ROLE OF CNS INSULIN AS A MODULATOR OF DIABETIC COMPLICATIONS

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DESCRIPTION (Adapted from the Applicant's Abstract): Diabetes is characterized by an absolute or relative insulin insufficiency. This deficiency sets in motion a sequence of events that leads to the major characteristic features 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 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 brain 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. Neuropeptide Y (NPY) has been demonstrated to strongly stimulate appetite when infused into IVC of normal animals. Additionally, it has been observed that NPY is increased in a number of hypothalamic nuclei in diabetes models and that insulin inhibits NPY synthesis. Thus, insulin may mediate its appetite suppressive effect through its regulation of CNS NPY concentration. It is conceivable that peripheral insulin insufficiency will result in CNS 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 the proposed study, attempts will be made to 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 metabolites, and CNS neuropeptide and biogenic amine levels will be quantitated in all of the experimental conditions. Attempts will also be made to characterize the CNS site of the coordination of these responses. Lastly, 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.