Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.
Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.
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DOI：
10.1038/ng.288
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发表时间：
2009-01
期刊：
影响因子：
30.8
通讯作者：
Groop, Leif
中科院分区：
文献类型：
--
作者：
Lyssenko, Valeriya;Nagorny, Cecilia L. F.;Erdos, Michael R.;Wierup, Nils;Jonsson, Anna;Spegel, Peter;Bugliani, Marco;Saxena, Richa;Fex, Malin;Pulizzi, Nicolo;Isomaa, Bo;Tuomi, Tiinamaija;Nilsson, Peter;Kuusisto, Johanna;Tuomilehto, Jaakko;Boehnke, Michael;Altshuler, David;Sundler, Frank;Eriksson, Johan G.;Jackson, Anne U.;Laakso, Markku;Marchetti, Piero;Watanabe, Richard M.;Mulder, Hindrik;Groop, Leif
全基因组关联研究表明，褪黑素受体1B基因(MTNR1B)的变异与胰岛素和葡萄糖浓度有关。在这里，我们在两项大型前瞻性研究中表明，该SNP的风险基因可以预测未来的2型糖尿病(T2D)。具体地说，风险基因型与口服和静脉注射葡萄糖的早期胰岛素反应受损以及随着时间的推移胰岛素分泌更快恶化有关。我们还发现褪黑素受体1BmRNA在人胰岛中表达，免疫细胞化学证实它主要定位于胰岛的β-细胞。携带风险等位基因的非糖尿病患者和T2D患者的胰岛中该受体的表达增加。在褪黑激素的存在下，克隆β细胞对葡萄糖的胰岛素释放受到抑制。这些数据表明，循环激素褪黑激素主要从大脑中的松果体释放，参与了T2D的发病机制。鉴于褪黑素受体1B在有T2D风险的个体中表达增加，其致病作用可能是通过对β-细胞的直接抑制作用而发挥的。鉴于这些结果，阻断褪黑素配体-受体系统可能是治疗T2D的一条途径。
Genome wide association studies revealed that variation in the Melatonin Receptor 1B gene (MTNR1B) 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 Melatonin Receptor 1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in β-cells in islets. Non-diabetic individuals carrying the risk allele and patients 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 Melatonin Receptor 1B 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.
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影响因子：
30.8
作者：
Zeggini, Eleftheria;Scott, Laura J.;Saxena, Richa;Voight, Benjamin F.;Marchini, Jonathan L.;Hu, Tianle;de Bakker, Paul I. W.;Abecasis, Goncalo R.;Almgren, Peter;Andersen, Gitte;Ardlie, Kristin;Bostroem, Kristina Bengtsson;Bergman, Richard N.;Bonnycastle, Lori L.;Borch-Johnsen, Knut;Burtt, Noel P.;Chen, Hong;Chines, Peter S.;Daly, Mark J.;Deodhar, Parimal;Ding, Chia-Jen;Doney, Alex S. F.;Duren, William L.;Elliott, Katherine S.;Erdos, Michael R.;Frayling, Timothy M.;Freathy, Rachel M.;Gianniny, Lauren;Grallert, Harald;Grarup, Niels;Groves, Christopher J.;Guiducci, Candace;Hansen, Torben;Herder, Christian;Hitman, Graham A.;Hughes, Thomas E.;Isomaa, Bo;Jackson, Anne U.;Jorgensen, Torben;Kong, Augustine;Kubalanza, Kari;Kuruvilla, Finny G.;Kuusisto, Johanna;Langenberg, Claudia;Lango, Hana;Lauritzen, Torsten;Li, Yun;Lindgren, Cecilia M.;Lyssenko, Valeriya;Marvelle, Amanda F.;Meisinger, Christa;Midthjell, Kristian;Mohlke, Karen L.;Morken, Mario A.;Morris, Andrew D.;Narisu, Narisu;Nilsson, Peter;Owen, Katharine R.;Palmer, Colin N. A.;Payne, Felicity;Perry, John R. B.;Pettersen, Elin;Platou, Carl;Prokopenko, Inga;Qi, Lu;Qin, Li;Rayner, Nigel W.;Rees, Matthew;Roix, Jeffrey J.;Sandbaek, Anelli;Shields, Beverley;Sjogren, Marketa;Steinthorsdottir, Valgerdur;Stringham, Heather M.;Swift, Amy J.;Thorleifsson, Gudmar;Thorsteinsdottir, Unnur;Timpson, Nicholas J.;Tuomi, Tiinamaija;Tuomilehto, Jaakko;Walker, Mark;Watanabe, Richard M.;Weedon, Michael N.;Willer, Cristen J.;Illig, Thomas;Hveem, Kristian;Hu, Frank B.;Laakso, Markku;Stefansson, Kari;Pedersen, Oluf;Wareham, Nicholas J.;Barroso, Ines;Hattersley, Andrew T.;Collins, Francis S.;Groop, Leif;McCarthy, Mark I.;Boehnke, Michael;Altshuler, David
通讯作者：
Altshuler, David
影响因子：
9.8
作者：
Chen, Wei-Min;Abecasis, Goncalo R.
通讯作者：
Abecasis, Goncalo R.
DOI：
10.1152/ajpendo.1996.271.2.e246
发表时间：
1996-08-01
影响因子：
5.1
作者：
Boden, G;Ruiz, J;Chen, XH
通讯作者：
Chen, XH
影响因子：
8.2
作者：
Eriksson, J. G.;Osmond, C.;Barker, D. J. P.
通讯作者：
Barker, D. J. P.
影响因子：
11.1
作者：
Berglund, G;Nilsson, P;Lingärde, F
通讯作者：
Lingärde, F