Kidney disease leads to clinically relevant disturbances in glucose and insulin homeostasis, but the pathophysiology in moderate-severe CKD remains incompletely defined. In a cross-sectional study of 59 participants with nondiabetic CKD (mean EGFR =37.6 ml/min per 1.73 m2) and 39 healthy control subjects, we quantified insulin sensitivity, clearance, and secretion and glucose tolerance using hyperinsulinemiceuglycemic clamp and intravenous and oral glucose tolerance tests. Participants with CKD had lower insulin sensitivity than participants without CKD (mean[SD] 3.9[2.0] versus 5.0 [2.0] mg/min per mU/ml; P,0.01). Insulin clearance correlated with insulin sensitivity (r=0.72; P,0.001) and was also lower in participants with CKD than controls (876  versus 998  ml/min; P,0.01). Adjustment for physical activity, diet, fat mass, and fatfree mass in addition to demographics and smoking partially attenuated associations ofCKDwith insulin sensitivity (adjusted difference,20.7; 95%confidence interval,21.4 to 0.0mg/min per mU/ml) and insulin clearance (adjusted difference, 285; 95% confidence interval, 2160 to 210 ml/min). Among participants with CKD, EGFR did not significantly correlate with insulin sensitivity or clearance. Insulin secretion and glucose tolerance did not differ significantly between groups, but 65%of participants with CKD had impaired glucose tolerance. In conclusion, moderate-severe CKD associated with reductions in insulin sensitivity and clearance that are explained, in part, by differences in lifestyle and body composition. We did not observe aCKD-specificdeficit in insulin secretion, but the combinationof insulin resistance and inadequate augmentation of insulin secretion led to a high prevalence of impaired glucose tolerance.
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