Diabetes-associated Genetic Variation in and Its Effect on Islet Function.

CONTEXT

Multiple common genetic variants have been associated with type 2 diabetes, but the mechanism by which they predispose to diabetes is incompletely understood. One such example is variation in which implicates melatonin and its receptor in the pathogenesis of type 2 diabetes.

OBJECTIVE

To characterize the effect of diabetes-associated genetic variation at rs10830963 in the locus on islet function in people without type 2 diabetes.

DESIGN

The association of genetic variation at rs10830963 with glucose, insulin, C-peptide, glucagon, and indices of insulin secretion and action were tested in a cohort of 294 individuals who had previously undergone an oral glucose tolerance test (OGTT). Insulin sensitivity, β-cell responsivity to glucose, and Disposition Indices were measured using the oral minimal model.

SETTING

The Clinical Research and Translation Unit at Mayo Clinic, Rochester, MN.

PARTICIPANTS

Two cohorts were utilized for this analysis: 1 cohort was recruited on the basis of prior participation in a population-based study in Olmsted County. The other cohort was recruited on the basis of genotype at rs7903146 from the Mayo Biobank.

INTERVENTION

Two-hour, 7-sample OGTT.

MAIN OUTCOME MEASURES

Fasting, nadir, and integrated glucagon concentrations.

RESULTS

One or 2 copies of the G-allele at rs10830963 were associated with increased postchallenge glucose and glucagon concentrations compared to subjects with the CC genotype.

CONCLUSION

The effects of rs10830963 on glucose homeostasis and predisposition to type 2 diabetes are likely to be partially mediated through changes in α-cell function.