Normalization of Plasma Glucose Concentration by Insulin Therapy Improves Insulin-Stimulated Glycogen Synthesis in Type 2 Diabetes

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 (HbA 1c 10.1%) and again after 3 months of intensive insulin therapy designed to produce near-normoglycemia (HbA 1c 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 −1 · min −1 ; P P −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.