0887 Effects of Melatonin on Glucose, Insulin, and C-Peptide Dynamics in Carriers of MTNR1B Type 2 Diabetes Risk Variant

Abstract Introduction Genome-wide association studies identified the common variant rs10830963 in the MTNR1B gene (encoding melatonin receptor 1B) as a risk factor for type 2 diabetes. This sparked great interest in the role of the circadian hormone melatonin in glycemic control; however, the mechanisms underlying this association remain unclear. We investigated whether exogenous melatonin administration worsens glucose tolerance, insulin sensitivity, and beta-cell function, and whether such effect is stronger in MTNR1B G-allele risk carriers compared to non-carriers. Methods Twenty-one healthy participants of European ancestry were studied in a double-blind, randomized, cross-over trial, including ten MTNR1B risk carriers (mean age±SD, 29±10y; BMI, 24.4±2.6kg/m2; 5 women) and eleven non-carriers (32±10y; 22.5±3.0kg/m2; 3 women). Each participant underwent a highly-controlled 5-day laboratory protocol, during which they received 5mg oral melatonin or placebo in randomized order on two nonconsecutive days. Elevated circulating melatonin levels after melatonin administration were confirmed by hourly blood draw. Insulin sensitivity (SI), beta-cell function, and disposition index (DI, product of insulin secretion and sensitivity) were derived from insulin-modified frequently-sampled intravenous glucose tolerance test (FSIGT) using minimal models. Results The effect of melatonin versus placebo differed significantly between MTNR1B genotypes for glucose incremental area under the curve (iAUC180min, Pinteraction=0.005), insulin iAUC20min (Pinteraction=0.03), and C-peptide iAUC20min (Pinteraction=0.03) during FSIGT, with 11.7% increase in glucose iAUC180min (95%CI 3.1%─20.2%, P=0.03), 25.2% decrease in insulin iAUC20min (4.4%─41.2%, P=0.06), and 19.2% decrease in C-peptide iAUC20min (4.9%─31.2%, P=0.04) in carriers, without significant changes in non-carriers (n.s.). While we did not find significant effects of melatonin nor its interaction effects with MTNR1B genotype on DI and SI, first-phase insulin secretion was affected differently by melatonin in carriers and non-carriers (Pinteraction=0.001), with a 40.0% reduction in carriers (27.6%─50.3%, P< 0.0001), but no significant changes in non-carriers (n.s.). Conclusion Exogenous melatonin administration significantly impaired glucose tolerance and beta-cell function in MTNR1B risk carriers, but not in non-carriers. These data suggest that first-phase insulin secretion plays an important role in mediating the effect of melatonin on glucose control and its interaction with MTNR1B genotype. Support (if any) NIDDK Grant R01-DK102696 to FAJLS and RS, ADA fellowship 1-17-PDF-103 to JQ, and CTSA-UL1RR025758 to Harvard University and Brigham and Women’s Hospital.