Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion

Abstract

Genome-wide association studies have shown that variation in MTNR1B (melatonin receptor 1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets. Nondiabetic individuals carrying the risk allele and individuals with T2D showed increased expression of the receptor in islets. Insulin release from clonal beta cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of T2D. Given the increased expression of MTNR1B in individuals at risk of T2D, the pathogenic effects are likely exerted via a direct inhibitory effect on beta cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.

Figure 1. Insulin secretion according to different MTNR1Brs10830963 genotypes

(A) Corrected early insulin response to glucose (CIR) during OGTT (Botnia PPP cohort; N=3,300), (B) Disposition index (DI) represents early insulin response to glucose corrected for insulin sensitivity by the Matsuda index (CIR × ISI, Botnia PPP cohort; N=3,300). (C) Insulin secretion measured as first phase insulin response during an IVGTT (Botnia cohort; N=505). (D) Intact proinsulin-to-insulin ratio in the fasting state (Helsinki Birth Cohort, N=1,600). (F) Change in fasting plasma glucose concentrations during 24-year follow-up in non-diabetic subjects (Malmoe study, N=13,674) (E) Change in insulin secretion (disposition index) over time in non-diabetic subjects (Botnia prospective cohort, N=2,444). Bars represent mean ± SEM. Blue lines represent non-risk and red lines risk genotype carriers of rs10830963 in MTNR1B.

Figure 2. Co-localization of MTNR1B expression with insulin in mouse, rat and human pancreatic islets

Scale bar = 50um.

Figure 3. Expression of MTNR1B in human pancreatic islets

(A) The MTNR1B mRNA levels were higher in risk GG genotype carriers (total n=51, CC=21, CG=25, GG=5; non-adjusted P=0.25, age-adjusted P=0.01). The insert graph shows expression of the MTNR1B mRNA levels in the individuals above mean age of 45 years (total n=25, CC=10, CG=13, GG=2; P=0.001): The MTNR1B mRNA levels were higher in risk GG genotype carriers. (B) Insulin secretion in INS-1 832/13 clonal β-cells in response to stimulation with 2.8 mM (grey bar) and 16.7 mM glucose (white bar) in with the presence and absence of 0.1µM melatonin (black bar). Individual experiments were performed in triplicate (n = 7, * p < 0.037). Bars represent mean ± SEM.