Editors' ChoiceDiabetes

Sleepless and Diabetic

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Science Translational Medicine  15 Feb 2012:
Vol. 4, Issue 121, pp. 121ec24
DOI: 10.1126/scitranslmed.3003836

Lack of sleep has been blamed for weight gain, heart disease, and now perhaps even diabetes. Feeding and metabolism are known to be synced to circadian (sleep) patterns, and secretion of many hormones, including insulin, follows periodic, pulsatile patterns. In recent years, disruptions in clock-related pathways have been linked to a higher risk of metabolic dysfunction and type 2 diabetes through genome-wide association studies (GWAS). Now, Bonnefond et al. provide a functional link between circadian patterns and diabetes risk through their focused characterization of rare variants in the MTNR1B gene.

The neurohormone melatonin is secreted in a circadian pattern and acts in part through the MT2 receptor, which is encoded by MTNR1B—a gene previously implicated as a common risk allele for type 2 diabetes. Bonnefond and colleagues hypothesized that the association between MTNR1B and diabetes could be explained by the contribution of rare genetic variants with strong, harmful effects. By sequencing the exons of MTNR1B in 7632 controls and 2186 subjects with type 2 diabetes, the authors identified 36 very rare variants in MTNR1B that were strongly associated with diabetes risk. Moreover, by functional assessment of individual mutants for melatonin binding and receptor activation in transfected human embryonic kidney cells, Bonnefond et al. found that the 13 rare variants with impaired MT2 function contributed most significantly to increased risk of type 2 diabetes, increasing the odds of diabetes fivefold. On the basis of the known ability of melatonin to inhibit insulin secretion in mouse pancreatic islet cell lines, the authors postulate that impaired MT2 function may lead to loss of negative feedback regulatory mechanisms that affect insulin secretion.

The link between defective MT2 receptor function and increased risk of type 2 diabetes establishes an intriguing intersection of circadian biology and metabolic disease. Melatonin receptor agonists currently approved to treat sleep and circadian rhythm disorders may find new application in diabetes therapy. For now, a better night’s sleep may be just what the doctor ordered.

A. Bonnefond et al., Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat. Genet. 29 January 2012 (10.1038/ng.1053). [Abstract]

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