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To examine whether this defect in glucose transport or hexokinase II activity was a primary defect or an acquired defect secondary to other factors, such as glucose toxicity (19), we studied insulin-resistant offspring of parents with type 2 diabetes, examining the rate of muscle glycogen synthesis and the muscle glucose-6-phosphate concentration under the same clamp conditions (20). Although these individuals were in all cases lean and normoglycemic, they were known to be at an approximately 40% increased risk for developing diabetes (2). Compared to age-and weight-matched control subjects, the children of diabetics had a 50% reduction in the rate of insulin-stimulated whole-body glucose metabolism, mainly due to a decrease in rates of muscle glycogen synthesis (20). Furthermore, their insulin-stimulated increment of intramuscular glucose-6-phosphate was severely reduced. This is consistent with …