Robert Stanley Sherwin, MD

C. N. H. Long Professor of Medicine (Endocrinology); Section Chief, Endocrinology; Director, Yale Center for Clinical Investigation

Research Interests

Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2

Research Summary

Reversal of defective defenses against hypoglycemia in diabetes requires a better understanding of the mechanisms used to sense hypoglycemia and trigger defenses against hypoglycemia.

Extensive Research Description

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.

Selected Publications

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Contact Info

Robert Stanley Sherwin, MD
Patient Care Locations
Yale Diabetes CenterDana Clinic Building
789 Howard Avenue, Ste Second floor

New Haven, CT 06519
Yale Endocrinology & MetabolismYale-New Haven Hospital
20 York Street

New Haven, CT 06510
Lab Location
SherwinThe Anlyan Center
300 Cedar Street, Ste S130/140

New Haven, CT 06519
Office Location
The Anlyan Center
300 Cedar Street, Ste S141D

New Haven, CT 06519
Mailing Address
PO Box 208020
333 Cedar Street

New Haven, CT 06520-8020