The majority of these gene variants affect genes encoding intracellular proteins that mediate the secretion of insulin by beta cells or that transduce the effects of insulin in target tissues. However, not all candidate genes encode proteins that function within the cell: one that does not is MTNR1B, which encodes MT2, a cell-surface G-protein–coupled receptor (GPCR). This receptor is expressed on islet beta cells and is activated by changes in circulating levels of the pinealderived hormone melatonin. Persons who have a variant of MTNR1B are at increased risk for the development of type 2 diabetes,1 and a recent study by Tuomi and colleagues,2 who discovered the genetic association, investigated the effects of melatonin, by means of the MT2 receptor, on beta-cell function.

Nonetheless, the study raises the question of whether the gain-of-function variant in MTNR1B could predispose persons to glucose intolerance or type 2 diabetes under conditions of insulin resistance such as obesity, in which beta cells are required to compensate for reduced insulin sensitivity by secreting more insulin and may be hindered in doing so by melatonin supplementation. Further studies testing the effects of melatonin on glucose intolerance in obese persons are warranted.

A Wake-up Call for Type 2 Diabetes? Shanta J. Persaud, Ph.D., and Peter M. Jones, Ph.D. N Engl J Med 2016; 375:1090-1092September 15, 2016DOI: 10.1056/NEJMcibr1607950