INTRACELLULAR GLUCOSE-METABOLISM AFTER LONG-TERM METABOLIC CONTROL WITH GLYBURIDE - IMPROVED GLUCOSE-OXIDATION WITH UNCHANGED GLYCOGEN-SYNTHASE ACTIVITY

To determine whether improved metabolic control with long term glyburi de treatment alters intracellular glucose metabolism independent of ef fects on glucose uptake (GU), we studied eight obese patients with non insulin-dependent diabetes mellitus before and 7 months after glyburid e therapy. Indirect calorimetry and skeletal muscle biopsies were perf ormed in the basal state and during 300 pmol/m2. min insulin infusions , with glucose turnover rates determined by [3-H-3]glucose turnover. D uring the glucose clamps, rates of GU were matched before and after tr eatment using equivalent hyperinsulinemia and variable levels of hyper glycemia. After glyburide treatment, rates of GU were decreased in the basal state [4.16 +/- 0.57 vs. 3.29 +/- 0.37 mg/kg fat free mass (FFM )/min; P < 0.05], but similar during glucose clamps (11.53 +/- 1.42 vs . 11.93 +/- 1.32 mg/kg FFM . min; P = NS) according to study design. I n both the basal state and during glucose clamps after glyburide thera py, rates of glucose oxidative metabolism (G(ox)) increased by 68-78% [1.21 +/- 0.16 vs. 2.03 +/- 0.31 mg/kg FFM-min (P < 0.05) and 3.13 +/- 0.51 vs. 5.58 +/- 0.55 mg/kg FFM . min (P < 0.05), respectively), and rates of nonoxidative glucose metabolism decreased [2.96 +/- 0.68 vs. 1.25 +/- 0.21 mg/kg FFM . min (P < 0.05) and 8.40 +/- 1.50 to 6.30 +/ - 1.40 mg/kg FFM - min (P < 0.01), respectively]. Circulating plasma F FA levels and rates of fat oxidation (F(ox)) remained unchanged in bot h the basal state and during clamp studies. Skeletal muscle glycogen s ynthase (GS) activity, expressed as fractional velocity, was unchanged by glyburide therapy (2.2 +/- 0.8 vs. 2.7 +/- 0.3% in the basal state and 7.3 +/- 1.8 vs. 6.1 +/- 0.9% during clamps; both P = NS). In summ ary, at both matched (during clamp studies) and unmatched (during basa l studies) rates of GU, improved metabolic control with glyburide ther apy resulted in marked improvement of G(ox) independent of the effects on GU. The improvement in G(ox) was not associated with changes in F( ox), circulating FFA, or muscle GS activity. These data indicate that long term metabolic control achieved by glyburide therapy markedly imp roves G(ox), but not skeletal muscle GS activity, in noninsulin-depend ent diabetes mellitus independent of GU and F(ox).