Lack of TRPM2 impaired insulin secretion and glucose metabolisms in mice.
Lack of TRPM2 impaired insulin secretion and glucose metabolisms in mice.
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DOI：
10.2337/db10-0276
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发表时间：
2011-01
期刊：
影响因子：
7.7
通讯作者：
Tominaga M
中科院分区：
文献类型：
--
作者：
Uchida K;Dezaki K;Damdindorj B;Inada H;Shiuchi T;Mori Y;Yada T;Minokoshi Y;Tominaga M
TRPM 2是一种由腺苷二核苷酸激活的Ca 2+渗透性非选择性阳离子通道。我们先前证明TRPM 2通过热和细胞内环腺苷5′-二磷酸核糖的共同应用而被激活，这已被认为参与免疫细胞和胰腺β细胞中细胞内Ca 2+的增加。为了阐明TRPM 2参与胰岛素分泌，我们分析了TRPM 2敲除（TRPM 2-KO）小鼠。在TRPM 2-KO和野生型小鼠中进行口服和腹膜内葡萄糖耐量试验（OGTT和IPGTT）。我们还测量了胞浆游离钙在单个胰腺细胞中使用Fura-2显微荧光和胰岛分泌的胰岛素。TRPM 2-KO小鼠的基础血糖水平高于野生型小鼠，血浆胰岛素水平无任何差异。OGTT和IPGTT表明TRPM 2-KO小鼠的血糖水平高于野生型小鼠，这与胰岛素分泌受损有关。在分离的β-细胞中，与野生型细胞相比，在TRPM 2-KO细胞中观察到响应于高浓度葡萄糖和肠促胰岛素激素的较小的细胞内Ca 2+增加。此外，TRPM 2-KO小鼠胰岛对葡萄糖和肠促胰岛素激素治疗的胰岛素分泌受损，而对甲苯磺丁脲（一种ATP敏感性钾通道抑制剂）的反应在两组之间没有差异。这些结果表明，TRPM 2参与葡萄糖刺激的胰岛素分泌，并通过肠促胰岛素进一步增强。因此，TRPM 2可能成为糖尿病治疗的新靶点。
TRPM2 is a Ca2+-permeable nonselective cation channel activated by adenosine dinucleotides. We previously demonstrated that TRPM2 is activated by coapplication of heat and intracellular cyclic adenosine 5′-diphosphoribose, which has been suggested to be involved in intracellular Ca2+ increase in immunocytes and pancreatic β-cells. To clarify the involvement of TRPM2 in insulin secretion, we analyzed TRPM2 knockout (TRPM2-KO) mice. Oral and intraperitoneal glucose tolerance tests (OGTT and IPGTT) were performed in TRPM2-KO and wild-type mice. We also measured cytosolic free Ca2+ in single pancreatic cells using fura-2 microfluorometry and insulin secretion from pancreatic islets. Basal blood glucose levels were higher in TRPM2-KO mice than in wild-type mice without any difference in plasma insulin levels. The OGTT and IPGTT demonstrated that blood glucose levels in TRPM2-KO mice were higher than those in wild-type mice, which was associated with an impairment in insulin secretion. In isolated β-cells, smaller intracellular Ca2+ increase was observed in response to high concentrations of glucose and incretin hormone in TRPM2-KO cells than in wild-type cells. Moreover, insulin secretion from the islets of TRPM2-KO mice in response to glucose and incretin hormone treatment was impaired, whereas the response to tolbutamide, an ATP-sensitive potassium channel inhibitor, was not different between the two groups. These results indicate that TRPM2 is involved in insulin secretion stimulated by glucose and that further potentiated by incretins. Thus, TRPM2 may be a new target for diabetes therapy.
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DOI：
10.1007/s00424-010-0835-z
发表时间：
2010-06
期刊：
Pflugers Archiv : European journal of physiology
影响因子：
--
作者：
Brixel LR;Monteilh-Zoller MK;Ingenbrandt CS;Fleig A;Penner R;Enklaar T;Zabel BU;Prawitt D
通讯作者：
Prawitt D
影响因子：
16
作者：
Hara, Y;Wakamori, M;Mori, Y
通讯作者：
Mori, Y
影响因子：
7.7
作者：
Sato, Y;Henquin, JC
通讯作者：
Henquin, JC
影响因子：
56.9
作者：
TAKASAWA, S;NATA, K;OKAMOTO, H
通讯作者：
OKAMOTO, H
影响因子：
4.8
作者：
Tong, Q;Zhang, WY;Miller, BA
通讯作者：
Miller, BA