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 β 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 β 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 β cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.
The DGI study was supported by a grant from Novartis.
Studies in Malmoe were supported by grants from the Swedish Research Council, including a Linné grant (No. 31475113580), the Diabetes Programme at Lund University, the Påhlsson Foundation, the Heart and Lung Foundation, the Wallenberg Foundation, the Swedish Diabetes Research Society, the Crafoord Foundation, Swedish Medical Society, Swedish Royal Physiographic Society, a Nordic Centre of Excellence Grant in Disease Genetics, the Finnish Diabetes Research Society, the Sigrid Juselius Foundation, Folkhälsan Research Foundation, Novo Nordisk Foundation, the European Network of Genomic and Genetic Epidemiology (ENGAGE), the Wallenberg Foundation, the European Foundation for the Study of Diabetes (EFSD) and the Human Tissue facility at the Lund University Diabetes Center. Studies in human islets were supported in part by the Italian Ministry of University and Research (PRIN 2007-2008) and the European Community (LSHM-CT-2006-518153).
Pancreatic islets at US National Institutes of Health were obtained through the ICR Basic Science Islet Distribution Program (City of Hope Hospital, Joslin Diabetes Center, Northwestern University, Southern California Islet Consortium, University of Alabama Birmingham, University of Illinois, University of Miami, University of Minnesota, University of Pennsylvania, University of Wisconsin and Washington University), the Juvenile Diabetes Research Foundation Islet Resources (Washington University) and the National Disease Resource Interchange (NDRI).
The FUSION study would like to thank the many research volunteers who generously participated in the various studies represented in FUSION. We also thank A.J. Swift, M. Morken, P.S. Chines and N. Narisu for genotying and informatics support. Support for FUSION was provided by the following: NIH grant DK062370 (M. Boehnke), American Diabetes Association research grant 1-05-RA-140 (R.M.W.), DK072193 (K.L. Mohlke) and National Human Genome Research Institute intramural project number 1 Z01 HG000024 (F.S. Collins). The METSIM study was supported by Academy of Finland grant 124243 (M.L.).
Supplementary Figure 1