# Diabetes-associated Genetic Variation in MTNR1B and Its Effect on Islet Function

## TL;DR

This study explores how a genetic variant in MTNR1B affects islet function and contributes to type 2 diabetes risk.

## Contribution

The study identifies a link between MTNR1B genetic variation and altered α-cell function in glucose regulation.

## Key findings

- The G-allele at rs10830963 is associated with higher postchallenge glucose and glucagon levels.
- The genetic variant likely influences type 2 diabetes risk through changes in α-cell function.
- Effects on glucose homeostasis were observed in individuals without diabetes.

## Abstract

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 MTNR1B, which implicates melatonin and its receptor in the pathogenesis of type 2 diabetes.

To characterize the effect of diabetes-associated genetic variation at rs10830963 in the MTNR1B locus on islet function in people without type 2 diabetes.

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.

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

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 TCF7L2 genotype at rs7903146 from the Mayo Biobank.

Two-hour, 7-sample OGTT.

Fasting, nadir, and integrated glucagon concentrations.

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.

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.