OBJECTIVE

Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action.

RESEARCH DESIGN AND METHODS

We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084).

RESULTS

The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 × 10−71). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction.

CONCLUSIONS

Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.

OBJECTIVE

To investigate whether variation in the melatonin receptor 1B gene (MTNR1B), recently identified as a common genetic determinant of fasting glucose levels in healthy, diabetes free individuals is associated with measures of beta-cell function and whole-body insulin sensitivity.

RESEARCH DESIGN AND METHODS

A total of 1,276 healthy individuals of European ancestry were studied at 19 centres of the RISC study. Whole-body insulin sensitivity (M/I) was assessed by hyperinsulinaemic-euglycemic clamp and indices of beta-cell function were derived from a 75-g oral glucose tolerance test (including 30-min insulin response and glucose sensitivity). We studied rs10830963 in MTNR1B using additive genetic models, adjusting for age, sex, and recruitment centre.

RESULTS

The minor (G) allele of rs10830963 in MTNR1B (frequency 0.30 in HapMap CEU; 0.29 in RISC participants) was associated with higher levels of fasting plasma glucose (standardized beta (95% CI) 0.17 (0.085; 0.25) per G allele; p=5.8×10e-5), consistent with recent observations. In addition, the G-allele was significantly associated with lower early insulin response (−0.19 (−0.28; −0.10); p=1.7×10e-5), as well as with decreased beta-cell glucose sensitivity (−0.11 (−0.20; −0.027); p=0.010). No associations were observed with clamp assessed insulin sensitivity (p=0.15) or different measures of body size (all p-values >0.7).

CONCLUSIONS

Genetic variation in MTNR1B is associated with defective early insulin response and decreased beta-cell glucose sensitivity, which may contribute to the higher glucose levels of non-diabetic individuals carrying the minor G allele of rs10830963 in MTNR1B.

Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 × 10−5], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.