RESUMO
OBJECTIVE: Type 2 diabetes is characterized by diminished pancreatic ß-cell mass and function. Insulin signaling within the ß-cells has been shown to play a critical role in maintaining the essential function of the ß-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 ß-cell mass and function. In this study, we investigated the effects of prolonged ß-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 ß-cell-specific PTEN deletion (RIPcre(+) Pten(fl/fl)). RESULTS: PTEN expression in islets was upregulated in both models of type 2 diabetes. RIPcre(+) Pten(fl/fl) mice were completely protected against diabetes in both models of type 2 diabetes. The islets of RIPcre(+) Pten(fl/fl) mice already exhibited increased ß-cell mass under basal conditions, and there was no further increase under diabetic conditions. Their ß-cell function and islet PI3K signaling remained intact, in contrast to HFD-fed wild-type and db/db islets that exhibited diminished ß-cell function and attenuated PI3K signaling. These protective effects in ß-cells occurred in the absence of compromised response to DNA-damaging stimuli. CONCLUSIONS: PTEN exerts a critical negative effect on both ß-cell mass and function. Thus PTEN inhibition in ß-cells can be a novel therapeutic intervention to prevent the decline of ß-cell mass and function in type 2 diabetes.
