DECREASED MUSCLE GLUCOSE-TRANSPORT PHOSPHORYLATION IS AN EARLY DEFECTIN THE PATHOGENESIS OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS

Recent studies have demonstrated that reduced insulin-stimulated muscl e glycogen synthesis is the major cause of insulin resistance in patie nts with non-insulin-dependent diabetes mellitus (NIDDM), This reduced rate has been assigned to a defect in either glucose transport or hex okinase activity, However it is unknown whether this is a primary or a cquired defect in the pathogenesis of NIDDM, To examine this question, we measured the rate of muscle glycogen synthesis and the muscle gluc ose 6-phosphate (G6P) concentration using C-13 and P-31 NMR spectrosco py as well as oxidative and nonoxidative glucose metabolism in six lea n, normoglycemic offspring of parents with NIDDM and seven age/weight- matched control subjects under hyperglycemic (approximate to 11 mM)-hy perinsulinemic (approximate to 480 pM) clamp conditions, The offspring of parents with NIDDM had a 50% reduction in total glucose metabolism , primarily due to a decrease in the nonoxidative component, The rate of muscle glycogen synthesis was reduced by 70% (P < 0.005) and muscle G6P concentration was reduced by 40% (P < 0.003), which suggests impa ired muscle glucose transport/hexokinase activity. These changes were similar to those previously observed in subjects with fully developed NIDDM, When the control subjects were studied at similar insulin level s (approximate to 440 pM) but euglycemic plasma glucose concentration (approximate to 5 mM), both the rate of glycogen synthesis and the G6P concentration were reduced to values similar to the offspring of pare nts with NIDDM, We conclude that insulin-resistant offspring of parent s with NIDDM have reduced nonoxidative glucose metabolism and muscle g lycogen synthesis secondary to a defect in muscle glucose transport/he xokinase activity prior to the onset of overt hyperglycemia. The prese nce of this defect in these subjects suggests that it may be the prima ry factor in the pathogenesis of NIDDM.