To examine the extent to which the defect in insulin action in subjects with non-insulin-dependent diabetes mellitus (NIDDM) can be accounted for by impairment of muscle glycogen synthesis, we performed combined hyperglycemic—hyperinsulinemic clamp studies with [13C]glucose in five subjects with NIDDM and in six age- and weight-matched healthy subjects. The rate of incorporation of intravenously infused [1–13C]glucose into muscle glycogen was measured directly in the gastrocnemius muscle by means of a nuclear magnetic resonance (NMR) spectrometer with a 15.5-minute time resolution and a 13C surface coil. The steady-state plasma concentrations of insulin (≈400 pmol per liter) and glucose (≈10 mmol per liter) were similar in both study groups. The mean (±SE) rate of glycogen synthesis, as determined by 13C NMR, was 78±28 and 183±39 μmol-glucosyl units per kilogram of muscle tissue (wet weight) per minute in the diabetic and normal subjects, respectively (P<0.05). The mean glucose uptake was markedly reduced in the diabetic (30±4 μmol per kilogram per minute) as compared with the normal subjects (51±3 μmol per kilogram per minute; P<0.005). The mean rate of nonoxidative glucose metabolism was 22±4 μmol per kilogram per minute in the diabetic subjects and 42±4 μmol per kilogram per minute in the normal subjects (P<0.005). When these rates are extrapolated to apply to the whole body, the synthesis of muscle glycogen would account for most of the total-body glucose uptake and all of the nonoxidative glucose metabolism in both normal and diabetic subjects. We conclude that muscle glycogen synthesis is the principal pathway of glucose disposal in both normal and diabetic subjects and that defects in muscle glycogen synthesis have a dominant role in the insulin resistance that occurs in persons with NIDDM. (N Engl J Med 1990; 322: 223–8.).
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