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.

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⁺ Pten^fl/fl).

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 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.

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.