PTEN Deletion in Pancreatic α Cells Protects Against High Fat Diet-induced Hyperglucagonemia and Insulin Resistance
- Linyuan Wang*,1,2,
- Cynthia T. Luk*,1,3,
- Erica P. Cai*,1,3,
- Stephanie A. Schroer1,
- Emma M. Allister4,
- Sally Y. Shi1,3,
- Michael B. Wheeler4,
- Herbert Y. Gaisano4 and
- Minna Woo1–,3,5⇑
- 1Toronto General Research Institute, University health Network, Toronto, Ontario, Canada
- 2Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- 3Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
- 4Department of Physiology, University of Toronto, Ontario, Canada
- 5Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, Toronto, Ontario, Canada
- Corresponding Author: Minna Woo, Email:
An aberrant increase in circulating catabolic hormone, glucagon, contributes to type 2 diabetes pathogenesis. However, mechanisms regulating glucagon secretion and α cell mass are not well understood. In this study, we aim to demonstrate that PI3K signaling is an important regulator of α cell function. Mice with deletion of PTEN, a negative regulator of this pathway, in α cells show reduced circulating glucagon levels and attenuated L-arginine-stimulated glucagon secretion both in vivo and in vitro. This hypoglucagonemic state is maintained after high fat diet feeding, leading to reduced expression of hepatic glycogenolytic and gluconeogenic genes. These beneficial effects protected high fat diet-fed mice against hyperglycemia and insulin resistance. Our data demonstrated an inhibitory role of PI3K signaling on α cell function and provide experimental evidence for enhancing α cell PI3K signaling for diabetes treatment.
- Received November 8, 2013.
- Accepted July 28, 2014.
- © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.