Clinical Correlates of Insulin Sensitivity and Its Association with Mortality among Men with CKD Stages 3 and 4

Abstract

Background and objectives Insulin resistance participates in the pathogenesis of multiple metabolic and cardiovascular diseases. CKD patients have impaired insulin sensitivity, but the clinical correlates and outcome associations of impaired insulin sensitivity in this vulnerable population are not well defined.Design, setting, participants, & measurements The prospective cohort study was from the third examination cycle of the Uppsala Longitudinal Study of Adult Men, a population-based survey of elderly men ages 70-71 years; insulin sensitivity was assessed by glucose disposal rate as measured with euglycemic clamps. Inclusion criterion was eGFR,60 ml/min per 1.73 m 2 (n=543). Exclusion criteria were incomplete data on euglycemic clamp and diabetes (n=97), leaving 446 men with CKD stages 3 and 4 (eGFR median=51.9 ml/min per 1.73 m 2 ; range=20.2-59.5 ml/min per 1.73 m 2 ).Results The mean of glucose disposal rate was 5.461.9 mg/kg per minute. In multivariable analysis, the independent clinical correlates of glucose disposal rate were eGFR (slope, 0.02; 95% confidence interval, 0.01 to 0.04), hypertension (20.48; 95% confidence interval, 20.86 to 20.11), hyperlipidemia (20.51; 95% confidence interval, 20.84 to 20.18), and body mass index (20.32; 95% confidence interval, 20.37 to 20.27). During follow-up (median=10.0 years; interquartile range=8.7-11.0 years), 149 participants died. In Cox regression models, glucose disposal rate was not associated with all-cause or cardiovascular mortality. Multiplicative interactions (P,0.05) were observed between glucose disposal rate and physical activity or smoking in total mortality association. After subsequent stratification, glucose disposal rate was an independent correlate of all-cause mortality in smokers (adjusted hazard ratio, 0.72; 95% confidence interval, 0.54 to 0.96 per 1 mg/kg per minute glucose disposal rate increase) and physically inactive individuals (hazard ratio, 0.77; 95% confidence interval, 0.61 to 0.97) but not their counterparts.Conclusion eGFR, together with various components of the metabolic syndrome, contributed to explain the variance of insulin sensitivity in men with CKD stages 3 and 4. Insulin sensitivity was associated with a lower mortality risk in individuals who smoked and individuals who were physically inactive.

Insulin Resistance in CKD

“…The data of Xu et al support the finding that insulin resistance can already be observed in early CKD stages. Insulin resistance was not directly associated with significantly increased cardiovascular mortality in patients with stages 3-4 CKD, but graded relations among physical inactivity and smoking, together with insulin resistance, were identified as a deleterious combination for increased mortality (19). Interestingly, in line with other observations, the presence of insulin resistance was independent of overweight-a major risk factor in the classic metabolic syndrome (8,9).…”

“…The inclusion criterion for analysis was an eGFR of 20-60 ml/min per 1.73 m 2 calculated on the basis of serum cystatin C concentrations. Exclusion criteria were incomplete data and preexisting diabetes (19). Definite strengths of the study were the use of serum cystatin C to estimate GFR in an elderly population and the assessment of insulin resistance by the euglycemic clamp technique.…”

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.…”

Nonesterified Fatty Acids and Cardiovascular Mortality in Elderly Men with CKD

“…Nevertheless, in agreement with community reports (26,27), our multivariate analysis showed that the presence of diabetes mellitus (or insulin resistance) and the concentrations of triglycerides were the main independent determinants of NEFA variance in our CKD population. Both diabetes and hypertriglyceridemia have been associated with increased CVD risk in patients with CKD (28)(29)(30), but the association between insulin resistance and CVD risk in nondiabetic CKD is less conclusive (31,32).…”