Insulin resistance in uremia mediated by postbinding defects

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Abstract

Uremic subjects exhibit reduced glucose uptake in response to physiological increments in plasma insulin concentration. The relative contributions of insulin binding versus postbinding defects to this insulin resistance are not known. Because insulin normally requires only a small portion of its receptors to exert maximal biological effects on glucose uptake, it should be possible to overcome the insulin resistance of uremia, if it is due to a binding defect, by utilizing sufficiently high insulin levels to draw on the large reserve of spare receptors. If postbinding defects are present, however, then a decreased response would be expected at high insulin concentrations. To determine whether or not the insulin resistance of uremia could be overcome by very high insulin levels, the dose-response relationship between plasma insulin concentration and insulin-mediated glucose uptake in seven chronically uremic and nine control subjects was evaluated. Insulin was infused at rates of 20, 40, 200, and 400 mU/min.m2, and the plasma glucose concentration was held constant at the basal level by a variable glucose infusion (euglycemia insulin clamp technique). Under these steady state conditions of euglycemia, the glucose infusion rate plus endogenous glucose production (measured with 3H-3-glucose) provides a measure of the amount of glucose taken up by the entire body. The steady state plasma insulin concentrations during the four insulin infusion protocols in the uremic subjects were consistently higher than in the controls. Despite the higher insulin levels in the uremics, the total amount of glucose taken up by the body was reduced by nearly 50% at each insulin plateau compared to controls. These results indicate that the in vivo dose-response curve relating plasma insulin concentration to glucose metabolism was shifted to the right in uremics and failed to normalize at high insulin levels. Basal hepatic glucose production was similar in uremic and control subjects. During the 20 and 40 mU/min.m2 insulin clamp studies, suppression of hepatic glucose production in uremics (83 and 94%, respectively) was similar to controls (88 and 98%, respectively). Specific 125I-insulin binding to circulating monocytes was measured in nine uremic and ten control subjects. No difference in insulin binding between the uremics and controls was observed. In normals, insulin binding correlated directly with glucose uptake and inversely with the fasting plasma insulin concentration. In uremics, no correlation was observed between insulin binding and glucose metabolism or between insulin binding and fasting plasma insulin concentration. It is concluded that in chronic renal failure insulin resistance is caused primarily by a postbinding defect in insulin action.

Original languageEnglish (US)
Pages (from-to)54-62
Number of pages9
JournalKidney International
Volume22
Issue number1
StatePublished - 1982
Externally publishedYes

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Uremia
Insulin Resistance
Insulin
Glucose
Fasting

ASJC Scopus subject areas

  • Nephrology

Cite this

Insulin resistance in uremia mediated by postbinding defects. / Smith, D.; Defronzo, Ralph A.

In: Kidney International, Vol. 22, No. 1, 1982, p. 54-62.

Research output: Contribution to journalArticle

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abstract = "Uremic subjects exhibit reduced glucose uptake in response to physiological increments in plasma insulin concentration. The relative contributions of insulin binding versus postbinding defects to this insulin resistance are not known. Because insulin normally requires only a small portion of its receptors to exert maximal biological effects on glucose uptake, it should be possible to overcome the insulin resistance of uremia, if it is due to a binding defect, by utilizing sufficiently high insulin levels to draw on the large reserve of spare receptors. If postbinding defects are present, however, then a decreased response would be expected at high insulin concentrations. To determine whether or not the insulin resistance of uremia could be overcome by very high insulin levels, the dose-response relationship between plasma insulin concentration and insulin-mediated glucose uptake in seven chronically uremic and nine control subjects was evaluated. Insulin was infused at rates of 20, 40, 200, and 400 mU/min.m2, and the plasma glucose concentration was held constant at the basal level by a variable glucose infusion (euglycemia insulin clamp technique). Under these steady state conditions of euglycemia, the glucose infusion rate plus endogenous glucose production (measured with 3H-3-glucose) provides a measure of the amount of glucose taken up by the entire body. The steady state plasma insulin concentrations during the four insulin infusion protocols in the uremic subjects were consistently higher than in the controls. Despite the higher insulin levels in the uremics, the total amount of glucose taken up by the body was reduced by nearly 50{\%} at each insulin plateau compared to controls. These results indicate that the in vivo dose-response curve relating plasma insulin concentration to glucose metabolism was shifted to the right in uremics and failed to normalize at high insulin levels. Basal hepatic glucose production was similar in uremic and control subjects. During the 20 and 40 mU/min.m2 insulin clamp studies, suppression of hepatic glucose production in uremics (83 and 94{\%}, respectively) was similar to controls (88 and 98{\%}, respectively). Specific 125I-insulin binding to circulating monocytes was measured in nine uremic and ten control subjects. No difference in insulin binding between the uremics and controls was observed. In normals, insulin binding correlated directly with glucose uptake and inversely with the fasting plasma insulin concentration. In uremics, no correlation was observed between insulin binding and glucose metabolism or between insulin binding and fasting plasma insulin concentration. It is concluded that in chronic renal failure insulin resistance is caused primarily by a postbinding defect in insulin action.",
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