Ernesto Bernal-Mizrachi is a Professor of internal medicine and Chief of the Division of Endocrinology, Diabetes and Metabolism in the University of Miami Miller School of Medicine. Over the last 15 years his research has focused on the regulation of pancreatic islet cell mass and function, with a particular interest in Akt and mTOR signaling pathways. Dr. Bernal-Mizrachi’s research is focused on understanding how pancreatic beta-cells (insulin producing cells) are born, divide and survive during states of type 1 and 2 diabetes. His laboratory icenters in several areas of research including: 1. Regulation of β-cell proliferation and regeneration. Our previous work demonstrated that activation of Akt signaling in β-cells is critical for regulation of β-cell proliferation and survival. This knowledge will provide new platforms to develop novel pharmacologic strategies to induce controlled β-cell mass by inducing selectively β-cell proliferation without altering the risk of oncogenic transformation. These agents could be used in translational experiments to treat T1D by expanding β-cell mass in vivo. At the same time, the pharmacologic manipulation of this pathway can be used to increase the pool of transplantable islets and enhance the success of islet transplantation. 2. Novel therapies for the treatment of T1D. We are currently designing a screening strategy to discover novel molecules that could be used to preserve beta cells in T1D. The idea here is to develop an agent that could be used to make beta cells resist autoimmune injury by manipulation of signaling pathways that regulate translation of critical molecules responsible to protect beta cells from apoptosis. These experiments will be a major focus of his laboratory at the University of Miami. 3. Nutrient signaling in alpha-cells: role in the pathogenesis of diabetes. Past effort has focused on the β-cell, presenting diabetes as a unihormonal disorder. Contrary to this current approach, clinical data and animal experiments have shown that glucagon plays a role in the pathogenesis of hyperglycemia in type 1 and 2 diabetes. During the last few years, his laboratory has been exploring how insulin signaling regulates the function and mass of α-cells in vivo and the potential contribution of this process to the regulation of glucose homeostasis. Therefore, this research is significant because a better understanding of how glucagon secretion and a-cell mass are regulated is critical to develop novel therapies for diabetes. 4. GHRH agonists for the treatment of type 1 diabetes: This project has been developed in collaboration with Dr. Andrew Schally at the Miami VA. The purpose of this study is to explore the effects of GHRH agonist (MR409) in diabetes with focus in pancreatic beta cells. The GHRH agonist (MR409) has been part of multiple compounds devel-oped by the Schally laboratory. In this project, we have been exploring the effects of MR409 in mouse and human islets. We found that treatment of MIN6 cells and mouse and human islets with MR409 protects rodent beta cells from apoptosis induced by a cocktail of proinflammatory cytokines (CTK) that resemble a type 1 diabetes environment. The antiapoptotic effect of MR409 resulted from induction of Insulin Receptor Substrate 2 (IRS2) levels. The increase in IRS2 levels was accompanied by increases in pCREB and pAKT signaling, a major prosurvival and mitogen-ic pathway in beta cells. Importantly, MR409 inhibited the degradation of IRS2 induced by CTKs induce. In addition, we found that pCREB levels were also increased by MR409 to the same magnitude as that observed with Exendin4. Given that IRS2 is a key survival molecule in beta cells, we then tested if MR409 induction of IRS2 protects beta cells in vivo using a model that re-sembles a type 1 diabetes environment. We observed that MR409 treatment of mice exposed to a multiple low dose STZ exhibited improved glucose levels, higher insulin and preservation of be-ta cell mass. These observations provide the steppingstone to design studies to assess the pro-tection of apoptosis by MR409 compounds. The potentiation of MR409 effects induced by GLP1 analogs provides exciting alternatives for a combination of these two agents for the treatment of diabetes.