Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes

Abstract

Type 2 diabetes (T2D) is a global pandemic. Genome-wide association studies (GWASs) have identified >100 genetic variants associated with the disease, including a common variant in the melatonin receptor 1 b gene (MTNR1B). Here, we demonstrate increased MTNR1B expression in human islets from risk G-allele carriers, which likely leads to a reduction in insulin release, increasing T2D risk. Accordingly, in insulin-secreting cells, melatonin reduced cAMP levels, and MTNR1B overexpression exaggerated the inhibition of insulin release exerted by melatonin. Conversely, mice with a disruption of the receptor secreted more insulin. Melatonin treatment in a human recall-by-genotype study reduced insulin secretion and raised glucose levels more extensively in risk G-allele carriers. Thus, our data support a model where enhanced melatonin signaling in islets reduces insulin secretion, leading to hyperglycemia and greater future risk of T2D. The findings also imply that melatonin physiologically serves to inhibit nocturnal insulin release.

Chronomedicine and type 2 diabetes: shining some light on melatonin

“…This increase in MT2 levels is proposed to heighten the insulin-inhibitory effect of melatonin. On the other hand, the same study confirmed that global deletion of the MT2 receptor in mice results in hyperinsulinaemia in response to glucose administration and reduced insulin sensitivity in the liver [165].…”

“…The adverse effects of excess melatonin signalling: the need for a personalised medicine approach One mechanism for these melatonin-induced negative effects in individuals with the MNTR1B risk allele was initially proposed by Lyssenko et al [106] and independently confirmed by others [165]. Tuomi and colleagues determined that overexpression of MNTR1B in carriers of the risk allele leads to elevated MT2 in pancreatic beta cells [165].…”

“…Tuomi and colleagues determined that overexpression of MNTR1B in carriers of the risk allele leads to elevated MT2 in pancreatic beta cells [165]. This increase in MT2 levels is proposed to heighten the insulin-inhibitory effect of melatonin.…”

“…Because much of the data showing a positive effect of melatonin is pre-clinical and generated using nocturnal rodents that were administered exceedingly high concentrations of melatonin at a time of heightened food intake, it is difficult to draw solid conclusions regarding its potential efficacy in a clinical setting. Enthusiasm for melatonin in the management of diabetes is dampened by reports that melatonin impairs glucose tolerance among healthy individuals and can increase Genetic assessment may help to avoid negative impacts of melatonin or MT2 agonists on glucose metabolism in diabetic individuals or those at risk of diabetes the risk of developing diabetes among those carrying the MNTR1B risk allele [28,29,138,165]. Thus, care should likely be taken when providing melatonin to individuals with sleep disturbances, especially those patients who are obese, at high risk for the development of diabetes or carriers of the MNTR1B risk allele, since these individuals may be at greater risk for experiencing the negative effects of the hormone.…”

The case for too little melatonin signalling in increased diabetes risk

“…Following a publication stating that enhanced melatonin signalling increases the risk of type 2 diabetes [1], two commentaries had opposite views on the relevance of these data [2,3]. This question is crucial as melatonin is available over-the-counter as a dietary supplement for its anti-oxidant/anti-ageing effect, and/or to treat acute or chronic sleep problems.…”