TY - JOUR

T1 - Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion

AU - Lyssenko, Valeriya

AU - Nagorny, Cecilia L F

AU - Erdos, Michael R

AU - Wierup, Nils

AU - Jonsson, Anna Elisabet

AU - Spégel, Peter

AU - Bugliani, Marco

AU - Saxena, Richa

AU - Fex, Malin

AU - Pulizzi, Nicolo

AU - Isomaa, Bo

AU - Tuomi, Tiinamaija

AU - Nilsson, Peter

AU - Kuusisto, Johanna

AU - Tuomilehto, Jaakko

AU - Boehnke, Michael

AU - Altshuler, David

AU - Sundler, Frank

AU - Eriksson, Johan G

AU - Jackson, Anne U

AU - Laakso, Markku

AU - Marchetti, Piero

AU - Watanabe, Richard M

AU - Mulder, Hindrik

AU - Groop, Leif

PY - 2009/1

Y1 - 2009/1

N2 - 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.

AB - 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.

KW - Aged

KW - Animals

KW - Cohort Studies

KW - Diabetes Mellitus, Type 2

KW - Female

KW - Gene Expression Regulation

KW - Genetic Predisposition to Disease

KW - Humans

KW - Insulin

KW - Islets of Langerhans

KW - Male

KW - Mice

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Protein Transport

KW - Rats

KW - Receptor, Melatonin, MT2

KW - Receptors, Melatonin

U2 - 10.1038/ng.288

DO - 10.1038/ng.288

M3 - Journal article

C2 - 19060908

VL - 41

SP - 82

EP - 88

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 1

ER -