Insulin resistance and hyperinsulinaemia in kidney disease: mechanisms and metabolic effects

The impact of insulin resistance and compensatory hyperinsulinaemia on kidney function, and their contribution to the development and progression of chronic kidney disease, have largely been overlooked in people with or without diabetes. Beyond its classical metabolic targets (muscle, liver and adipocytes), insulin has an essential role in kidney metabolism and physiology, regulating podocyte integrity, tubular sodium handling and gluconeogenesis. In states of insulin resistance, these homeostatic functions are disrupted, leading to glomerular hyperfiltration, proteinuria, sodium retention, progressive kidney injury and exacerbation of hyperglycaemia. Simultaneously, chronic hyperinsulinaemia activates pro-growth and pro-fibrotic pathways, resulting in vascular dysfunction, inflammation and fibrosis. The emerging framework of a cardiovascular-kidney-metabolic syndrome reframes kidney disease as a manifestation of systemic metabolic dysfunction with insulin resistance and impaired insulin signaling at its core. Here, we provide mechanistic insights linking insulin resistance, hyperinsulinaemia, lipotoxicity and inflammation to kidney pathology and highlight the therapeutic implications of this paradigm for renoprotective agents, including sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide 1 receptor agonists and thiazolidinediones. Recognition of the pathogenic role of insulin resistance and hyperinsulinaemia will advance the development of novel therapeutic approaches to prevent and slow the progression of chronic kidney disease.