Journal
NATURE GENETICS
Volume 41, Issue 1, Pages 82-88Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.288
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Funding
- Novartis
- Swedish Research Council [31475113580]
- Lund University
- Pahlsson Foundation
- Heart and Lung Foundation
- Wallenberg Foundation
- Swedish Diabetes Research Society
- Crafoord Foundation
- Swedish Medical Society
- Swedish Royal Physiographic Society
- Nordic Centre of Excellence Grant in Disease Genetics
- Finnish Diabetes Research Society
- Sigrid Juselius Foundation
- Folkhalsan Research Foundation
- Novo Nordisk Foundation
- European Network of Genomic and Genetic Epidemiology (ENGAGE)
- Italian Ministry of University and Research [PRIN 2007-2008]
- European Community [LSHM-CT-2006-518153]
- NIH [DK062370]
- American Diabetes Association [1-05-RA-140, DK072193]
- Academy of Finland [124243]
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [Z01HG000024] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R56DK062370, R01DK072193, U01DK062370, R01DK062370] Funding Source: NIH RePORTER
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Genome-wide association studies have shown that variation in MTNR1B (melatonin receptor 1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets. Nondiabetic individuals carrying the risk allele and individuals with T2D showed increased expression of the receptor in islets. Insulin release from clonal beta cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of T2D. Given the increased expression of MTNR1B in individuals at risk of T2D, the pathogenic effects are likely exerted via a direct inhibitory effect on beta cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.
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