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 hyperinsulinemic-euglycemic 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 µU/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, -0.7; 95% confidence interval, -1.4 to 0.0 mg/min per µU/ml) and insulin clearance (adjusted difference, -85; 95% confidence interval, -160 to -10 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.

Keywords: chronic kidney disease; insulin resistance; metabolism; obesity; renal insulin resistance.

Figure 1.

Estimated GFR<60 mL/min/1.73 m² was associated with reduced insulin sensitivity and clearance but not insulin secretion or glucose tolerance. Distributions of insulin sensitivity (measured by hyperinsulinemic-euglycemic clamp), insulin clearance (measured by hyperinsulinemic-euglycemic clamp), insulin secretion (acute insulin response to intravenous glucose), and glucose tolerance (glucose AUC during the OGTT) are summarized using boxplots and scatterplots.

Figure 2.

Insulin sensitivity and insulin clearance were highly correlated. Scatterplots show linear regression lines stratified by CKD status.

Figure 3.

Insulin secretion (quantified as the acute insulin response to intravenous or oral glucose) and glucose tolerance (measured during the OGTT) did not differ among participants with and without CKD. Data points and error bars are means and 95% CIs, respectively. (A) Plasma insulin during the IVGTT; acute insulin response is calculated as incremental AUC from minutes 2–10. (B) Plasma insulin during the OGTT. (C) Plasma glucose during the OGTT.

Figure 4.

The insulin infusion rate used during the hyperinsulinemic-euglycemic clamp was determined using an insulin dose-ranging study. Five participants completed hyperinsulinemic-euglycemic clamps with multiple insulin infusion rates (40 and 80 mU/m² per minute, with n=3 also receiving 400 mU/m² per minute) on a single day. (A) Endogenous glucose production and (B) glucose disposal rate are plotted for each participant by insulin infusion rate or attained insulin concentration, respectively, with lines connecting data points for each individual. Dotted lines in B reflect the break in x axis for insulin concentrations attained at 80 versus 400 mU/m² per minute. Endogenous glucose production, determined using infusion of deuterated glucose, was suppressed for two of five participants at 40 mU/m² per minute, five of five participants at 80 mU/m² per minute, and three of three participants at 400 mU/m² per minute (data points for highest dose not shown). Glucose disposal rate, a measure of insulin sensitivity, increased fairly linearly from fasting to 40 and 80 mU/m² per minute. For three participants receiving insulin at 400 mU/m² per minute, glucose disposal rate was higher at 400 versus 80 mU/m² per minute.