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Deletion of Pten in Pancreatic β-Cells Protects Against Deficient β-Cell Mass and Function in Mouse Models of Type 2 Diabetes

American Diabetes Association
Publication Date
DOI: 10.2337/db09-1805
  • Islet Studies
  • Medicine


Deletion of Pten in Pancreatic �-Cells Protects Against Deficient �-Cell Mass and Function in Mouse Models of Type 2 Diabetes Linyuan Wang,1 Yunfeng Liu,2 Shun Yan Lu,3 Kinh-Tung T. Nguyen,4 Stephanie A. Schroer,3 Akira Suzuki,5 Tak W. Mak,1,6 Herbert Gaisano,2,4 and Minna Woo1,4,7 OBJECTIVE—Type 2 diabetes is characterized by diminished pancreatic �-cell mass and function. Insulin signaling within the �-cells has been shown to play a critical role in maintaining the essential function of the �-cells. Under basal conditions, en- hanced insulin-PI3K signaling via deletion of phosphatase with tensin homology (PTEN), a negative regulator of this pathway, leads to increased �-cell mass and function. In this study, we investigated the effects of prolonged �-cell–specific PTEN dele- tion 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 �-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 �-cell mass under basal conditions, and there was no further increase under diabetic conditions. Their �-cell function and islet PI3K signaling remained intact, in contrast to HFD-fed wild-type and db/db islets that exhibited diminished �-cell function and atten- uated PI3K signaling. These protective effects in �-cells occurred in the absence of compromised response to DNA-damaging stimuli. CONCLUSIONS—PTEN exerts a critical negative effect on both �-cell mass and function. Thus PTEN inhibition in �-cells can be a novel therapeutic intervention to prevent the decline of �-cell mass and function in type 2 diabetes. Dia

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