Journal
CELL METABOLISM
Volume 23, Issue 6, Pages 1067-1077Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2016.04.009
Keywords
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Categories
Funding
- European Foundation for the Study of Diabetes
- Swedish Research Council (Linnaeus Centre of Excellence) [349-2006-237]
- Swedish Research Council (EXODIAB Strategic Research Grant) [2009-1039]
- Swedish Research Council [521-2010-3490, 521-2012-1743, 521-2012-2119, 325-2012-6778]
- Pahlsson Foundation
- Medical Faculty at Lund University
- Diabetes Wellness Sweden
- Swedish Diabetes Foundation
- Novo Nordisk Foundation
- Family Ernfors Fund
- European Research Council [299045]
- Sigrid Juselius Foundation
- Folkhalsan Research Foundation (Finland)
- Academy of Finland [263401, 267882]
- Folkhalsan Research Foundation
- Nordic Center of Excellence in Disease Genetics
- Signe and Ane Gyllenberg Foundation
- Swedish Cultural Foundation in Finland
- Finnish Diabetes Research Foundation
- Foundation for Life and Health in Finland
- Finnish Medical Society
- Paavo Nurmi Foundation
- Helsinki University Central Hospital Research Foundation
- Perklen Foundation
- Ollqvist Foundation
- Narpes Health Care Foundation
- Ahokas Foundation
- Ministry of Education in Finland
- Municipal Heath Care Center and Hospital in Jakobstad
- Health Care Center in Vasa
- Health Care Center in Narpes
- Health Care Center in Korsholm
- European Foundation for the Study of Diabetes [MSD 2014_2] Funding Source: researchfish
- Novo Nordisk Fonden [NNF16OC0020766, NNF14OC0010995, NNF14OC0010363] Funding Source: researchfish
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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.
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