Ernesto Bernal- Mizrachi, MD

BIOGRAPHY

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. He is also a physician at the Miami Veterans Administration Hospital. Dr. Bernal-Mizrachi received his medical degree from the Universidad del Valle Medical School in Cali, Colombia, and completed a residency in internal medicine there. He then came to the United States for additional residency training in internal medicine at the University of Miami, followed by a three-year fellowship in endocrinology and metabolism at Washington University in St. Louis. He joined Washington University faculty in 1999 and held the academic titles of assistant professor of medicine and assistant professor of cell biology from 2004, until 2009 when he moved to Michigan to assume the Soderquist Professorship. In 2015, he moved to the University of Miami as Chief of the Division of Endocrinology, Diabetes and Metabolism and Deputy Director for Signal Transduction at the Diabetes Research Institute. His research over the last 15 years has focused on the regulation of pancreatic beta cell mass and function, with a particular interest in Akt and mTOR signaling pathways in beta cell proliferation. His laboratory has made major contributions to our understanding of signaling pathways that regulate beta cell expansion and survival. The long term goal of these signaling studies is to develop novel pharmacological agents for the treatment and cure of type 1 and 2 diabetes. In addition, his laboratory also explores how the fetal environment can alter the susceptibility to diabetes later in life, a concept that has major implications to human diabetes. Finally, his group has been exploring the importance of glucagon and alpha cells in the regulation of glucose homeostasis with particular interest in discovering avenues to decrease hypoglycemia in diabetes. He has an excellent record of grant funding and currently is principal investigator on RO1 grants from the National Institutes of Health, a VA MERIT award and two foundation grants including American Diabetes Association and Juvenile Diabetes Research Foundation. He has mentored over 15 undergraduate students and postdoctoral fellows, many of whom are now highly successful academic scientists and physicians. He has been consistently active in postdoctoral education and has served on the fellowship Training Operating Committee at Washington University and The University of Michigan. In addition, he has served on study sections and review panels for the National Institutes of Health and the Juvenile Diabetes Research Foundation. He has also is a member of the editorial board of the American Journal of Physiology- Endocrinology and Metabolism and ad hoc reviewer for various specialty journals, Diabetes, Cell Metabolism, Diabetologia, Nature Medicine, Scientific Reports, Science, Gastroenterology, the Journal of Clinical Investigation, Cell Metabolism and Annual Review of Physiology. Dr. Bernal-Mizrachi has received many wards including a Junior Faculty Award and a Career Development Award from the American Diabetes Association and he was elected a member of the American Society for Clinical Investigation (ASCI).

RESEARCH INTEREST

1.-Developing new avenues to make insulin-producing cells. These studies use novel methods that will transform acinar cell (responsible for producing digestive enzymes) to become insulin-producing cells (beta cells). The acinar cell is a favorable source because it is the most abundant pancreatic cell type and is a close neighbor of the beta cell. Findings from these studies are relevant to Type 1 Diabetes (T1D) in that it will identify molecules and cells that can be used to make beta cells. This information is useful when developing therapies to protect beta cells in T1D patients, as well as generate beta cells for transplantation purposes. Once this strategy becomes available, it would be possible to induce acinar to beta-cell conversion in animal/human models, and generate a sufficient number of beta cells. This strategy could be modulated to achieve insulin independence or to provide easier glucose control and to prevent hypoglycemia, a limiting factor for tight glucose control. These exciting studies will serve to develop novel drugs that could be tested in humans with insulin-dependent diabetes. The Juvenile Diabetes Research Foundation has continuously funded this area of research for the last 10 years.

2.       Regulation of β-cell regeneration. Our previous work demonstrated that activation of Akt signaling in β-cells is critical for regulation of β-cell proliferation and survival. During the last 15 years, Dr. Bernal-Mizrachi has build on these observations and identified that downstream of Akt, TSC2/mTOR signaling pathway is a critical pathway for β-cells. The current work is dissecting the specific contribution of different components of the pathway by using in vitro studies and animal models. 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. Another major impact of these studies is obtaining a better understanding of the effects of rapamycin in β-cells mass and function. This is particularly interesting because rapamycin induced diabetes is a common complication of immunosuppressive therapy after transplantation. The work in this area has been supported by an NIH/NIDDK R01 for 10 years.

3.       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.

4.       Nutrient regulation of fetal b-cell programming. Extensive epidemiological evidence in humans and animal models suggests that poor maternal nutrition or imbalance increases the susceptibility of the offspring to develop type 2 diabetes. Defects in pancreas development leading to long-term changes on b-cell mass and function are major components of this phenotype. These observations identified the phenomena of fetal b-cell programming. I have been interested in uncovering the mechanisms by which adverse intrauterine environment increase susceptibility to development of glucose intolerance and type 2 diabetes. I am interested in the idea that a fetal insult alters organogenesis/signaling in the developing endocrine pancreas, particularly in pancreatic b-cells. These studies have shown that maternal-low protein induces impaired glucose tolerance due to β-cell dysfunction and not to a defect in β-cell mass. This work identified mTOR as a major target of b-cell fetal programming and discovered a subset of b-cell microRNAs responsible for the effects of nutrient deprivation on insulin secretion and regulation of mTOR levels. The results of these studies are part of manuscript currently under revision at the Journal of Clinical Investigation. Current studies are exploring how fetal nutrients induce permanent changes on microRNA expression with special focus on novel cellular processes such as O-GlcNAcylation of proteins and insulin biosynthesis and secretion. Finally, knowing the increased prevalence of gestational diabetes and the use of metformin to treat this disease, I am currently exploring the importance of Metformin on b-cell development and programming. In summary, the work in this area is clinically relevant because this knowledge will facilitate development of strategies to prevent diabetes in growth retarded fetuses and to identify pharmacological targets to improve β-cell mass and function. The research program in is supported by NIH/NIDDK.

5.       Identification of novel pathways responsible for β-cell proliferation. Developing pharmacological agents that expand β-cells in vivo and in vitro and resist autoimmune injury could have major implications to cure T1D. During the last five years, Dr Bernal-Mizrachi has identified two other major pathways involved in β-cell proliferation. The first pathway involves the enzyme protein L-isoaspartyl methyltransferase (PIMT). PIMT is highly expressed in human and rodent β-cells and induction of this enzyme delays diabetes onset and reduces the severity of the disease in diabetes-prone BB rats. His laboratory has demonstrated that PIMT activation induces β-cell proliferation by regulation of IRS2 levels, a critical molecule responsible for β-cell proliferation and survival. The second pathway identified as important for β-cell proliferation and survival is JNK3 signaling.  He has shown that activation of this pathway can modulate β-cell survival and proliferation by inducing IRS2 levels. Future experiments will validate these pathways as potential pharmacological targets and will design strategies to discover novel small molecules. These novel molecules could be used in translational experiments to treat diabetes by expanding β-cell mass in vivo.

6.       Nutrient signaling in a-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 increased glucagon secretion by α-cells play a role in the pathogenesis of hyperglycemia in type 1 and 2 diabetes. In T1DM, hyperglucagonemia induced by the lack of paracrine control from insulin has a major impact in the glycemic volatility, glucose control and increased susceptibility to hypoglycemia, a devastating complication of 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. These agents could be used in translational experiments to treat diabetes by controlling glucagon secretion. At the same time, the pharmacologic manipulation of this pathway can be used to increase the pool of a-cells as a source to generate b-cells. Another major impact of these studies is obtaining a better understanding of the effects of rapamycin in a-cells mass and function. He has received VA funding for this area of investigation.