Class IA Phosphatidylinositol 3-Kinase in Pancreatic β Cells Controls Insulin Secretion by Multiple Mechanisms

被引：96

作者：

Kaneko, Kazuma ^{[1
]}

Ueki, Kohjiro ^{[1
,2
]}

Takahashi, Noriko ^{[3
]}

Hashimoto, Shinji ^{[1
]}

Okamoto, Masayuki ^{[1
]}

Awazawa, Motoharu ^{[1
]}

Okazaki, Yukiko ^{[1
]}

Ohsugi, Mitsuru ^{[1
]}

Inabe, Kazunori ^{[1
]}

Umehara, Toshihiro ^{[1
]}

Yoshida, Masashi ^{[4
]}

Kakei, Masafumi ^{[4
]}

Kitamura, Tadahiro ^{[5
]}

Luo, Ji ^{[6
]}

Kulkarni, Rohit N. ^{[7
]}

Kahn, C. Ronald ^{[7
]}

Kasai, Haruo ^{[3
]}

Cantley, Lewis C. ^{[6
]}

Kadowaki, Takashi ^{[1
,8
]}

机构：

[1] Univ Tokyo, Dept Diabet & Metab Dis, Grad Sch Med, Tokyo 1138655, Japan

[2] Univ Tokyo, Translat Syst Biol & Med Initiat, Tokyo 1138655, Japan

[3] Univ Tokyo, Div Biophys, Ctr Dis Biol & Integrat Med, Fac Med, Tokyo 1138655, Japan

[4] Jichi Med Univ, Dept Comprehens Med 1, Saitama Med Ctr, Sch Med, Saitama 3308503, Japan

[5] Gunma Univ, Metab Signal Res Ctr, Lab Metab Signal, Inst Mol & Cellular Regulat, Gunma 3718512, Japan

[6] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02215 USA

[7] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA

[8] Natl Inst Hlth & Nutr, Div Appl Nutr, Tokyo 1628636, Japan

来源：

CELL METABOLISM | 2010年 / 12卷 / 06期

关键词：

RECEPTOR SUBSTRATE 2; PHOSPHOINOSITIDE; 3-KINASE; MICE LACKING; REGULATORY SUBUNIT; SIGNALING PATHWAYS; GLUCOSE; RESISTANCE; EXPRESSION; P85-ALPHA; EXOCYTOSIS;

D O I：

10.1016/j.cmet.2010.11.005

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Type 2 diabetes is characterized by insulin resistance and pancreatic beta cell dysfunction, the latter possibly caused by a defect in insulin signaling in beta cells. Inhibition of class IA phosphatidylinositol 3-kinase (PI3K), using a mouse model lacking the pik3r1 gene specifically in beta cells and the pik3r2 gene systemically (beta DKO mouse), results in glucose intolerance and reduced insulin secretion in response to glucose. beta cells of beta DKO mice had defective exocytosis machinery due to decreased expression of soluble N-ethylmaleimide attachment protein receptor (SNARE) complex proteins and loss of cell-cell synchronization in terms of Ca2+ influx. These defects were normalized by expression of a constitutively active form of Akt in the islets of beta DKO mice, preserving insulin secretion in response to glucose. The class IA PI3K pathway in beta cells in vivo is important in the regulation of insulin secretion and may be a therapeutic target for type 2 diabetes.

引用

页码：619 / 632

页数：14

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