Neurochemical mechanisms in the hypothalamus and attenuation of compensatory hormone responses to recurrent hypoglycemia

Intensive insulin therapy in the treatment of diabetes was designed to minimize long-term complications of this disease to chronically elevated levels of blood glucose. However, patients using this therapy are at increased risk of severe hypoglycemia, further augmented by the development of hypoglycemia unawareness. The syndrome of hypoglycemia unawareness is a combination of diminished warning symptoms to a progressively hypoglycemic state, e.g. tremor, sweating, anxiety, blurred vision, bradycardia etc., and attenuated compensatory hormone responses, such as secretion of epinephrine and glucagon. It is generally accepted that hypoglycemia unawareness develops in a vicious cycle as a consequence of antecedent hypoglycemia. But very little is known about the underlying mechanisms. The work presented in this thesis was aimed at evaluating neurochemical mechanisms in the hypothalamus that play an important role in the endogenous regulation of glucose homeostasis. It was hypothesized that these hypothalamic processes might somehow be altered during recurrent hypoglycemia and thereby impair the generation of appropriate compensatory responses.;For the purpose of testing this hypothesis a new rat model of recurrent hypoglycemia was used in combination with in vivo microdialysis. This enabled the simultaneous evaluation of circulating glucose and hormones, as well as extracellular concentrations of glucose and norepinephrine (NE) in discrete hypothalamic nuclei. It was demonstrated that attenuated autonomic activation to recurrent hypoglycemia in rats is not caused by a previously presumed maladaptive increase of glucose uptake by the brain. The fall in brain glucose concentration is proportional to that in the blood, and this fall is not prevented during recurrent hypoglycemia. Moreover, noradrenergic neurotransmitter systems in the hypothalamus are activated to a decrease in ambient glucose, and their responsiveness is preserved after recurrent daily hypoglycemic episodes on three consecutive days. From the present work it became evident that the observed increase in liver glycogen content after recurrent hypoglycemia plays an essential role in the development of hypoglycemia unawareness. In contrast to fed controls, compensatory hormone responses during recurrent hypoglycemia were not attenuated when liver glycogen was depleted after an overnight fast. It is suggested that increased hepatic glycogen facilitates restoration of euglycemia, and thus alleviates extrahepatic compensatory processes.