IS NON-DIABETIC FASTING HYPERGLYCEMIA EXPLAINED BY IMPAIRED GLUCOSE UPTAKE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: To assess the contribution of decrease in insulin independent glucose uptake to the rise in fasting hyperglycemia in the non-diabetic range. RESEARCH PLAN: Insulin independent glucose uptake will be directly measured with two step hyperglycemic clamp and compared among three groups of subjects: (i) 20 subjects with NFG and NGT; (ii) 20 subjects with isolated IGT; and (iii) 20 subjects with IFG, according to ADA criteria. METHODS: Insulin independent glucose uptake will be measured with two step hyperglycemic clamp with tritiated glucose. Tritiated glucose will be infused throughout the study to measure hepatic glucose production. Somatostatin will be infused to achieve pancreatic clamp. Basal insulin and glucagon will be replaced. Plasma glucose will be raised in two steps, 90 minutes each (for eg. from ~100 to 225 and then 350). Insulin independent glucose uptake will be calculated as the sum of glucose infusion rate and endogenous glucose production. CLINICAL RELEVANCE: T2DM is a common metabolic disorder that is associated with high morbidity and mortality. Hyperglycemia is the principal risk factor for microvascular complications (e.g. blindness, kidney failure, and neuropathy). Fasting hyperglycemia is the major contributor to glycemic load in subjects with type 2 diabetes. Better understanding of the mechanisms which contribute to fasting hyperglycemia will aid in the development of therapies which correct the underlying pathogenic disturbance and thereby prevent diabetic complications. Importantly, subjects with isolated IFG are at increased risk for developing T2DM. Effective therapies which target fasting hyperglycemia could be effective in preventing the conversion from IFG to T2DM.