Glucose intolerance in uremia: site and mechanism

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Abstract
The pathogenesis of glucose intolerance in uremia was examined with the glucose clamp technique. Hyperglycemic clamp (n = 8): the plasma glucose concentration is acutely raised and maintained at 125 mg/dl above basal levels. Under these steady state conditions the glucose infusion rate, M, equals the amount of glucose metabolized: predialysis M averaged 4.23 ± 0.36 mg/kg per min and increased to 7.71 ± 0.43 postdialysis (P < 0.001). The plasma insulin (I) response predialysis was 90 ± 20 µU/ml and decreased to 80 ± 23 µU/ml after dialysis. Consequently the M/I ratio, a measure of tissue sensitivity to insulin, increased by 80% ± 25% (P < 0.001) but still remained less than controls (P < 0.01). Euglycemic insulin clamp (n = 10): The plasma insulin concentration is acutely raised by 100 µU/ml and the plasma glucose concentration is held constant at the basal level. Predialysis M/I (3.56 ± 0.33 mg/kg per min per µU/ml × 100) was significantly less than controls (P < 0.01). Postdialysis M/I increased significantly (P < 0.01) to a mean that was not significantly different from controls. Basal hepatic glucose production (n = 10), 2.1 ± 0.1 mg/kg per min, was similar to controls and fell (87% ± 4%) normally during the insulin clamp. This normal suppression of hepatic glucose production was confirmed in four uremic subjects by direct hepatic venous catheterization. In five uremic subjects in whom insulin binding to monocytes was measured, there was no correlation with tissue sensitivity to insulin (M/I). In conclusion, glucose intolerance is universally present in uremic subjects and results primarily from peripheral tissue insensitivity to insulin. Insulin secretion is usually enhanced in an attempt to compensate for this insulin resistance but in occasional subjects uremia also inhibits beta cell sensitivity to glucose. Hepatic glucose production is unaffected by uremia. The lack of correlation between insulin binding and tissue sensitivity to insulin suggests that the cellular mechanism accounting for the insulin resistance is probably the result of a defect in intracellular metabolism or in the glucose transport system.