Class IA phosphatidylinositol 3-kinase in pancreatic β cells controls insulin secretion by multiple mechanisms.
Type 2 diabetes is characterized by insulin resistance and pancreatic β cell dysfunction, the latter possibly caused by a defect in insulin signaling in β cells. Inhibition of class IA phosphatidylinositol 3-kinase (PI3K), using a mouse model lacking the pik3r1 gene specifically in β cells and the pik3r2 gene systemically (βDKO mouse), results in glucose intolerance and reduced insulin secretion in response to glucose. β cells of βDKO 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 Ca(2+) influx. These defects were normalized by expression of a constitutively active form of Akt in the islets of βDKO mice, preserving insulin secretion in response to glucose. The class IA PI3K pathway in β cells in vivo is important in the regulation of insulin secretion and may be a therapeutic target for type 2 diabetes.
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Kazuma
K
Kaneko
Kohjiro
K
Ueki
Noriko
N
Takahashi
Shinji
S
Hashimoto
Masayuki
M
Okamoto
Motoharu
M
Awazawa
Yukiko
Y
Okazaki
Mitsuru
M
Ohsugi
Kazunori
K
Inabe
Toshihiro
T
Umehara
Masashi
M
Yoshida
Masafumi
M
Kakei
Tadahiro
T
Kitamura
Ji
J
Luo
Rohit N
RN
Kulkarni
C Ronald
CR
Kahn
Haruo
H
Kasai
Lewis C
LC
Cantley
Takashi
T
Kadowaki
D000704:Analysis of Variance; D000818:Animals; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005089:Exocytosis / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050600:SNARE Proteins / Q000378:metabolism
D007328:Insulin; D050600:SNARE Proteins; D058543:Class Ia Phosphatidylinositol 3-Kinase