THE EFFECT OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS AND OBESITY ON GLUCOSE-TRANSPORT AND PHOSPHORYLATION IN SKELETAL-MUSCLE

Defects of glucose transport and phosphorylation may underlie insulin resistance in obesity and non-insulin-dependent diabetes mellitus (NID DM), To test this hypothesis, dynamic imaging of F-18-2-deoxy-glucose uptake into mid-thigh muscle was performed using positron emission tom ography during basal and insulin-stimulated conditions (40 mU/m(2) per min), in eight lean nondiabetic, eight obese non-diabetic, and eight obese subjects with NIDDM. In additional studies, vastus lateralis mus cle was obtained by percutaneous biopsy during basal and insulin-stimu lated conditions for assay of hexokinase and citrate synthase, and for immunohistochemical labeling of Glut 4. Quantitative confocal laser s canning microscopy was used to ascertain Glut 4 at the sarcolemma as a n index of insulin-regulated translocation. In lean individuals, insul in stimulated a 10-fold increase of 2-deoxy-2[F-18]fluoro-D-glucose (F DG) clearance into muscle and significant increases in the rate consta nts for inward transport and phosphorylation of FDG. In obese individu als, the rate constant for inward transport of glucose was not increas ed by insulin infusion and did not differ from values in NIDDM, Insuli n stimulation of the rate constant for glucose phosphorylation was sim ilar in obese and lean subjects but reduced in NIDDM. Insulin increase d by nearly twofold the number and area of sites labeling for Glut 4 a t the sarcolemma in lean volunteers, but in obese and NIDDM subjects t ranslocation of Glut 4 was attenuated. Activities of skeletal muscle H K I and II were similar in lean, obese and NIDDM subjects, These in vi vo and ex vivo assessments indicate that impaired glucose transport pl ays a key role in insulin resistance of NIDDM and obesity and that an additional impairment of glucose phosphorylation is evident in the ins ulin resistance of NIDDM.