title: Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.
abstract: 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.
authors.affiliation: Department of Clinical Sciences in Malmoe, Unit of Diabetes and Endocrinology, Lund University Diabetes Centre, University Hospital, Malmoe, Sweden.
authors.forename: Valeriya
authors.initials: V
authors.lastname: Lyssenko
authors.forename: Cecilia L F
authors.initials: CL
authors.lastname: Nagorny
authors.forename: Michael R
authors.initials: MR
authors.lastname: Erdos
authors.forename: Nils
authors.initials: N
authors.lastname: Wierup
authors.forename: Anna
authors.initials: A
authors.lastname: Jonsson
authors.forename: Peter
authors.initials: P
authors.lastname: Spégel
authors.forename: Marco
authors.initials: M
authors.lastname: Bugliani
authors.forename: Richa
authors.initials: R
authors.lastname: Saxena
authors.forename: Malin
authors.initials: M
authors.lastname: Fex
authors.forename: Nicolo
authors.initials: N
authors.lastname: Pulizzi
authors.forename: Bo
authors.initials: B
authors.lastname: Isomaa
authors.forename: Tiinamaija
authors.initials: T
authors.lastname: Tuomi
authors.forename: Peter
authors.initials: P
authors.lastname: Nilsson
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
authors.forename: Jaakko
authors.initials: J
authors.lastname: Tuomilehto
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Frank
authors.initials: F
authors.lastname: Sundler
authors.forename: Johan G
authors.initials: JG
authors.lastname: Eriksson
authors.forename: Anne U
authors.initials: AU
authors.lastname: Jackson
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.forename: Richard M
authors.initials: RM
authors.lastname: Watanabe
authors.forename: Hindrik
authors.initials: H
authors.lastname: Mulder
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
mesh_terms: D000368:Aged; D000818:Animals; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D021381:Protein Transport; D051381:Rats; D044123:Receptor, Melatonin, MT2 / Q000235:genetics* / Q000378:metabolism; D044094:Receptors, Melatonin / Q000235:genetics* / Q000378:metabolism
chemical_list: D007328:Insulin; D044123:Receptor, Melatonin, MT2; D044094:Receptors, Melatonin