MULTIPLE DEFECTS OF BOTH HEPATIC AND PERIPHERAL INTRACELLULAR GLUCOSEPROCESSING CONTRIBUTE TO THE HYPERGLYCEMIA OF NIDDM

Non-insulin-dependent diabetic (NIDDM) patients were studied during a modified euglycaemic state when fasting hyperglycaemia was normalized by a prior (-210 to -150 min) - and later withdrawn (-150-0 min) - int ravenous insulin infusion. Glucose metabolism was assessed in NIDDM pa tients (n = 10) and matched control subjects (n = 10) using tritiated glucose turnover rates, indirect calorimetry and skeletal muscle glyco gen synthase activity determinations. Total and non-oxidative exogenou s glycolytic flux rates were measured using appearance rates of tritia ted water. A + 180 min euglycaemic hyperinsulinaemic (40 mU . m(-2). m in(-1)) clamp was performed to determine the insulin responsiveness of the various metabolic pathways. Plasma glucose concentration increase d spontaneously during baseline measurements in the NIDDM patients (-1 20 to 0 min: 4.8 +/- 0.3 to 7.0 +/- 0.3 mmol/l; p < 0.01), acid was pr imarily due to an elevated rate of hepatic glucose production (3.16 +/ - 0.13 vs 2.51 +/- 0.16 mg kg FFM(-1). min(-1); p < 0.01). In the NIDD M subjects baseline glucose oxidation was decreased (0.92 +/- 0.17 vs 1.33 +/- 0.14 mg . kg FFM(-1). min(-1); p < 0.01) in the presence of a normal rate of total exogenous glycolytic flux and skeletal muscle gl ycogen synthase activity. The simultaneous finding of an in-creased li pid oxidation rate (1.95 +/- 0.13 vs 1.61 +/- 0.07 mg . kg FFM(-1). mi n(-1); p = 0.05) and increased plasma lactate concentrations (0.86 +/- 0.05 vs 0.66 +/- 0.03 mmol/l; p = 0.01) are consistent with a role fo r both the glucose-fatty acid cycle and the Cori cycle in the maintena nce and development of fasting hyperglycaemia in NIDDM during decompen sation. Insulin resistance was demonstrated during the hyperinsulinaem ic clamp in the NIDDM patients with a decrease in the major peripheral pathways of intracellular glucose metabolism (oxidation, storage and muscle glycogen synthase activity), but not in the pathway of non-oxid ative glycolytic flux which was not completely suppressed during insul in infusion in the NIDDM patients (0.55 +/- 0.15 mg . kg FFM(-1). min( -1); p < 0.05 vs 0; control subjects: 0.17 +/- 0.29; NS vs 0). Thus, t hese data also indicate that the defect(s) of peripheral (skeletal mus cle) glucose processing in NIDDM goes beyond the site of glucose trans port across the cell membrane.