1. Deletion of Pten in Pancreatic β-Cells Protects Against Deficient β-Cell Mass and Function in Mouse Models of Type 2 Diabetes.
- Author
-
Wang, Linyuan, Liu, Yunfeng, Shun Yan Lu, Nguyen, Kinh-Tung T., Schroer, Stephanie A., Suzuki, Akira, Mak, Tak W., Gaisano, Herbert, and Woo, Minna
- Subjects
PANCREATIC beta cells ,TYPE 2 diabetes ,INSULIN ,LABORATORY mice ,PHOSPHATASES ,CELL physiology - Abstract
OBJECTIVE--Type 2 diabetes is characterized by diminished pancreatic β-cell mass and function. Insulin signaling within the β-cells has been shown to play a critical role in maintaining the essential function of the β-cells. Under basal conditions, enhanced insulin-PI3K signaling via deletion of phosphatase with tensin homology (PTEN), a negative regulator of this pathway, leads to increased β-cell mass and function. In this study, we investigated the effects of prolonged β-cell-specific PTEN deletion in models of type 2 diabetes. RESEARCH DESIGN AND METHODS--Two models of type 2 diabetes were employed: a high-fat diet (HFD) model and a db/db model that harbors a global leptin-signaling defect. A Cre-loxP system driven by the rat insulin promoter (RIP) was employed to obtain mice with β-cell-specific PTEN deletion (RIPcre
+ Ptenfl/fl ). RESULTS--PTEN expression in islets was upregulated in both models of type 2 diabetes. RIPcre+ Ptenfl/fl mice were completely protected against diabetes in both models of type 2 diabetes. The islets of RIPcre+ Ptenfl/fl mice already exhibited increased β-cell mass under basal conditions, and there was no further increase under diabetic conditions. Their β-cell function and islet PI3K signaling remained intact, in contrast to HFD-fed wild-type and db/db islets that exhibited diminished β-cell function and attenuated PI3K signaling. These protective effects in β-cells occurred in the absence of compromised response to DNA-damaging stimuli. CONCLUSIONS--PTEN exerts a critical negative effect on both β-cell mass and function. Thus PTEN inhibition in β-cells can be a novel therapeutic intervention to prevent the decline of β-cell mass and function in type 2 diabetes. Diabetes 59: 3117-3126, 2010 [ABSTRACT FROM AUTHOR]- Published
- 2010
- Full Text
- View/download PDF