Pten (phosphatase with tensin homology), a dual-specificity phosphatase, is a negative regulator of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Pten regulates a vast array of biological functions including growth, metabolism, and longevity. Although the PI3K/Akt pathway is a key determinant of the insulin-dependent increase in glucose uptake into muscle and adipose cells, the contribution of this pathway in muscle to whole-body glucose homeostasis is unclear. Here we show that muscle-specific deletion of Pten protected mice from insulin resistance and diabetes caused by high-fat feeding. Deletion of muscle Pten resulted in enhanced insulin-stimulated 2-deoxyglucose uptake and Akt phosphorylation in soleus but, surprisingly, not in extensor digitorum longus muscle compared to littermate controls upon high-fat feeding, and these mice were spared from developing hyperinsulinemia and islet hyperplasia. Muscle Pten may be a potential target for treatment or prevention of insulin resistance and diabetes.

Local failures following radiation therapy are multifactorial and the contributions of the tumor and the host are complex. Current models of tumor equilibrium suggest that a balance exists between cell birth and cell death due to insufficient angiogenesis, immune effects, or intrinsic cellular factors. We investigated whether host immune responses contribute to radiation induced tumor equilibrium in animal models. We report an essential role for immune cells and their cytokines in suppressing tumor cell regrowth in two experimental animal model systems. Depletion of T cells or neutralization of interferon-gamma reversed radiation-induced equilibrium leading to tumor regrowth. We also demonstrate that PD-L1 blockade augments T cell responses leading to rejection of tumors in radiation induced equilibrium. We identify an active interplay between tumor cells and immune cells that occurs in radiation-induced tumor equilibrium and suggest a potential role for disruption of the PD-L1/PD-1 axis in increasing local tumor control.

␤-Cell apoptosis is a key event contributing to the pathogenesis of type 1 diabetes mellitus. In addition to apoptosis being the main mechanism by which ␤ cells are destroyed, ␤-cell apoptosis has been implicated in the initiation of type 1 diabetes mellitus through antigen cross-presentation mechanisms that lead to ␤-cellspecific T-cell activation. Caspase-3 is the major effector caspase involved in apoptotic pathways. Despite evidence supporting the importance of ␤-cell apoptosis in the pathogenesis of type 1 diabetes, the specific role of caspase-3 in this process is unknown. Here, we show that Caspase-3 knockout (Casp3 ؊/؊ ) mice were protected from developing diabetes in a multiple-low-dose streptozotocin autoimmune diabetes model. Lymphocyte infiltration of the pancreatic islets was completely absent in Casp3 ؊/؊ mice. To determine the role of caspase-3-dependent apoptosis in disease initiation, a defined antigen-T-cell receptor transgenic system, RIP-GP/P14 double-transgenic mice with Casp3 null mutation, was examined. ␤-cell antigen-specific T-cell activation and proliferation were observed only in the pancreatic draining lymph node of RIP-GP/P14/ Casp3 ؉/؊ mice, but not in mice lacking caspase-3. Together, our findings demonstrate that caspase-3-mediated ␤-cell apoptosis is a requisite step for T-cell priming, a key initiating event in type 1 diabetes.

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 ␤ 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 ␤ cells led to increased islet mass without compromise of ␤-cell function. Parallel enhancement in PI3K signaling was found in PTEN-deficient hypothalamus and ␤ cells. Together, we have shown that PTEN in insulin-transcribing cells may play an integrative role in regulating growth and metabolism in vivo.The phosphoinositide 3-kinase (PI3K) pathway is a key signaling cascade that is activated in response to growth factors such as insulin and insulin-like growth factor 1 (IGF-1) (30). PTEN (phosphatase with tensin homology) is a dual-specificity phosphatase that dephosphorylates phosphatidylinositol 3,4,5-trisphosphate to phosphatidylinositol-4,5-bisphosphate and thus is a potent antagonist of PI3K signaling (32,35). Although initially discovered as a tumor suppressor with a regulatory role in cell survival and proliferation, particularly in tumorprone tissues such as the breast and endometrium (33), more recent studies have highlighted a role for PTEN in metabolism (5). Tissue-targeted ablation in fat, muscle, and liver generally led to improved insulin sensitivity in these classical peripheral insulin target tissues (13,19,36,41). Furthermore, Pten has been implicated in determining differentiated cellular function in other tissues, such as the cardiomyocytes and lymphocytes (7,38). This wide array of distinct PTEN function is highly tissue and context dependent.Tissue-specific genetic targeting strategies have shown signaling molecules of the insulin-and/or IGF-1-PI3K pathway to play a critical role in ␤-cell mass and function. ␤-Cell-specific deletion of the insulin or IGF-1 receptor leads to impaired differentiated ␤-cell function (16, 17), while insulin receptor substrate 2 (IRS-2) appears to be a key factor in ␤-cell mass determination (12,15,23,42). Constitutive overexpression of protein kinase B/Akt leads to increased islet mass, ␤-cell proliferation, and protection from experimental diabetes (3, 40). Recent reports have shown that the insulin promoter commonly ...