The overall purpose of this application is to continue our work elucidating the mechanisms and processes involved in the control of glucose metabolism in humans; in particular, we shall focus on factors dealing with glucose production by liver and kidney. Presently the role of the kidney in glucose homeostasis in humans is poorly understood and somewhat controversial. Recent studies indicate that release of glucose by the kidney normally accounts on average for 20% of overall glucose release and for about 40% of all gluconeogenesis in the postabsorptive state. Furthermore, there is evidence that it could become more important in situations where alterations in gluconeogenesis are involved and where hepatic glucose production is reduced. Therefore it is proposed to use a combination of isotopic (U-13C glucose) and organ (renal) balance techniques to evaluate the regulation of renal glucose release and its contribution to glucose homeostasis in a variety of conditions where alterations in renal glucose release might be important, e.g. counterregulation of hypoglycemia in diabetic patients with impaired glucagon responses, patients with renal insufficiency, postprandial glucose physiology and pathophysiology. An underlying theme of these studies will be evaluation of the recently proposed novel concept Hepatorenal Glucose Reciprocity. According to this concept, reciprocal changes in hepatic and renal glucose release occur under both physiologic (e.g. postprandial suppression of hepatic glucose release) and pathologic (e.g. renal/hepatic disease) conditions so as to prevent hypoglycemia and/or optimize homeostatic processes (e.g. postprandial hepatic glycogen repletion). There is evidence that the kidney participates in defense against hypoglycemia which is generally considered to be a major rate-limiting factor in the management of diabetes mellitus. Moreover, there is evidence that excessive renal glucose release contributes to hyperglycemia in diabetes mellitus. Further knowledge of the control of renal glucose release could therefore have therapeutic implications for this disorder and in people with liver and kidney disease. [unreadable] [unreadable]