Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans

Abstract

Aims: The common MTNR1B genetic variant rs10830963 is associated with an increased risk of type 2 diabetes (T2D). To date, no experimental study has tested the effect of the MTNR1B variant on glucose metabolism in humans during exposure of the melatonin receptors to their ligand. The aim of this study was to investigate whether this MTNR1B variant influenced the effect of melatonin (5mg) on glucose tolerance assessed by an oral glucose tolerance test (OGTT; 75 g) at different times of the day (morning and evening) as compared to a placebo.

Methods: Seventeen normoglycemic women (24 ± 6 years; BMI 23.0 ± 3.3 kg/m(2)) completed the study (11 carriers of the risk allele [CG] and 6 noncarriers [CC]).

Results: The effect of melatonin on glucose tolerance depended on the genotype. In the morning, the effect of melatonin (melatonin-placebo) on the glucose area under the curve (AUC) above baseline differed significantly (P=0.036) between the carriers and noncarriers. This effect of melatonin in the carriers was six times as large as that in the noncarriers. The MTNR1B SNP explained over one-quarter (26%) of the inter-individual differences in the effect of melatonin on glucose AUC. However, in the evening, the effect of melatonin on glucose AUC of the carriers and noncarriers did not differ significantly (P>0.05).

Conclusions: MTNR1B rs10830963 risk variant worsens the effect of melatonin on glucose tolerance, suggesting the importance of genotyping and personalized recommendations, especially in people consuming food when melatonin levels are elevated. Large-scale studies in vulnerable populations are necessary to translate these results into real-world, clinically relevant recommendations.

Keywords: Genetic variation; Glucose tolerance; MTNR1B; Melatonin; Type 2 diabetes.

Figure 1

Comparison between the effects of exogenous placebo and melatonin administrations on plasma glucose concentrations in response to an oral load of glucose in the morning and evening in carriers of the risk allele (CG) (top panels) and in non-carriers (CC) (middle panels). Responses of glucose during OGTT were examined as area under the curve above baseline across 120 minutes following the oral glucose load (AUC), calculated by the trapezoidal method. Furthermore, the time-dependent effects were tested by two-way ANOVA for time and treatment effects with repeated measurements. paired t-test was used to evaluate times in which variations were different. *Different from placebo at that time, P<0.05. Differences between carriers of the MTNR1B risk variant (CG) and non-carriers (CC) in the effect of melatonin (melatonin-placebo) on AUC for glucose in the morning and in the evening (lower panels) were analyzed by unpaired t-test and further analyses were performed by ANCOVA in which effects were adjusted for age and BMI. Data are represented as mean ± SEM. TF, time fasting; T30, 60, 90, 120, time after OGTT (min).

Figure 2

Comparison between the effects of exogenous placebo and melatonin administrations on plasma insulin concentrations in response to an oral load of insulin in the morning and evening in carriers of the risk allele (CG) (top panels) and in non-carriers (CC) (middle panels). Responses of glucose during OGTT were examined as area under the curve above baseline across 120 minutes following the oral insulin load (AUC), calculated by the trapezoidal method. Furthermore, the time-dependent effects were tested by two-way ANOVA for time and treatment effects with repeated measurements. Paired t-test was used to evaluate times in which variations were different. *Different from placebo at that time, P<0.05. Differences between carriers of the MTNR1B risk variant (CG) and non-carriers (CC) in the effect of melatonin (melatonin-placebo) on AUC for glucose in the morning and in the evening (lower panels) were analyzed by unpaired t-test and further analyses were performed by ANCOVA in which effects were adjusted for age and BMI. Data are represented as mean ± SEM. TF, time fasting; T30, 60, 90, 120, time after OGTT (min).