Complete correction of anemia by erythropoiesis-stimulating agents is associated with insulin resistance in hemodialysis patients

Abstract

Insulin resistance and anemia secondary to erythropoietin deficiency characterize patients with end-stage kidney disease. In a cross-sectional analysis, we examined the relationship between erythropoietin-mediated correction of anemia and insulin sensitivity in nondiabetic hemodialysis patients. Insulin sensitivity (euglycemic-hyperinsulinemic clamp) and endogenous glucose production (primed-continuous infusion of [6,6-(2)H(2)]glucose) were determined in two groups of patients with normal hemoglobin (n:8; mean hemoglobin: 14.0 ± 0.3 g/dl) or with mild anemia (n:10; mean hemoglobin: 12.1 ± 0.9 g/dl). The patients with normal hemoglobin were receiving higher (P < 0.05) erythropoietin doses than those with mild anemia (171 ± 73 and 91 ± 39 U kg(-1) wk(-1), respectively). The two groups were matched for all other potential determinants of insulin resistance. Endogenous glucose production was similar in the two groups of patients in the postabsorptive state and was completely suppressed by insulin infusion. During the hyperinsulinemic clamp, the rate of glucose infusion to maintain euglycemia was significantly lower (P < 0.01) in the patients with normal hemoglobin levels [166 ± 31 mg (m(2))(-1) min(-1)] than in those with mild anemia [251 ± 49 mg (m(2))(-1) min(-1)] and in a group of matched controls [275 ± 68 mg (m(2))(-1) min(-1)]. In pooled patients, individual values of hemoglobin concentrations inversely correlated with the rates of insulin-mediated glucose infusion, both as absolute values (r = -0.58; P < 0.05) and as values normalized by steady-state plasma insulin concentration (r = -0.74; P < 0.001). In conclusion, this exploratory study indicates that complete correction of anemia by erythropoietin treatment in patients with end-stage kidney disease on hemodialysis is associated with impaired insulin sensitivity.

Insulin resistance in chronic kidney disease: a systematic review

“…Interestingly, EPO therapy for 2 mo decreased PC-1 activity, and this effect was associated with an improvement in IR in hemodialysis patients treated with this drug (194). While partial correction of anemia has a favorable effect on IR, complete correction of anemia by EPO treatment worsens IR in dialysis patients (20). Iron deficiency is associated with activation of hypoxia-inducible factor-1-alpha (HIF-1␣), which stimulates glucose transporters and glycolytic enzyme synthesis as an adaptive response to relative hypoxia (13).…”

Metformin and the Risk of Anemia of Advanced Chronic Kidney Disease in Patients With Type 2 Diabetes Mellitus

“…This therapeutic effect of metformin is consistent with the result from a reduction in mean glucose levels and/or the slow decline of aging glomerular filtration rate. Several studies have revealed a significantly higher risk of ESA use in association with hyperinsulinemia and insulin resistance 31 . Metformin is known to correct hyperinsulinemia and insulin resistance, resulting in an association with preventing erythropoietin‐secreting cells from being damaged by hyperglycemia.…”

“…Aminoglycosides are one of the commonest causes of drug‐induced nephrotoxicity 27,28 and long‐term use of aspirin may increase the risk of renal failure 29 . Both ACE inhibitors and ARBs are widely used in patients with renal failure for treating hypertension, though these drugs may decrease erythropoietin formation by inhibiting angiotensin II production and decreasing plasma erythropoietin concentrations, thereby inducing anemia before renal failure 30,31 . The usage of metformin was divided into 3 sections, according to the number of patients.…”