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

被引:567
作者
Lyssenko, Valeriya [1 ]
Nagorny, Cecilia L. F. [2 ]
Erdos, Michael R. [3 ]
Wierup, Nils [4 ]
Jonsson, Anna [1 ]
Spegel, Peter [2 ]
Bugliani, Marco [5 ]
Saxena, Richa [6 ,7 ]
Fex, Malin [8 ]
Pulizzi, Nicolo [5 ]
Isomaa, Bo [9 ]
Tuomi, Tiinamaija [9 ,10 ,11 ]
Nilsson, Peter [12 ]
Kuusisto, Johanna [13 ,14 ]
Tuomilehto, Jaakko [15 ,16 ,17 ]
Boehnke, Michael [18 ]
Altshuler, David [6 ,7 ]
Sundler, Frank [4 ]
Eriksson, Johan G. [19 ]
Jackson, Anne U. [18 ]
Laakso, Markku [13 ,14 ]
Marchetti, Piero [5 ]
Watanabe, Richard M. [20 ,21 ]
Mulder, Hindrik [2 ]
Groop, Leif [1 ,10 ,11 ]
机构
[1] Lund Univ, Univ Hosp, Dept Clin Sci Malmoe, Unit Diabet & Endocrinol,Diabet Ctr, S-20520 Malmo, Sweden
[2] Lund Univ, Ctr Diabet, Dept Clin Sci Malmoe, Unit Mol Metab, S-20502 Malmo, Sweden
[3] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA
[4] Lund Univ, Dept Expt Med Sci, Unit Neuroendocrine Cell Biol, S-22184 Lund, Sweden
[5] Univ Pisa, Dept Endocrinol & Metab, I-56124 Pisa, Italy
[6] Harvard & Massachusetts Inst Technol, Program Med & Populat Genet, Broad Inst, Cambridge, MA 02142 USA
[7] Massachusetts Gen Hosp, Boston, MA 02114 USA
[8] Lund Univ, Ctr Diabet, Dept Clin Sci Malmoe, Unit Diabet & Celiac Dis, S-20502 Malmo, Sweden
[9] Folkhalsan Res Ctr, Helsinki 00251, Finland
[10] Univ Helsinki, Cent Hosp, Dept Med, Helsinki 00140, Finland
[11] Univ Helsinki, Res Program Mol Med, Helsinki 00140, Finland
[12] Lund Univ, Dept Clin Sci, S-20502 Malmo, Sweden
[13] Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland
[14] Kuopio Univ Hosp, SF-70210 Kuopio, Finland
[15] Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, Diabet Unit, SF-00300 Helsinki, Finland
[16] Univ Helsinki, Dept Publ Hlth, Helsinki 00014, Finland
[17] S Ostrobothnia Cent Hosp, Senajoki 60220, Finland
[18] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA
[19] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, FIN-00014 Helsinki, Finland
[20] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA
[21] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA
基金
芬兰科学院; 瑞典研究理事会;
关键词
GENOME-WIDE ASSOCIATION; MELATONIN RECEPTORS; SENSITIVITY; EXPRESSION; PANCREAS; LOCI; REPLICATION; INDEXES; ISLET;
D O I
10.1038/ng.288
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:82 / 88
页数:7
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