Phosphatidylinositol 3-Kinase Suppresses Glucose-Stimulated Insulin Secretion by Affecting Post-Cytosolic [Ca2+] Elevation Signals
- Kazuhiro Eto1,
- Tokuyuki Yamashita1,
- Yoshiharu Tsubamoto1,
- Yasuo Terauchi1,
- Kenzo Hirose2,
- Naoto Kubota1,
- Shigeo Yamashita1,
- Junko Taka1,
- Shinobu Satoh3,
- Hisahiko Sekihara3,
- Kazuyuki Tobe1,
- Masamitsu Iino2,
- Mitsuhiko Noda1,
- Satoshi Kimura1 and
- Takashi Kadowaki1
- 1Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
- 2Department of Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
- 3Third Department of Internal Medicine, Yokohama City University, Yokohama, Japan
Abstract
The role of phosphatidylinositol (PI) 3-kinase in the regulation of pancreatic β-cell function was investigated. PI 3-kinase activity in p85α regulatory subunit–deficient (p85α−/−) islets was decreased to ∼20% of that in wild-type controls. Insulin content and mass of rough endoplasmic reticula were decreased in β-cells from p85α−/− mice with increased insulin sensitivity. However, p85α−/− β-cells exhibited a marked increase in the insulin secretory response to higher concentrations of glucose. When PI 3-kinase in wild-type islets was suppressed by wortmannin or LY294002, the secretion was also substantially potentiated. Wortmannin’s potentiating effect was not due to augmentation in glucose metabolism or cytosolic [Ca2+] elevation. Results of p85α−/− islets and wortmannin-treated wild-type islets stimulated with diazoxide and KCl showed that inhibition of PI 3-kinase activity exerted its effect on secretion, at least in part, distal to a cytosolic [Ca2+] elevation. These results suggest that PI 3-kinase activity normally plays a crucial role in the suppression of glucose-stimulated insulin secretion.
Footnotes
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Address correspondence and reprint requests to Takashi Kadowaki, Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: kadowaki-3im{at}h.u-tokyo.ac.jp.
Received for publication 5 March 2001 and accepted in revised form 28 September 2001.
ER, endoplasmic reticulum; IRS-1, insulin receptor substrate-1; KATP, ATP-sensitive K+ channel; KRB, Krebs-Ringer bicarbonate; MAP, mitogen-activated protein; PDE, phosphodiesterase; PI, phosphatidylinositol.
