BRAIN GLUCOSENSING NEURONS IN HEALTH AND DIABETES

Veterans Biomedical Research Institute, East Orange NJ

Investigators

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Abstract

DESCRIPTION(Adapted from applicant's abstract): The brain requires glucose for its normal physiologic function. It has evolved neurons which both sense and regulate peripheral glucose metabolism and energy balance. Such glucose responsive neurons utilize an ATP-sensitive K+ channel (Katp) to increase firing rate when glucose availability increases. Dr. Levin will use a molecular probe (Kir6.2) as a marker for these neurons to investigate the ways the brain monitors and regulates glucose metabolism in healthy animals and why this glucosensing is often dysfunctional in diabetics. A rat model of diet-induced obesity will be used as a model of non-insulin-dependent diabetes (NIDDM). Streptozotocin will be used to induce insulin-dependent diabetes (IDDM) in the presence or absence of repeated bouts of insulin-induced hypoglycemia. In his first specific aim Dr. Levin will assess the cellular location and anatomical distribution of the Kir6.2 on brain neurons by in situ hybridization. The effect of diabetes and selective neurotoxins for glucosensing neurons will be studied as clues to the regulation of Kir6.2 expression in disorders of glucose metabolism and body weight regulation. Next, he will assess the local vs. systemic effects of altering glucose availability on the release of brain catecholamines. This will be done with combinations of cerebral microdialysis with local, forebrain or systemic manipulation of glucose availability in both normal and diabetic rats. Finally, Dr. Levin will assess the way in which diabetes affects the autonomic responses which result when glucose availability is altered in specific autonomic effector areas of the hypothalamus. These studies are expected to provide important insights into the ways in which the brain regulates glucose metabolism in health and disease.