Hindbrain Mechanisms of Hypoglycemia Unawareness

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Glucagon and epinephrine are glucoregulatory hormones that mobilize stored glucose during glucose deficit (glucoprivation). When plasma glucose concentration decreases, as it does during insulin-induced hypoglycemia, release of these two hormones fosters restoration of plasma glucose, thereby protecting the brain, which has a continuous and absolute metabolic requirement for glucose. Control of glucagon and epinephrine secretion during glucoprivation is mediated by neural circuits in the brain and spinal cord. In diabetic patients undergoing insulin therapy hypoglycemic episodes can lead to the development of a lifethreatening condition known as hypoglycemia-associated autonomic failure (HAAF). During HAAF, the central neural controls or glucoregulatory responses, including glucagon and adrenal medullary secretion, fail to respond to glucoprivation. This failure of response exacerbates the brain glucose deficit and can lead to permanent brain damage or death. While it is clear that HAAF involves impairment of centrally mediated glucoregulatory responses, specifics of its pathogenesis are few. In fact, our appreciation of the basic central neural circuitry that controls these important glucoregulatory mechanisms is itself very incomplete. Clearly, a complete appreciation of the central glucoregulatory circuits and how they are altered by prior glucoprivic events is important in order to understand and prevent HAAF. The goal of our proposed research plan is to detail the anatomy of the central circuitry that controls two critical glucoregulatory responses, secretion of pancreatic glucagon and adrenal medullary epinephrine. We have already shown that hindbrain, not hypothalamic, glucoreceptors mediate key glucoregulatory responses and have demonstrated that spinally projecting catecholamine neurons are essential for the adrenal medullary response to glucoprivation. In the proposed work, we will identify the specific location and phenotypes of the catecholamine neurons that control adrenal medullary secretion. We also will determine the involvement of both catecholamine and spinally-projecting serotonin neurons in the central glucoprivic control of glucagon secretion. Finally, we will determine that role of hindbrain inhibitory neurons, which innervate hindbrain catecholamine neurons and adrenal medullary and pancreatic autonomic preganglionic neurons, in the control of glucagon and adrenal medullary secretion during glucoprivation and HAAF. We anticipate that our results will provide a detailed map of the circuitry for glucoprivic control of glucagon and adrenal medullary secretion, which ultimately will allow us to specify which circuit components are impaired during HAAF.