title: Melatonin signalling and type 2 diabetes risk: too little, too much or just right?
abstract: Of the associations of genetic variants with type 2 diabetes, the one of an SNP in an intron of the gene encoding the melatonin receptor 1B (MTNR1B) has been remarkably robust. Work from our group and others has provided support for a model where carriers of this risk G allele exhibit increased MTNR1B expression in islets of Langerhans. Most published studies to date favour that melatonin's action on the beta cell is inhibition of insulin secretion. Hence, our model proposes that this inhibitory effect of melatonin is exaggerated in carriers of the MTNR1B risk G allele. This would explain why this genetic association causes reduced insulin secretion and greater risk of future type 2 diabetes, as has been observed in numerous studies. Concurrently, another body of work has shown that rare MTNR1B alleles, which could perturb receptor function, also associate with type 2 diabetes. In this commentary, it is suggested that such apparently conflicting observations can be reconciled by the fact that non-coding (intronic; frequent) and coding (exonic; rare) alleles of MTNR1B give rise to different phenotypes. Thus, altered gene transcription may explain why SNPs, which do not alter coding sequences, exhibit cell-specific effects. In contrast, SNPs that change protein sequences are more likely to exert generalised effects since an altered protein will appear in all cells expressing the gene.
authors.affiliation: Unit of Molecular Metabolism, Lund University Diabetes Centre, Jan Waldenströms gata 35, SE-205 02, Malmö, Sweden. hindrik.mulder@med.lu.se.
authors.forename: Hindrik
authors.initials: H
authors.lastname: Mulder
mesh_terms: D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008550:Melatonin / Q000378:metabolism*; D008875:Middle Aged; D057185:Sedentary Behavior; D015398:Signal Transduction / Q000502:physiology
chemical_list: D008550:Melatonin
keywords: G-protein-coupled; Genome-wide association study (GWAS); Inhibitory G-protein (Gi); Insulin secretion; Islet; Melatonin; Quantitative trait locus; Receptors; Single nucleotide polymorphism (SNP); cAMP