Title: Pre-Conditioning and the Development of Hypoglycemia Tolerance
Funder: Juvenile Diabetes Research Foundation

Abstract: To test the hypothesis that hypoglycemia unawareness develops because of changes in specialized brain cells in the ventromedial hypothalamus that sense low glucose. The application also explores the possibility that urocortin 3 a brain neuropeptide that plays a major role in the regulation of physiological and behavioral stress is important in this process. Hypoglycemia is the major metabolic side-effect of insulin therapy and greatly feared by people with type 1 diabetes. We now know that even one episode of hypoglycemia makes a person with type 1 diabetes more likely to have another because their ability to respond, in terms of a hormone (adrenaline) response, to the second challenge is impaired. This size of this defect relates directly to the depth, duration and frequency of the preceding hypoglycemia. This application hypothesizes that these changes develop as a protective response, i.e. a means by which the cell becomes better able to cope with marked stresses such as severe hypoglycemia. This protective response is well recognized and is called pre-conditioning. This means that hypoglycemia unawareness develops as a form of tolerance and that other stresses such as exercise or cold exposure affect hypoglycemia responses through cross-tolerance between these stressors. We have recently shown that the ventromedial hypothalamus, a key brain glucose-sensing region, can be directly modulated by the opposing actions of urocortin 3 (UCN3), and corticotrophin releasing hormone (CRH); neuropeptides that play a critical role in modulating cellular responses to a number of physiological and behavioral stressors. In three individual aims in this application we will examine; (1) different stresses, including hypoglycemia, can be prevented by changing UCN3/CRH-R2 levels in the VMH; (2) If hypoglycemia is acting to pre-condition the VMH to further hypoglycemia, and (3) if UCN 3 acts directly on VMH glucose-sensing neurons. These aims will be addressed in animal models in vivo and ex vivo using a variety of techniques. Understanding why hypoglycemia counterregulation is defective in insulin-treated diabetes is a scientific question of immediate relevance to people with diabetes and consistent with the stated goals of organizations such as the JDRF. This application tests the hypothesis that hypoglycemia unawareness develops because of changes in specialized brain cells that sense low glucose. The application also explores the possibility that urocortin 3 a brain neuropeptide that plays a major role in the regulation of stress is important in this process. We now know that even one episode of hypoglycemia makes a person with type 1 diabetes more likely to have another because their ability to respond, in terms of a hormone (adrenaline) response, to the second challenge is impaired. This size of this defect relates directly to the depth, duration and frequency of the preceding hypoglycemia. This application hypothesizes that these changes develop as a protective response, i.e. a means by which the cell becomes better able to cope with marked stresses such as severe hypoglycemia. This protective response is well recognized and is called pre-conditioning. This means that hypoglycemia unawareness develops as a form of tolerance and that other stresses such as exercise or cold exposure affect hypoglycemia responses through cross-tolerance between these stressors. We have recently shown that the ventromedial hypothalamus, a key brain glucose-sensing region, can be directly modulated by the opposing actions of urocortin 3 (UCN3), and corticotrophin releasing hormone (CRH); neuropeptides that play a critical role in modulating cellular responses to a number of physiological and behavioral stressors. In three individual aims in this application we will examine; (1) different stresses, including hypoglycemia, can be prevented by changing UCN3/CRH-R2 levels in the VMH; (2) If hypoglycemia is acting to pre-condition the VMH to further hypoglyc


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE