Considerable evidence suggests that skeletal muscle insulin resistance is an inherent feature of type 2 diabetes and contributes to the pathogenesis of the disease. In patients with poorly controlled diabetes, hyperglycemia is thought to produce additional insulin resistance in muscle. The magnitude and nature of hyperglycemia-induced insulin resistance is not known. The purpose of the present study was to determine the biochemical mechanisms responsible for increased insulin-stimulated glucose disposal after the achievement of tight glycemic control with a mixed-split regimen. We performed hyperinsulinemic-euglycemic clamps with indirect calorimetry and vastus lateralis muscle biopsies in eight type 2 diabetic patients who had poor glycemic control (HbA1c 10.1%) and again after 3 months of intensive insulin therapy designed to produce near-normoglycemia (HbA1c 6.6%). Improved glycemic control increased insulin-stimulated glucose disposal (5.16 ± 0.32 vs. 3.69 ± 0.33 mg · kg−1 · min−1; P < 0.01); nonoxidative glucose disposal, which primarily reflects glycogen synthesis (2.11 ± 0.26 vs. 0.90 ± 0.16 mg · kg−1 · min−1; P < 0.01); and glycogen synthase fractional velocity (0.094 ± 0.017 vs. 0.045 ± 0.007; P < 0.05). There was no improvement in insulin-stimulated glucose oxidation (3.05 ± 0.25 vs. 2.79 ± 0.20 mg · kg−1 · min−1), hexokinase II mRNA expression (increase over basal values), or hexokinase II enzymatic activity (0.51 ± 0.16 vs. 0.42 ± 0.18 pmol · min−1 · μg−1 protein). All of the increase in insulin-stimulated glucose disposal could be accounted for by increased glycogen synthesis, which is likely attributable to increased activation of glycogen synthase by insulin.
Address correspondence and reprint requests to Lawrence J. Mandarino, The Diabetes Division, Mail Code 7886, Department of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. E-mail:.
Received for publication 10 July 2001 and accepted in revised form 31 October 2001.
FFA, free fatty acid; FFM, fat-free mass; G6P, glucose 6-phosphate; GS0.1, glycogen synthase determined using 0.1 mmol/l G6P; GS10, glycogen synthase determined using 10 mmol/l G6P; GSfv, glycogen synthase fractional velocity; HK, hexokinase.