Insulin resistance in chronic kidney disease: new lessons from experimental models

Insulin resistance (IR) is a common feature of chronic kidney disease (CKD), but the underlying mechanisms still remain unclear. A growing body of evidence suggests that IR and its associated metabolic disorders are important contributors for the cardiovascular burden of these patients. In recent years, the modification of the intestinal flora and activation of inflammation pathways have been implicated in the pathogenesis of IR in obese and diabetic patients. All these pathways ultimately lead to lipid accumulation in ectopic sites and impair insulin signalling. These important discoveries have led to major advances in understanding the mechanisms of uraemia-induced IR. Indeed, recent studies show impairment of the intestinal barrier function and changes in the composition of the gut microbiome during CKD that can contribute to the prevailing inflammation, and the production and absorption of toxins generated from bacterial metabolism. The specific role of individual uraemic toxins in the pathogenesis of IR has been highlighted in rodents. Moreover, correcting some uraemia-associated factors by modulating the intestinal flora improves insulin sensitivity. This review outlines potential mechanisms by which important modifications of body homeostasis induced by the decline in kidney function can affect insulin sensitivity, and the relevance of recent advances in the field to provide novel therapeutic approaches to reduce IR associated cardiovascular mortality.