Effect of Acute Hyperglycemia on Glucose Metabolism in Skeletal Muscles in IDDM Patients

The effect of acute hyperglycemia on glucose metabolism in skeletal muscles was assessed during replacement insulin infusion in 11 patients with insulin-dependent diabetes mellitus (IDDM). With a primed continuous [3-³H]glucose infusion and indirect calorimetry, glucose metabolism was assessed during a basal period (plasma glucose [PG] 5 mM) and during a hyperglycemic period (4-h i.v. glucose infusion, PG 12.1 mM). Biopsies were taken from the vastus lateralis muscle during both periods. On a control day, glucose metabolism was assessed in 10 patients during a basal period (PG 5.2 mM) and after 4 h with no glucose infusion (PG 4.2 mM). Nonoxidative glucose disposal increased during hyperglycemia (32 ± 7 vs. 51 ± 9 mg · m⁻² · min⁻¹, P < 0.05), whereas glucose oxidation remained constant. On the control day, nonoxidative glucose disposal decreased from the basal to the second (control) period (33 ± 7 vs. 22 ± 6 mg · m⁻² · min⁻¹, P < 0.05), and glucose oxidation remained constant. The activity of glycogen synthase in muscle biopsies (fractional velocities [0.1 and 10 mM glucose 6-phosphate (G6P)]) decreased slightly during hyperglycemia (18 ± 2 vs. 12 ± 2%, P < 0.05) and on the control day (26 ± 4 vs. 20 ± 3%, P < 0.05). Hyperglycemia increased the intracellular concentration of free glucose, corrected for estimated extracellular glucose (0.56 ± 0.11 vs. 1.43 ± 0.19 mM, P < 0.01), G6P (0.14 ± 0.04 vs. 0.23 ± 0.08 mM, P < 0.02), and lactate (2.88 ± 0.33 vs. 4.46 ± 0.61 mM, P < 0.05), whereas these substrate concentrations remained constant on the control day. Muscle glycogen content failed to increase during hyperglycemia but decreased from the basal to the second (euglycemic) period on the control day (398 ± 16 vs. 369 ± 15 mmol glucose/kg dry wt, P < 0.05). In conclusion, hyperglycemia predominantly stimulates nonoxidative glucose disposal during low physiological insulin concentrations. The mechanism may partly be an allosteric activation of glycogen synthase in skeletal muscles in vivo due to an accumulation of G6P. The accumulation of free glucose and G6P indicates that glucose metabolism in skeletal muscles is not regulated solely by the membrane glucose transport system.