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

Abstract Objective: Type 2 diabetes is characterized by diminished function in pancreatic β cells. Insulin signaling within the β cells has been shown to play a critical role in maintaining its essential function. Under basal conditions, enhanced insulin-PI3K signaling via deletion of 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: high fat diet and db/db model which harbors a global leptin signaling defect. Cre-loxP system, driven by the rat insulin promoter, was employed to obtain mice with β cell-specific PTEN deletion (RIP cre + Pten fl/fl ). Results: Islet PTEN expression was increased in type 2 diabetes. RIP cre + Pten fl/fl mice were completely protected from hyperglycemia and glucose intolerance in both models. These mice exhibited similarly increased β cell mass under basal and diabetic conditions. Their β cell function and islet PI3K signaling remained intact, in contrast to HFD-fed wildtype 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. Conclusion: PTEN exerts a critical negative effect on both β cell mass and function. Alleviating the brake through PTEN inhibition in β cells can be a novel therapeutic target to prevent the decline of β cell mass and function in type 2 diabetes.