DIFFERENTIAL REGULATION OF INTRACELLULAR GLUCOSE-METABOLISM BY GLUCOSE AND INSULIN IN HUMAN MUSCLE

Insulin and glucose stimulate glucose uptake in human muscle by differ ent mechanisms. Insulin has well-known effects on glucose transport, g lycogen synthesis, and glucose oxidation, but the effects of hyperglyc emia on the intracellular routing of glucose are less well characteriz ed. We used euglycemic and hyperglycemic clamps with leg balance measu rements to determine how hyperglycemia affects skeletal muscle glucose storage, glycolysis, and glucose oxidation in normal human subjects. Glycogen synthase (GS) and pyruvate dehydrogenase complex (PDHC) activ ities were determined using muscle biopsies. During basal insulin repl acement, hyperglycemia (11.6 +/- 0.31 mM) increased leg muscle glucose uptake (0.522 +/- 0.129 vs. 0.261 +/- 0.071 mumol . min-1 . 100 ml le g tissue-1, P < 0.05), storage (0.159 +/- 0.082 vs. -0.061 +/- 0.055, P < 0.05), and oxidation (0.409 +/- 0.080 vs. 0.243 +/- 0.085, P < 0.0 5) compared with euglycemia (6.63 +/- 0.33 mM). The increase in basal glucose oxidation due to hyperglycemia was associated with increased m uscle PDHC activity (0.499 +/- 0.087 vs. 0.276 +/- 0.049, P < 0.05). H owever, the increase in leg glucose storage was not accompanied by an increase in muscle GS activity. During hyperinsulinemia, hyperglycemia (11.9 +/- 0.49 mM) also caused an additional increase in leg glucose uptake over euglycemia (6.14 +/- 0.42 mM) alone (5.75 +/- 1.25 vs. 3.7 5 +/- 0.58 mumol . min-1 . 100 ml leg-1, P < 0.05). In this case the m ajor intracellular effect of hyperglycemia was to increase glucose sto rage (5.03 +/- 1.16 vs. 2.39 +/- 0.37, P < 0.05). At hyperinsulinemia, hyperglycemia had no effect on muscle GS or PDHC activity. We conclud e that at basal insulin levels, hyperglycemia increases muscle glucose storage and glycolysis by increasing substrate availability and that glucose oxidation is preferentially increased by covalent activation o f PDHC. During hyperinsulinemia, additional increases in substrate ava ilability further activate GS allosterically and preferentially stimul ate glycogen synthesis.