Insulin resistance in chronic kidney disease

The relationship among insulin resistance, adiponectin, and cardiovascular (CV) morbidity in patients with mild and moderate kidney disease was investigated. Insulin sensitivity (Homeostasis Model Assessment of Insulin Resistance [HOMA-IR]) and adiponectin plasma levels were assessed in 227 nondiabetic renal patients at different degrees of renal dysfunction and in 76 healthy subjects of similar age and gender distribution and body mass index. In renal patients, association with prevalent CV events was evaluated, and incident CV events were evaluated in a prospective study. HOMA-IR was markedly higher in patients than in healthy subjects (3.59 +/- 3.55 versus 1.39 +/- 0.51; P < 0.01). In renal patients, HOMA-IR was significantly correlated with body mass index (r = 0.477; P < 0.01), triglycerides (r = 0.384; P < 0.01), adiponectin plasma levels (r = -0.253; P < 0.01), and age (r = 0.164; P < 0.05), but not with renal function (GFR by iod-thalamate clearance). Patients with previous CV events were significantly older, had higher HOMA-IR and serum triglycerides, and had lower adiponectin plasma levels (all P < 0.05). Logistic regression analysis revealed age (P < 0.001) and adiponectin (P < 0.002) as independent variables related to prevalent CV events. In the prospective study, median follow-up was 54 mo. Patients who experienced CV events had significantly higher serum glucose and lower adiponectin plasma levels (both P < 0.05). In patients with chronic kidney diseases, a syndrome of insulin resistance is present even in the earliest stage of renal dysfunction, and several components of this syndrome are associated with CV events. Moreover, hypoadiponectinemia is a novel putative CV risk factor in patients with mild and moderate renal failure.

Tissue sensitivity to insulin was examined with the euglycemic insulin clamp technique in 17 chronically uremic and 36 control subjects. The plasma insulin concentration was raised by approximately 100 microU/ml and the plasma glucose concentration was maintained at the basal level with a variable glucose infusion. Under these steady-state conditions of euglycemia, the glucose infusion rate is a measure of the amount of glucose taken up by the entire body. In uremic subjects insulin-mediated glucose metabolism was reduced by 47% compared with controls (3.71 +/- 0.20 vs. 7.38 +/- 0.26 mg/kg . min; P less than 0.001). Basal hepatic glucose production (measured with [3H]-3-glucose) was normal in uremic subjects (2.17 +/- 0.04 mg/kg . min) and suppressed normally by 94 +/- 2% following insulin administration. In six uremic and six control subjects, net splanchnic glucose balance was also measured directly by the hepatic venous catheterization technique. In the postabsorptive state splanchnic glucose production was similar in uremics (1.57 +/- 0.03 mg/kg . min) and controls (1.79 +/- 0.20 mg/kg . min). After 90 min of sustained hyperinsulinemia, splanchnic glucose balance reverted to a net uptake which was similar in uremics (0.42 +/- 0.11 mg/kg . min) and controls (0.53 +/- 0.12 mg/kg . min). In contrast, glucose uptake by the leg was reduced by 60% in the uremic group (21 +/- 1 vs. 52 +/- 8 mumol/min . kg of leg wt; P less than 0.005) and this decrease closely paralleled the decrease in total glucose metabolism by the entire body. These results indicate that: (a) suppression of hepatic glucose production by physiologic hyperinsulinemia is not impaired by uremia, (b) insulin-mediated glucose uptake by the liver is normal in uremic subjects, and (c) tissue insensitivity to insulin is the primary cause of insulin resistance in uremia.

Insulin resistance is closely associated with atherosclerosis and cardiovascular mortality in the general population. Patients with end-stage renal disease (ESRD) are known to have insulin resistance, advanced atherosclerosis, and a high cardiovascular mortality rate. We evaluated whether insulin resistance is a predictor of cardiovascular death in a cohort of ESRD. A prospective observational cohort study was performed in 183 nondiabetic patients with ESRD treated with maintenance hemodialysis. Insulin resistance was evaluated by the homeostasis model assessment method (HOMA-IR) using fasting glucose and insulin levels at baseline, and the cohort was followed for a mean period of 67 mo. Forty-nine deaths were recorded, including 22 cardiovascular deaths. Cumulative incidence of cardiovascular death by Kaplan-Meier estimation was significantly different between subjects in the top tertile of HOMA-IR (1.40 to 4.59) and those in the lower tertiles of HOMA-IR (0.28 to 1.39), and the hazard ratio (HR) was 2.60 (95% confidence interval [CI], 1.12 to 6.01; P = 0.026) in the univariate Cox proportional hazards model. In multivariate Cox models, the positive association between HOMA-IR and cardiovascular mortality remained significant (HR, 4.60; 95% CI, 1.83 to 11.55; P = 0.001) and independent of age, C-reactive protein, and presence of preexisting vascular complications. Further analyses showed that the effect of HOMA-IR on cardiovascular mortality was independent of body mass index, hypertension, and dyslipidemia. In contrast, HOMA-IR did not show such a significant association with noncardiovascular mortality. These results indicate that insulin resistance is an independent predictor of cardiovascular mortality in ESRD.