| The specific neural circuitry meditating the launch of the counterregulatory response to insulin-induced hypoglycemia in Type I diabetes is still a topic of debate amongst researchers. Glucosensors have been identified in the brain and the hepato-portal region, and it is thought that glucose homeostasis relies on the integration of sensory input from both types of sensors. Although much is known about the post cranial efferent action in response to hypoglycemia, less is certain regarding the afferent integration of glucose signals. The objectives of this dissertation were (1) to identify the neuronal locus in the central nervous system (CNS) which integrates both central and peripheral glucosensors, (2) to clarify the anatomy of the neural pathway that interrelates glucosensing information from the periphery to the brain, and (3) to examine the differences in hormonal and neuronal responses to slowly- and rapidly-developing hypoglycemia.; All objectives were addressed with experiments employing surgical cannulations and denervations, glucose clamps, hormone analyses, brain immunocytochemisty, and vascular immunohistochemistry. To identify the locus of integration, rats underwent hyperinsulinemic-hypoglycemic clamps with portal-mesenteric glucosensors left intact, or denervated via topical capsaicin. Data from this experiment revealed that hypoglycemia-induced Fos expression in hindbrain neurons relies largely on peripheral gluco-sesensing at the portal and superior mesenteric veins (PMV). The next experiment elucidated a large part of the afferent neural pathway linking the peripheral and central glucosesensors. Utilizing celiac-ganglionectomy and vagotomy techniques, in conjunction with glucose clamps, results demonstrated that hypoglycemia-induced Fos expression in hindbrain neurons relies on input from spinal, not vagal, afferent nerve fibers innervating the PMV. The final experiment examined the importance of the peripheral glucosensors when hypoglycemia develops rapidly. Findings from this study indicated that, in contrast to slowly developing hypoglycemia, neuronal activation in both the hindbrain and hypothalamus is independent of PMV glucose sensory input when glycemia drops rapidly, suggesting that the locus of hypoglycemic detection shifts with the rate of fall in glycemia. Taken together, the results of these experiments have provided important information about the physiological, neuronal, and anatomical mechanisms which underlie the complications of both slowly- and rapidly-developing hypoglycemia in diabetic patients. |
