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The Relationship between Glucose Disposal in Response to Physiological Hyperinsulinemia and Basal Glucose and Free Fatty Acid Concentrations in Healthy Volunteers¹

Department of Medicine, Stanford University School of Medicine, Stanford, California 94080

Address correspondence and requests for reprints to: Gerald M. Reaven, M.D., Shaman Pharmaceuticals, Inc., 213 East Grand Avenue, South San Francisco, California 94080-4812; E-mail: greaven{at}shaman.com

This study was initiated to see if defects in the ability of physiological hyperinsulinemia (60 µU/mL) to stimulate glucose uptake in healthy, nondiabetic volunteers are associated with increases in concentrations of plasma glucose and free fatty acid (FFA) when measured at basal insulin concentrations (10 µU/mL). We recruited 22 volunteers (12 women and 10 men) for these studies, with a (mean ± SEM) body mass index of 24.8 ± 0.5 kg/m². Resistance to insulin-mediated glucose disposal during physiological hyperinsulinemia was determined by suppressing endogenous insulin and determining the steady-state plasma glucose (SSPG) and steady-state plasma insulin (SSPI) concentrations at the end of a 3-h infusion, period during which glucose (267 mg/m²·min) and insulin (32 mU/m²·min) were infused at a constant rate. Glucose, insulin and FFA concentrations were also measured in response to infusion rates of glucose (50 mg/m²·min) and insulin (6 mU/m²·min). The SSPI concentration (mean ± SEM) during physiological hyperinsulinemia was 64 ± 3 µU/mL), in contrast to 12 ± 0.4 µU/mL during the basal insulin study. The results demonstrated a significant relationship between SSPG concentration in response to physiological hyperinsulinemia (SSPG₆₀) and SSPG_Basal (r = 0.57, P < 0. 01) and FFA_Basal (r = 0.73, P < 0.001). Furthermore, FFA_Basal and SSPG_Basal were significantly correlated (r = 0.47, P < 0.05). Comparison of the seven most insulin-resistant and seven most insulin sensitive individuals (SSPG₆₀ values of 209 ± 16 vs. 64 ± 8 mg/dL) revealed that the insulin-resistant group also had significantly higher SSPG_Basal (105 ± 5 vs. 78 ± 7 mg/dL, P < 0.01) and FFA_Basal (394 ± 91 vs. 104 ± 41, P < 0.02) concentrations. However, random fasting plasma glucose and FFA concentrations of the two groups were not different. The results presented demonstrate that individual differences in the ability of elevated insulin concentrations to stimulate muscle glucose disposal are significantly correlated with variations in insulin regulation of plasma glucose and FFA concentrations at basal insulin concentrations.

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