Impaired Glucose Tolerance is Characterized by Multiple Abnormalities in the Regulation of Intermediary Metabolism

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Abstract
The responses of circulating intermediary metabolites to a low‐dose sequential insulin infusion (basal, 0.005, 0.01, and 0.05 U kg‐1 h‐1) were assessed in eight non‐obese men with Impaired Glucose Tolerance (IGT), and in eight healthy control subjects with normal glucose tolerance matched for age, gender, and body mass index. Fasting hyperinsulinaemia was observed in the subjects with IGT (7.4 ± 1.0 vs 2.9 ± 0.3 mU l‐1, p < 0.001). While there was no significant difference (p < 0.1) in fasting venous glucose levels between the groups, fasting concentrations of lactate (p < 0.02), alanine (p > 0.01), and glycerol (p < 0.05) were significantly elevated in the subjects with IGT. During the incremental insulin infusion, overall concentrations of glucose (p < 0.05), lactate (p < 0.05), alanine (p < 0.05), glycerol (p < 0.05), immunoreactive insulin (p < 0.001), and C‐peptide (p < 0.01) were significantly higher in the subjects with IGT. Linear dose–response relationships (p < 0.005) for circulating immunoreactive insulin (log) vs metabolite concentrations were demonstrated by analysis of variance for glucose, non‐esterified fatty acids (NEFA), glycerol, and total ketone bodies. For glucose, glycerol, and NEFA, group dose–response regression lines for the subjects with IGT were displaced significantly to the right (p < 0.001 for each) of those for the normal control subjects, implying insulin insensitivity. In addition to the recognized defect in glucose homeostasis, these results indicate impaired regulation of multiple aspects of intermediary metabolism including lipolysis in IGT.