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

N Engl J Med. 1999 Jul 22;341(4):240-6. doi: 10.1056/NEJM199907223410404.


Background: Insulin resistance, a major factor in the pathogenesis of type 2 diabetes mellitus, is due mostly to decreased stimulation of glycogen synthesis in muscle by insulin. The primary rate-controlling step responsible for the decrease in muscle glycogen synthesis is not known, although hexokinase 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, and glycogen concentrations under hyperglycemic conditions (plasma glucose concentration, approximately 180 mg per deciliter [10 mmol per liter]) and hyperinsulinemic conditions in six patients with type 2 diabetes and seven normal 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 insulin 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 rates of whole-body glucose metabolism and muscle glycogen synthesis and the glucose-6-phosphate concentrations in muscle were approximately 80 percent lower in the patients with diabetes than in the normal subjects under conditions of matched plasma insulin concentrations. The mean (+/-SD) intracellular glucose concentration was 2.0+/-8.2 mg per deciliter (0.11+/-0.46 mmol per liter) in the normal subjects. In the patients with diabetes, the intracellular glucose concentration was 4.3+/-4.9 mg per deciliter (0.24+/-0.27 mmol per liter), a value that was 1/25 of what it would be if hexokinase were the rate-controlling enzyme in glucose metabolism.

Conclusions: Impaired insulin-stimulated glucose transport is responsible for the reduced rate of insulin-stimulated muscle glycogen synthesis in patients with type 2 diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Biological Transport
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / metabolism*
  • Extracellular Space / metabolism
  • Female
  • Glucose / metabolism*
  • Glucose-6-Phosphate / metabolism
  • Glycogen / biosynthesis
  • Glycogen / metabolism*
  • Hexokinase / metabolism
  • Humans
  • Hyperglycemia / metabolism
  • Hyperinsulinism / metabolism
  • Insulin / metabolism*
  • Insulin / physiology
  • Magnetic Resonance Spectroscopy
  • Male
  • Middle Aged
  • Models, Biological
  • Muscle, Skeletal / metabolism*


  • Blood Glucose
  • Insulin
  • Glucose-6-Phosphate
  • Glycogen
  • Hexokinase
  • Glucose