Protein Kinase B/Akt in the human islet

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DESCRIPTION (provided by applicant): Recent clinical studies have documented that human islet transplantation has the potential to replace pancreatic endocrine function in patients with Type I diabetes. However, these studies have also highlighted an enormous shortage of human islets that impedes the use of islet transplantation in clinical practice on a larger scale. To solve this problem, one potential approach is to develop methods to increase human islet cell replication, to improve human islet cell function and to enhance human islet cell survival. We have shown that hepatocyte growth factor (HGF) stimulates proliferation, enhances function and promote survival of the pancreatic beta cell in rodents. In addition, overexpression of HGF in rodent islets: (i) reduces the number of islets required for successful islet transplantation, and (ii) markedly improves transplant outcomes. Activation of Protein-Kinase B (PKB)/Akt by growth factors such as HGF and insulin-like growth factor-I, and nutrients such as glucose, has been shown to be an important intracellular signaling requirement for increasing proliferation and preventing pancreatic beta cell death in rodents. Moreover, beta cell-specific expression of a constitutively active form of PKB/Akt in transgenic mice markedly increases beta cell mass, by enhancing beta cell size, islet neogenesis, beta cell proliferation and improving beta cell survival, resulting in hyperinsulinemia and hypoglycemia. However, whether constitutive activation of PKB/Akt has any impact on these parameters in human islet cells is completely unknown. The primary goal of the proposed research project is to determine the efficacy of constitutive activation of PKB/Akt in enhancing human islet engraftment and survival in a marginal mass model of human islet transplantation in SClD mice. We propose the following Specific Aims: 1. To evaluate the efficacy of constitutive activation of PKB/Akt in increasing human islet cell proliferation, function and survival in vitro. 2. To assess the efficacy of constitutive activation of PKB/Akt in improving in vivo human islet transplant outcomes in a marginal mass model of human islet transplantation in SCID mice. The results obtained in this study will provide information on whether constitutive activation of PKB/Akt in human islets will result in enhanced proliferation, function and survival of human islet cells and a concomitant improvement in human islet transplantation in mice. If translated into humans, constitutive activation of PKB/Akt might be an attractive therapeutic strategy for reducing the number of islets required for successful transplantation