Clinical Trials as Topic; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Endocrinology; Glucose; Hypoglycemia; Insulin
Reversal of defective defenses against hypoglycemia in diabetes requires a better understanding of the mechanisms used to sense hypoglycemia and trigger defenses against hypoglycemia.
Specialized Terms: Glucose counterregulation; Brain fuel metabolism; Effect of insulin on brain function; Immune mechanisms leading to type 1 diabetes.
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 expressio.. 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.
- Chan O, Paranjape S; Horblitt A; Zhu W; Sherwin, R. Lactate-Induced Release of GABA in the Ventromedial Hypothalamus Contributes to Counterregulatory Failure in Recurrent Hypoglycemia and Diabetes. Diabetes 62: 4239-4246, 2013.
- Szepietowska B, Zhu W, Czyzyk J, Eid T, Sherwin RS. EphA5-EphrinA5 Interactions Within the Ventromedial Hypothalamus Influence Counterregulatory Hormone Release and Local Glutamine/Glutamate Balance During Hypoglycemia. Diabetes. 62(4):1282-1288, 2013.
- Page KA*, Seo D*, Belfort-DeAguiar R, Lacadie C, Dzuira J, Naik S, Amarnath S, Constable T, Sherwin RS*, Sinha R*. Circulating glucose levels modulate neural control of desire for high-calorie foods in humans. J Clin Invest; 121:4161-4169, 2011. *equal contribution.
- Page KA, Chan O, Arora J, Belfort-Deaguiar R, Dzuira J, Roehmholdt B, Cline GW, Naik S, Sinha R, Constable RT, Sherwin RS. Effects of fructose vs glucose on regional cerebral blood flow in brain regions involved with appetite and reward pathways. JAMA. 309: 63-70, 2013.
- Herzog RI, Jiang L, Herman P, Zhao C, Sanganahalli BG, Mason GF, Hyder F, Rothman,DL, Sherwin RS, Behar KL. Lactate preserves neuronal metabolism an function following antecedent recurrent hypoglycemia. J Clin Invest. 123: 1988-1998, 2013.
- 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.
- 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.