETICS of disease susceptibility; ALLERGENICITY of insulin; MECHANISM of action for insulin; GENETIC polymorphisms; CAUCASIAN race; GLUCOSE tolerance tests; GENEALOGY; DISEASES
- Publication
Diabetes, 2007, Vol 56, pA300
- ISSN
0012-1797
- Publication type
Article