Robert S. Sherwin

C.N.H. Long Professor of Medicine
Interim Section Chief
Section of Endocrinology & Metabolism

Robert S. Sherwin. MD is the C.N.H. Professor of Medicine in the Section of Endocrinology at Yale University School of Medicine in New Haven, CT. He graduated from the Albert Einstein College of Medicine in 1967. After completing his residency in internal medicine at Mount Sinai Hospital (N Y), he moved to the National Institutes of Health to undertake a fellowship in metabolism and diabetes. In 1972 Dr Sherwin moved to Yale University School of Medicine as a postdoctoral fellow and was subsequently appointed to the faculty in 1974. He serves as the Director of the Yale Center for Clinical Investigation as well as the Diabetes Endocrinology Research Center and the JDRF Center for the Study of Hypoglycemia at Yale. His special clinical interests include patients with type 1 diabetes, intensified insulin therapy, complicated type 2 diabetes patients, and hypoglycemia associated with diabetes. Dr Sherwin’s research activities span clinical and basic research and are focused on glucose counterregulation and the immune mechanisms leading to type 1 diabetes mellitus. The studies dealing with counter regulation examine the brain glucose sensing mechanisms mediating the activation of counterregulatory responses and the impact of hypoglycemia and insulin on brain function and metabolism. Research in immunology has led to the isolation of islet-specific T cell clones from diabetic mice that adoptively transfer diabetes and studies of an islet protein linked to islet regeneration. Dr. Sherwin has served as President of the American Diabetes Association and as a member of the FDA Advisory Committee for Endocrinologic and Metabolic Drugs. He is editor of one of the major medical textbooks on diabetes mellitus and wrote the chapter on diabetes for the Cecil Textbook of Medicine. Dr. Sherwin has served as the Chairman of the Medical Science Advisory Board of the JDRF and on the editorial boards of leading diabetes and endocrine journals. He has published over 300 articles in peer-reviewed journals. Dr. Sherwin is the recipient of the American Diabetes Association’s Banting Award for lifetime scientific achievement, the Novartis Award for long-standing achievement in diabetes and 2 MERIT Awards from the NIH.

Research Interests

Research activities are focused in two areas: 1) glucose counterregulation and 2) the immune mechanisms leading to IDDM.

Reversal of defective defenses against hypoglycemia in diabetes requires a better understanding of the mechanisms used to sense hypoglycemia and trigger glucose counterregulation. Dr. Sherwin’s laboratory has provided strong evidence that the ventromedial hypothalamus (VMH) plays a critical glucose-sensing role. Experiments in rodents exposed to recurrent hypoglycemia indicated that defective hormone secretion induced by antecedent iatrogenic hypoglycemia in diabetes could be explained by a failure of the VMH to activate counterregulatory responses. His laboratory is now focused on the molecular mechanisms used by the VMH to sense glucose, an area of importance not only for glucose counteregulation, but also for the regulation of feeding. He is testing the intriguing hypothesis that the VMH senses glucose via mechanisms similar to those used by the beta cell and that GABA neurotransmission is involved. This concept is supported by studies showing that like the beta cell local glucose availability regulates KATP channels in the VMH, which in turn modulate the release of counterregulatory hormones. A link with local VHM GABA neurotransmission is supported by data showing the activation state of VMH KATP channels modulates GABA levels in the VMH interstitial fluid. Thus, GABA release by beta cell-like neurons in the VMH could play an important role in modulating hormonal responses to hypoglycemia. The lab has also generated interesting data suggesting that this is not be the whole story. Some VMH glucose sensing neurons appear to use the enzyme AMP-K, which serves as a “fuel gauge” in a variety of cells in peripheral tissues, such as muscle. Reduction of AMP-K gene expression (bilateral VMH injection of AMP-K siRNA) suppresses glucose counterregulation. The lab is also examining the mechanism mediating defective glucose counterregulation after intensive treatment of diabetes., the major cause of severe hypoglycemia in patients. These studies suggest that multiple adaptive mechanisms may be involved including: upregulation of VMH CRFR2 recectors , increased VMH GABA tone and AMP-Kinase activity. These studies have generated plans for several novel therapeutic interventions to reduce hypoglycemia risk.

Research in immunology focuses on molecular and cell biology, genetically modified (transgenic) rodents, and immunobiology. We have generated diabetogenic and disease suppressive T cells that recognize peptides derived from beta cell autoantigens (GAD, and insulin) and modify disease expression.. In addition, we have generated transgenic mice that express HLA genes linked to type 1 diabetes and hope to use these genetically altered mice to isolate and clone diabetes producing T lymphocytes from humans. Such cells may provide a tool for developing new strategies for immunotherapy. Finally, we are testing the hypothesis that the early insult to beta cells initiates a vicious circle involving attempted islet cell regeneration followed by enhanced autoimmunity. One of the targets of this autoimmune-response we believe is a family of proteins termed Reg that support islet regeneration and paradoxically generate an autoimmune response against beta cells in spontaneously diabetic NOD mice as well as humans with type 1 diabetes. Understanding this process might significantly affect current approaches to therapies.

Representative Publications

• Amiel SA, Tamborlane WV, Simonson DC, Sherwin RS. Defective glucose counterregulation after strict control of insulin-dependent diabetes mellitus. N Engl J Med 316:1376-1383, 1987.
• McCrimmon RJ, Fan X, Cheng H, McNay EC, Chan O, Shaw M, Ding Y, Zhu, Fan X, Sherwin, RS. Activation of AMP-activated protein kinase within the ventromedial hypothalamus amplifies counterregulatory hormone responses in rats with defective counterregulation. Diabetes, 55:1755-1760, 2006.
• McCrimmon RJ, Song Z, Cheng H, McNay EC, Weikart-Yeckel C, Fan X, Routh VH, Sherwin, RS. Corticotrophin releasing factor (CRF) receptors within the ventromedial hypothalamus (VMH) regulate hypoglycemia-induced hormonal counterregulation. J Clin Invest, 116:1723-1730, 2006.
• Chan O, Lawson M, Zhu W, Beverly JL, Sherwin RS. ATP-sensitive potassium channels regulate the release of GABA in the ventromedial hypothalamus during hypoglycemia. Diabetes 56:1120-1126, 2007.
• Wen L, Wong FS, Tan J, Chen N-Y, Altieri M, David C, Flavell R, Sherwin R. In vivo evidence for the contribution of HLA-DQ molecules to the development of diabetes. J Exp Med, 191:97-104, 2000.
• Gurr W, Yavari R, Wen L, Shaw M, Mora C, Christa L, Sherwin RS. A reg family protein is overexpressed in islets from a patient with new onset type 1 diabetes and acts as T cell autoantigen in NOD mice. Diabetes, 51:339-346, 2002.

A list of Dr. Sherwin’s publications is available via COS.

Contact

Campus Address
Department of Internal Medicine
Section of Endocrinology
Yale University
School of Medicine
P.O.Box 208020
New Haven, CT 06520-8020

E-mail
robert.sherwin@yale.edu

Telephone
203.785.4183

Fax
203.737.5558