Ron T Varghese1, Chiara Dalla Man1, Anu Sharma1, Ivan Viegas1, Cristina Barosa1, Catia Marques1, Meera Shah1, John M Miles1, Robert A Rizza1, John G Jones1, Claudio Cobelli1, Adrian Vella1. 1. Division of Endocrinology, Diabetes, and Metabolism (R.T.V., A.S., M.S., J.M.M., R.A.R., A.V.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; Department of Information Engineering (C.D.M., C.C.), Universitá di Padova, 35122 Padova, Italy; Center for Neurosciences and Cell Biology (I.V., C.B., C.M., J.G.J.), University of Coimbra, 3000-370 Coimbra, Portugal; and APDP-Portuguese Diabetes Association (J.G.J.), 1250-203 Lisbon, Portugal.
Abstract
CONTEXT: Prediabetes is a heterogeneous disorder classified on the basis of fasting glucose concentrations and 2-hour glucose tolerance. OBJECTIVE: We sought to determine the relative contributions of insulin secretion and action to the pathogenesis of isolated impaired glucose tolerance (IGT). DESIGN: The study consisted of an oral glucose tolerance test and a euglycemic clamp performed in two cohorts matched for anthropometric characteristics and fasting glucose but discordant for glucose tolerance. SETTING: An inpatient clinical research unit at an academic medical center. PATIENTS OR OTHER PARTICIPANTS: Twenty-five subjects who had normal fasting glucose (NFG) and normal glucose tolerance (NGT) and 19 NFG/IGT subjects participated in this study. INTERVENTION(S): Subjects underwent a seven-sample oral glucose tolerance test and a 4-hour euglycemic, hyperinsulinemic clamp on separate occasions. Glucose turnover during the clamp was measured using tracers, and endogenous hormone secretion was inhibited by somatostatin. MAIN OUTCOME MEASURES: We sought to determine whether hepatic glucose metabolism, specifically the contribution of gluconeogenesis to endogenous glucose production, differed between subjects with NFG/NGT and those with NFG/IGT. RESULTS: Endogenous glucose production did not differ between groups before or during the clamp. Insulin-stimulated glucose disappearance was lower in NFG/IGT (24.6 ± 2.2 vs 35.0 ± 3.6 μmol/kg/min; P = .03). The disposition index was decreased in NFG/IGT (681 ± 102 vs 2231 ± 413 × 10-14 dL/kg/min2 per pmol/L; P < .001). CONCLUSIONS: We conclude that innate defects in the regulation of glycogenolysis and gluconeogenesis do not contribute to NFG/IGT. However, insulin-stimulated glucose disposal is impaired, exacerbating defects in β-cell function.
CONTEXT: Prediabetes is a heterogeneous disorder classified on the basis of fasting glucose concentrations and 2-hour glucose tolerance. OBJECTIVE: We sought to determine the relative contributions of insulin secretion and action to the pathogenesis of isolated impaired glucose tolerance (IGT). DESIGN: The study consisted of an oral glucose tolerance test and a euglycemic clamp performed in two cohorts matched for anthropometric characteristics and fasting glucose but discordant for glucose tolerance. SETTING: An inpatient clinical research unit at an academic medical center. PATIENTS OR OTHER PARTICIPANTS: Twenty-five subjects who had normal fasting glucose (NFG) and normal glucose tolerance (NGT) and 19 NFG/IGT subjects participated in this study. INTERVENTION(S): Subjects underwent a seven-sample oral glucose tolerance test and a 4-hour euglycemic, hyperinsulinemic clamp on separate occasions. Glucose turnover during the clamp was measured using tracers, and endogenous hormone secretion was inhibited by somatostatin. MAIN OUTCOME MEASURES: We sought to determine whether hepatic glucose metabolism, specifically the contribution of gluconeogenesis to endogenous glucose production, differed between subjects with NFG/NGT and those with NFG/IGT. RESULTS: Endogenous glucose production did not differ between groups before or during the clamp. Insulin-stimulated glucose disappearance was lower in NFG/IGT (24.6 ± 2.2 vs 35.0 ± 3.6 μmol/kg/min; P = .03). The disposition index was decreased in NFG/IGT (681 ± 102 vs 2231 ± 413 × 10-14 dL/kg/min2 per pmol/L; P < .001). CONCLUSIONS: We conclude that innate defects in the regulation of glycogenolysis and gluconeogenesis do not contribute to NFG/IGT. However, insulin-stimulated glucose disposal is impaired, exacerbating defects in β-cell function.
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