The case for too little melatonin signalling in increased diabetes risk

Abstract

Genome-wide association studies have detected an association between type 2 diabetes risk and a non-coding SNP located in MTNR1B, the gene encoding melatonin receptor 2 (MT2). Melatonin regulates circadian rhythms and sleep and associates with metabolic disorders. However, the mechanisms underlying these actions are still unclear. Functional genomic, animal and clinical studies have not reached the same conclusions: while some studies have reported that decreased melatonin signalling increases type 2 diabetes risk, others have found the opposite. In this commentary, we have tried to provide an explanation for these contradictions and we suggest how the community may progress to reach a unified picture of the effect of melatonin and its signalling on type 2 diabetes.

Enhancement of high glucose‐induced PINK1 expression by melatonin stimulates neuronal cell survival: Involvement of MT2/Akt/NF‐κB pathway

“…22,23 Previous data suggested that decreased melatonin signaling through deleterious MT 2 receptor activity increases type 2 diabetes risk. 24 These results were line with various studies, which showed that high melatonin levels lead to decreased risk of diabetes. 25,26 However, increased melatonin signaling is a risk factor for T2DM.…”

“…Results of genome‐wide association studies have shown a relationship between variation of MT 2 ( MTNR1B ) in pancreatic islet cells and type 2 diabetes mellitus (T2DM) occurrence, highlighting the role of MT 2 in T2DM pathogenesis . Previous data suggested that decreased melatonin signaling through deleterious MT 2 receptor activity increases type 2 diabetes risk . These results were line with various studies, which showed that high melatonin levels lead to decreased risk of diabetes .…”

A brief review about melatonin, a pineal hormone

“…This melatoninreceptor dysfunction is usually a consequence of melatonin receptors genetic variations (e.g. single nucleotide polymorphisms) and affect either MT1 or MT2 receptors (55,56).…”

Melatonin attenuates smoking‐induced hyperglycemia via preserving insulin secretion and hepatic glycogen synthesis in rats

“…Many of melatonin's biological effects are mediated by the activation of melatonin receptors . The effects of melatonin are mediated by two receptors, which are expressed in a function‐specific fashion .…”

“…Both receptors, but predominantly the MT2 receptor, are subject to internalization, maintaining homeostasis . A previous study suggested that the MT2 receptor regulates β cell function; further, deleterious MT2 receptor activity is known to increase diabetes risk . The stimulatory effects of melatonin on insulin secretion rely that the melatonin receptors couple to G proteins mediating a stimulatory effect on insulin secretion .…”