Insulin resistance in patients with chronic kidney disease

Abstract

Metabolic syndrome and its components are associated with chronic kidney disease (CKD) development. Insulin resistance (IR) plays a central role in the metabolic syndrome and is associated with increased risk for CKD in nondiabetic patients. IR is common in patients with mild-to-moderate stage CKD, even when the glomerular filtration rate is within the normal range. IR, along with oxidative stress and inflammation, also promotes kidney disease. In patients with end stage renal disease, IR is an independent predictor of cardiovascular disease and is linked to protein energy wasting and malnutrition. Systemic inflammation, oxidative stress, elevated serum adipokines and fetuin-A, metabolic acidosis, vitamin D deficiency, depressed serum erythropoietin, endoplasmic reticulum stress, and suppressors of cytokine signaling all cause IR by suppressing insulin receptor-PI3K-Akt pathways in CKD. In addition to adequate renal replacement therapy and correction of uremia-associated factors, thiazolidinedione, ghrelin, protein restriction, and keto-acid supplementation are therapeutic options. Weight control, reduced daily prednisolone dosage, and the use of cyclosporin decrease the risk of developing new-onset diabetes after kidney transplantation. Improved understanding of the pathogenic mechanisms underlying IR in CKD may lead to more effective therapeutic strategies to reduce uremia-associated morbidity and mortality.

Figure 1

Insulin resistance in chronic kidney disease. Renal failure and adipose tissue lead to systemic inflammation and increased plasma levels of adipokines. TNF-α activates adipose tissue lipolysis, which generates free-fatty acids (FFAs). On muscle cells, FFAs activate transcription factors, such as peroxisome proliferator-activated receptor (PPAR), and generate messengers including diacylglycerol (DAG) and long-chain acyl-CoA (LCA-CoA), which will lead to protein kinase C (PKC) activation and dephosphorylation of insulin receptor substrate (IRS)-1/2. On muscle cells, TNF-α activates a series of kinases including IKK-β, c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), protein kinase C (PKC), Akt (PKB), mammalian target of rapamycin (mTOR), and glycogen synthase kinase 3 (GSK3) responsible for phosphorylation of insulin receptor (InsR) and IRS-1 on serine/threonine residues. Inhibition of IRS-1 function will block Akt leading to cytosol glucose transporter 4 (GLUT4) sequestration. Fetuin-A could also inhibit IRS and induce low-grade inflammation. IL-6 is responsible for the induction of different suppressors of cytokine signaling (SOCS) proteins through the Janus kinase/signal transducer and activator of transcription (Jak/STAT)-signaling pathway. SOCS will inhibit IRS-1/2 and protein kinase A. Endoplasmic reticulum stress seems to be another factor linking inflammation and insulin resistance at the molecular level. Red line illustrates the mechanism of CKD-related factors in IR.