PATHOGENESIS OF DIABETES MELLITUS

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During the post-absorptive period hepatic glucose production becomes the major source of new glucose production and the major determinant of hyperglycemia in the diabetic state. Evidence suggests that during this period hepatic glucose production (HGP) may be controlled by peripheral events. The major hypothesis to be tested is that a signalling mechanism exists between the periphery and the liver which may play an important role in post- absorptive hyperglycemia of diabetes. Peripheral signalling will be examined in two situations in which HGP may be controlled by peripheral events--during (1) sleep when HGP and peripheral metabolic events are synchronized and (2) following administration of insulin in quantities not increasing Rd or portal vein insulin levels. Peripheral signalling will be evaluated in terms of body composition (males, females, young, old thin obese, growth hormone deficient). The specific signal(s) involved will be assessed by replacement of any metabolites whose plasma concentration has fallen in conjunction with reduced HGP (free fatty acids, glycerol, lactate, alanine). The effect of these signals on qualitative aspects of HGP such as the proportion of HGP from gluconeogenesis vs glycogenolysis and the rate of futile cycling will also be evaluated. The association between android obesity, HGP, and carbohydrate metabolism will be explored by portal vein studies assessing the signal/substrate release from omental vs peripheral fat and the metabolic activity (lipolysis and re-esterification) of omental compared to peripheral fat. Finally, the signalling nature of peripherally derived metabolites will be examined in a well- defined hepatocyte culture system designed to examine carbon flux into glucose via either the direct pyruvate carboxylase or TCA pathway at the first branch point in gluconeogenesis. The putative signalling mechanism will be examined in non-obese, non-diabetic, obese, and diabetic subjects. The experiments are expected to indicate that signals (independent of substrate provision) from the periphery including omental fat stimulate gluconeogenesis, futile cycling, and HGP, but that the hyperinsulinemia of obesity restrains the latter two. Only in the diabetic state when insulin secretion has decreased are the increase in futile cycling and HGP observed.