Until the causes of diabetic complications are known, presumably therapy should attempt to normalize glucose metabolism as well as glucose concentration. This requires an understanding of how glucose, insulin, and glucagon interact to regulate glucose metabolism in nondiabetic humans and how these interactions are influenced by NIDDM. The investigators will examine these questions by first testing the hypothesis that short term (overnight) changes in glycemic control alters insulin action and glucose effectiveness (i.e. the ability of glucose to stimulate its own uptake and to suppress its own release) in people with NIDDM. Having defined the conditions of study, the investigators will then examine the assumptions of several widely used models of glucose metabolism (e.g. the """"""""cold"""""""" and """"""""hot"""""""" minimal models). The investigators will determine whether, in the presence of """"""""basal"""""""" insulin concentrations, increases in glucose concentration within the physiologic range result in linear suppression of hepatic glucose release and linear stimulation of disposal, whether NIDDM alters this relationship, whether hyperglycemia alters the kinetic as well as well as the absolute response to insulin, and whether NIDDM alters the inhibitory effects of glucose on its own clearance. The investigators also will use the triple tracer technique to examine the mechanism(s) by which glucose facilitates its own uptake in nondiabetic humans and to determine whether NIDDM alters glucose induced stimulation of transport and/or phosphorylation in muscle. The investigators will simultaneously use splanchnic catheterization to establish the contribution of splanchnic and extrasplanchnic tissues to glucose uptake and to test the hypothesis that NIDDM impairs glucose induced stimulation of glucose uptake in the splanchnic bed. The investigators will explore the interactions between insulin and glucagon by determining whether NIDDM alters the hepatic response to glucagon and by testing the hypotheses that lack of suppression of glucagon exacerbates hyperglycemia in people with NIDDM when insulin secretion is delayed and decreased but not when there is a rapid increase in insulin as occurs in nondiabetic humans after food ingestion. Finally, the investigators will determine whether the novel therapeutic agent GLP-1, in addition to increasing insulin secretion and suppression of glucagon, also improves insulin action and glucose effectiveness in people with NIDDM.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Metabolism Study Section (MET)
Program Officer
Laughlin, Maren R
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Mayo Clinic, Rochester
United States
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