[HTML][HTML] Cellular mechanisms of insulin resistance

GI Shulman - The Journal of clinical investigation, 2000 - Am Soc Clin Investig
The Journal of clinical investigation, 2000Am Soc Clin Investig
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 …
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 impaired muscle glucose transport or reduced hexokinase II activity, and is similar to changes seen in patients with fully developed type 2 diabetes. When control subjects were studied at similar insulin levels but at euglycemia, both the rate of glycogen synthesis and the glucose-6-phosphate concentration decreased to values similar to that of the type 2 diabetic offspring. Therefore, we found that even before the onset of diabetes, insulin-resistant offspring of patients with type 2 diabetes have reduced rates of muscle glycogen synthesis that are secondary to a defect in either muscle glucose transport or hexokinase II activity. Clearly, defects in one or both of these activities occur early in the pathogenesis of type 2 diabetes. To determine whether glucose transport or hexokinase II activity is rate controlling for insulin-stimulated muscle glycogen synthesis in patients with type 2 diabetes, we used a novel 13C NMR method to assess intracellular glucose concentrations in muscle under similar hyperglycemic, hyperinsulinemic conditions as those used in the previous studies (21). Intracellular glucose is an intermediary metabolite between glucose transport and glucose phosphorylation, and its concentration reflects the relative activities of glucose transporters (particularly GLUT4) and of hexokinase II. Unlike the standard biopsy method, this approach is noninvasive and is not subject to the errors caused by contamination of biopsy tissue with plasma glucose or incomplete removal of nonmuscle constituents. If hexokinase II activity is reduced relative to glucose transport activity in diabetes, one would predict a substantial increase in intracellular glucose (21), whereas if glucose transport is primarily responsible for maintaining intracellular glucose metabolism, intracellular glucose and glucose-6-phosphate should change proportionately. We found that the intracellular glucose concentration was far lower in the diabetic subjects than the concentration expected if hexokinase II was the primary rate-controlling enzyme for glycogen synthesis. When the rates of muscle glycogen synthesis in the diabetic subjects were increased by infusing greater amounts of insulin, the changes in the concentrations of intracellular glucose and glucose-6-phosphate indicated that the rates of glucose transport were matched by increases in the rates of glucose phosphorylation and glycogen synthesis. These data suggest a predominant role for glucose transport control of insulinstimulated muscle glycogen synthesis in patients with type 2 diabetes, but they do not rule out the possibility that there are other downstream abnormalities in the pathway of glycogen synthesis that do not exert rate-controlling effects under these conditions. It has also been hypothesized that decreased delivery …
The Journal of Clinical Investigation