Deletion of Pten in pancreatic ß-cells protects against deficient ß-cell mass and function in mouse models of type 2 diabetes.

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.

PTEN deletion and concomitant c-Myc activation do not lead to tumor formation in pancreatic beta cells.

Phosphatase and tensin homologue (PTEN) deleted on chromosome 10 is a dual-specific phosphatase and a potent antagonist of the phosphoinositide 3-kinase signaling pathway. Although first discovered as a tumor suppressor, emerging evidence supports PTEN as a potential therapeutic target for diabetes. PTEN deletion in beta cells leads to increased beta cell mass and protection from streptozotocin-induced diabetes. Importantly, PTEN deletion does not lead to tumor formation in beta cells. To further assess the potential tumorigenic role of PTEN, we tested the biological role of PTEN in the context of activation of the proto-oncogene c-Myc. We generated and characterized beta cell-specific PTEN knock-out mice expressing an inducible c-Myc transgene in beta cells. Surprisingly, we found that PTEN loss did not confer protection from the overwhelming apoptosis and diabetes development seen with c-Myc activation. Importantly, despite the combined effect of the loss of a tumor suppressor and activation of an oncogene in beta cells, there was no evidence of tumor development with sustained c-Myc activation.

Partial deletion of Pten in the hypothalamus leads to growth defects that cannot be rescued by exogenous growth hormone.

The GH/IGF-I axis plays a critical role in mammalian body growth. GH is secreted by the anterior pituitary, and its actions are primarily mediated by IGF-I that is secreted by the liver and other tissues. Local and circulating IGF-I action is largely mediated by the phosphoinositide 3-kinase signaling pathway, and phosphatase with tensin homology (PTEN) is a potent negative regulator of this pathway. Here we show that RIPcre+Ptenfl/fl mice, which exhibit PTEN deletion in insulin-transcribing neurons of the hypothalamus in addition to pancreatic beta-cells, result in a small-body phenotype that is associated with an unexpected increase in serum IGF-I levels. We tested whether exogenous GH can override the growth defect in RIPcre+Ptenfl/fl mice. Our results showed no significant difference in their growth between the RIPcre+Ptenfl/fl mice injected with GH or vehicle. Together, PTEN in the hypothalamic insulin-transcribing neurons plays an essential role in body size determination, and systemic GH cannot overcome the growth defect in these mice.

Essential role of Pten in body size determination and pancreatic beta-cell homeostasis in vivo.

PTEN (phosphatase with tensin homology) is a potent negative regulator of phosphoinositide 3-kinase (PI3K)/Akt signaling, an evolutionarily conserved pathway that signals downstream of growth factors, including insulin and insulin-like growth factor 1. In lower organisms, this pathway participates in fuel metabolism and body size regulation and insulin-like proteins are produced primarily by neuronal structures, whereas in mammals, the major source of insulin is the pancreatic beta cells. Recently, rodent insulin transcription was also shown in the brain, particularly the hypothalamus. The specific regulatory elements of the PI3K pathway in these insulin-expressing tissues that contribute to growth and metabolism in higher organisms are unknown. Here, we report PTEN as a critical determinant of body size and glucose metabolism when targeting is driven by the rat insulin promoter in mice. The partial deletion of PTEN in the hypothalamus resulted in significant whole-body growth restriction and increased insulin sensitivity. Efficient PTEN deletion in beta cells led to increased islet mass without compromise of beta-cell function. Parallel enhancement in PI3K signaling was found in PTEN-deficient hypothalamus and beta cells. Together, we have shown that PTEN in insulin-transcribing cells may play an integrative role in regulating growth and metabolism in vivo.