THE ROLE OF CNS INSULIN AS A MODULATOR OF DIABETIC COMPLICATIONS

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Diabetes in characterized by an absolute or relative insulin insufficiency. This deficiency sets in motion and a sequence of events that leads to tahe major features characteristic of diabetes; polyphagia, polydipsia and polyuria. The increased appetite, thirst and urine production have been attributed to the physiologic response to nutrient (glucose) and water loss. However, more recent studies have demonstrated that central nervous system (CNS) deprivation as well as peripheral deprivation is significant in mediating the expression of some of the characteristics of diabetes. it is now generally accepted that insulin does gain access to the b rain and that the brain has insulin receptors. Indeed the infusion of insulin into the intracerebroventricles (IVC) has been shown to decrease appetite and weight gain. It is then conceivable that a peripheral insulin insufficiency will result in a CNS insufficiency, and that chronic CNS insufficiency may lead to specific dysfunctions in central autonomic control mechanisms and thereby play a consequential role in the secondary and long term viscerobehavioral complications found in chronic diabetes. The most significant of these complications are cardiovascular changes, gastrointestinal disturbances and metabolic alterations, especially of glucose and fat metabolism. In this proposed study we will investigate the effect of the CNS insulin status in normal and diabetic animals on: (1) cardiovascular regulation and performance, (2) feeding behavior, (3) gastrointestinal secretion and motility, (4) hepatic glucose production and (5) lipoprotein lipase activity in white adipose tissue. Peripheral hormones, plasma metabolite and CNS neuropeptide and biogenic amine levels will be quantitated in all of the experimental conditions. We will also characterize the CNS site of the coordination of these responses. Finally, visceroendocrine response patterns mediated by the nucleus of the solitary tract (NTS) in the medulla will be examined and compared to response patterns mediated by rostral CNS regulatory sites such as the hypothalamus. These studies on the role of CNS insulin in diabetic and normal animals will shed light on mechanisms involved in coordinating neural, endocrine and behavioral determinants of nutrient homeostasis. Additionally, this study will be utilized to train minority students in research and investigative techniques. Because this program has many different levels of experimental rigor, it will be excellent in the development of both undergraduate and graduate students.