Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus

Seven non-insulin-dependent diabetes mellitus (NIDDM ) patients participated in three clamp studies performed with [3-³H]- and [U-¹⁴C]glucose and indirect calorimetry: study I, euglycemic (5.2±0.1 mM) insulin (269±39 pM) clamp; study II, hyperglycemic (14.9±1.2 mM) insulin (259±19 pM) clamp; study III, euglycemic (5.5±0.3 mM) hyperinsulinemic (1650±529 pM) clamp. Seven control subjects received a euglycemic (5.1±0.2 mM) insulin (258±24 pM) clamp. Glycolysis and glucose oxidation were quantitated from the rate of appearance of ³H₂O and ¹⁴CO₂; glycogen synthesis was calculated as the difference between body glucose disposal and glycolysis. In study I, glucose uptake was decreased by 54% in NIDDM vs. controls. Glycolysis, glycogen synthesis, and glucose oxidation were reduced in NIDDM patients (P < 0.05-0.001 ). Nonoxidative glycolysis and lipid oxidation were higher. In studies II and III, glucose uptake in NIDDM was equal to controls (40.7±2.1 and 40.7±1.7 μmol/min·kg fat-free mass, respectively). In study II, glycolysis, but not glucose oxidation, was normal (P < 0.01 vs. controls). Nonoxidative glycolysis remained higher (P < 0.05). Glycogen deposition increased (P <0.05 vs. study I), and lipid oxidation remained higher (P <0.01). In study III, hyperinsulinemia normalized glycogen formation, glycolysis, and lipid oxidation but did not normalize the elevated nonoxidative glycolysis or the decreased glucose oxidation. Lipid oxidation and glycolysis (r = -0.65; P <0.01), and glucose oxidation (r = -0.75; P<0.01) were inversely correlated. In conclusion, in NIDDM: (a) insulin resistance involves glycolysis, glycogen synthesis, and glucose oxidation; (b) hyperglycemiaand hyperinsulinemia can normalize total body glucose uptake; (c) marked hyperinsulinemia normalizes glycogen synthesis and total flux through glycolysis, but does not restore a normal distribution between oxidation and nonoxidative glycolysis; (d) hyperglycemia cannot overcome the defects in glucose oxidation and nonoxidative glycolysis; (e) lipid oxidation is elevated and is suppressed only with hyperinsulinemia.