Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes

Background Insulin resistance, a major factor in the pathogenesis of type 2 diabetes mellitus, is due mostly to decreased stimulation of glycogen synt hesis in muscle by insulin. The primary rate-controlling step responsible f or the decrease in muscle glycogen synthesis is not known, although hexokin ase activity and glucose transport have been implicated. Methods We used a novel nuclear magnetic resonance approach with carbon-13 and phosphorus-31 to measure intramuscular glucose, glucose-6-phosphate, an d glycogen concentrations under hyperglycemic conditions (plasma glucose co ncentration, approximately 180 mg per deciliter [10 mmol per liter]) and hy perinsulinemic conditions in six patients with type 2 diabetes and seven no rmal subjects. In vivo microdialysis of muscle tissue was used to determine the gradient between plasma and interstitial-fluid glucose concentrations, and open-flow microperfusion was used to determine the concentrations of i nsulin in interstitial fluid. Results The time course and concentration of insulin in interstitial fluid were similar in the patients with diabetes and the normal subjects. The rat es of whole-body glucose metabolism and muscle glycogen synthesis and the g lucose-6-phosphate concentrations in muscle were approximately 80 percent l ower in the patients with diabetes than in the normal subjects under condit ions of matched plasma insulin concentrations. The mean (+/-SD) intracellul ar glucose concentration was 2.0+/-8.2 mg per deciliter (0.11+/-0.46 mmol p er liter) in the normal subjects. In the patients with diabetes, the intrac ellular glucose concentration was 4.3+/-4.9 mg per deciliter (0.24+/-0.27 m mol per liter), a value that was 1/25 of what it would be if hexokinase wer e the rate-controlling enzyme in glucose metabolism. Conclusions Impaired insulin-stimulated glucose transport is responsible fo r the reduced rate of insulin-stimulated muscle glycogen synthesis in patie nts with type 2 diabetes mellitus. (N Engl J Med 1999;341:240-6.) (C) 1999, Massachusetts Medical Society.