Impaired Glucose and Insulin Homeostasis in Moderate-Severe CKD

Abstract

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 m 2 ) 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 [226] versus 998 [212] ml/min; P,0.01). Adjustment for physical activity, diet, fat mass, and fatfree mass in addition to demographics and smoking partially attenuated associations of CKD with insulin sensitivity (adjusted difference, 20.7; 95% confidence interval, 21.4 to 0.0 mg/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 a CKD-specific deficit in insulin secretion, but the combination of insulin resistance and inadequate augmentation of insulin secretion led to a high prevalence of impaired glucose tolerance.

Leucine disposal rate for assessment of amino acid metabolism in maintenance hemodialysis patients

“…This is also one of the few studies where MHD patients are studied with appropriate controls, especially ones that have similar demographic and nutritional characteristics such as age, race, gender and body mass index. This may suggest that the difference between the two appropriately matched populations is not quite as large for GDR as previously suggested and is consistent with a recently published study in CKD patients not yet on maintenance dialysis [20]. Implementation of suitable control groups in future studies would provide valuable insight to this question.…”

Urea, a true uremic toxin: the empire strikes back

“…Insulin resistance in both CKD and normal mice were prevented by antioxidant superoxide dismutase (SOD)/catalase mimetic treatment; however potential confounders such as urea-induced intestinal inflammation and hepatic recycling of the infused urea were not addressed. Overall, these experiments suggest that urea-induced insulin resistance may contribute to the high rates of impaired glucose homoeostasis observed in the CKD population [76,77] but the clinical significance remains to be confirmed via human trials.…”

The systemic nature of CKD

“…Insulin resistance. Insulin resistance occurs in the early stages of CKD 90,91 and is present in almost every patient with end-stage renal disease (ESRD) 92 . The mobilization of energy-rich fuels through activation of neuroendocrine pathways results in high levels of free fatty acids, which lead to insulin resistance in the liver, muscle cells and adipocytes in chronic inflammatory conditions 93 .…”