The integration of peripheral and central glucose sensing with the rate of fall in glycemia

Iatrogenic hypoglycemia is the limiting factor to glycemic control in type I diabetes and in the course of late stages of type II diabetes. Profound, prolonged hypoglycemia, if unchecked, can cause brain death. When glucose levels fall, an elaborate and redundant feedback loop involving counterregulatory endocrine responses operates synchronously to prevent or correct hypoglycemia in humans. Glucose sensing elements located in the hypothalamus, hindbrain, and portal-mesenteric veins are responsible mediating this homeostatic mechanism. Individuals with diabetes are unable to maintain blood glucose within a narrow healthy physiologic range because of therapeutic insulin excess and compromised glycemic defenses. Understanding the functional organization and how glucose sensing information is integrated between these networks should provide insight into the pathogenic mechanisms underlying impaired hypoglycemic detection.;Therefore, the overall goal was to 1) investigate the interaction between the peripheral glucose sensors and those of the central nervous system (CNS) when hypoglycemia develops at different rates and 2) whether catecholaminergic projections from the hindbrain to forebrain are required linkage for the control of counterregulation during insulin induced hypoglycemia and to 3) examine the role of portal-mesenteric glucagon-like peptide-1 (GLP-1) receptors in hypoglycemic sensing.;These goals were addressed with studies utilizing specific lesioning techniques, surgical catheterizations, hyperinsulinemic-hypoglycemic clamps, hormone measurements, brain and portal-mesenteric vein immunocytochemistry. In the first study we investigated the effect of portal-mesenteric vein denervation via capsaicin on the sympathoadrenal response and on the neuronal activation in the hindbrain and hypothalamic neurons in response to four different rates of glycemic decline. We found that, consistent with our previous results, portal-mesenteric glucose sensors are primary in the detection of slow-onset hypoglycemia. However, as the development of hypoglycemia accelerates the contribution from central glucose sensing loci rises in a graded fashion.;The next experiment addressed the question whether catecholaminergic afferent projections from the hindbrain to hypothalamus are required component for sympathoadrenal response to fast- or/and slow-onset hypoglycemia. We employed models of the in vivo rapidly- and slowly-induced hypoglycemic clamps together with the anti-dopamine-beta-hydroxylase serum conjugated to saporin (DSAP) immunotoxin lesioning technique in the paraventricular nucleus of the hypothalamus (PVH) on the counterregulatory response. Our data revealed that hindbrain catecholaminergic neurons that project to the hypothalamus are required for sympathoadrenal responses to slow-onset but not rapid-onset hypoglycemia.;The final study we examined the impact of a GLP-1 receptor antagonist in hypoglycemic detection at the portal vein. We found that, after the portal-mesenteric vein GLP-1 receptors were inactivated by the antagonist, there was a reduction in the sympathoadrenal response to slow-onset hypoglycemia. Results indicate that GLP-1-receptor competency contributes to hypoglycemic detection at the portal-msenteric vein. Overall, data from this dissertation open the door to elucidate a neuroanatomical framework for considering how information derived from glucose sensing elements is distributed within the brain to control counteregulation. The identification of key integrative sites of functional neurocircuits during slow- and fast-onset hypoglycemia should provide insight to identify the pathogenic mechanisms that underlie the defective hypoglycemic detection in diabetic patients.