Insulin Resistance, Hyperinsulinemia, and Renal Injury: Mechanisms and Implications

Abstract

Most of the basic components of the metabolic syndrome, namely type 2 diabetes mellitus, hypertension, obesity, or low high-density lipoprotein cholesterol levels, apart from being major risk factors for cardiovascular disease have been also associated with an increased risk of chronic kidney disease. However, several epidemiologic studies conducted over the past years suggest that the central component of the syndrome, insulin resistance, as well as compensatory hyperinsulinemia are independently associated with an increased prevalence of chronic kidney disease. In addition, background studies support the existence of several pathways linking insulin resistance and hyperinsulinemia with kidney damage. Insulin per se promotes the proliferation of renal cells and stimulates the production of other important growth factors such as insulin-like growth factor-1 and transforming growth factor beta. Insulin also upregulates the expression of angiotensin II type 1 receptor in mesangial cells, thus enhancing the deleterious effects of angiotensin II in the kidney, and stimulates production and renal action of endothelin-1. Moreover, insulin resistance and hyperinsulinemia are associated with decreased endothelial production of nitric oxide and increased oxidative stress which have been also implicated in the progression of diabetic nephropathy. This review analyzes the above and other potential mechanisms, through which insulin resistance and hyperinsulinemia can contribute to renal injury.

Postprandial hyperglycemia and hyperinsulinemia associated with renal arterio-arteriolosclerosis in chronic kidney disease

“…27,28 On the other hand, hyperinsulinemia has a variety of harmful effects potentially leading to vascular changes, such as anti-natriuretic effect, oxidant stress and decreased production of nitric oxide. 29 Considering these results, it seems likely that postprandial hyperglycemia and hyperinsulinemia may contribute to renal arterio-arteriolosclerosis.…”

One-Hour Postload Plasma Glucose Levels Are Associated with Kidney Dysfunction

“…We found that the association between 1-hour postload hyperglycemia and CKD was abrogated after adjustment for the Matsuda ISI, suggesting that kidney dysfunction may reflect an impairment in insulin sensitivity. Insulin resistance has been suggested to contribute to renal damage through several pathophysiologic mechanisms, including upregulation of TGF-␤, endothelin-1, and components of the renin-angiotensin-aldosterone system, which have been shown to promote mitogenic and fibrotic processes in the kidney (20). Furthermore, it has been shown that insulin has an important role for growth hormone (GH)-stimulated hepatic IGF-I production.…”

Insulin Sensitivity Measured With Euglycemic Clamp Is Independently Associated With Glomerular Filtration Rate in a Community-Based Cohort

“…These factors have been shown to promote mitogenic and fibrotic processes in the kidney, such as proliferation of mesangial cells and extracellular matrix expansion (13). Moreover, insulin resistance and hyperinsulinemia are closely associated with oxidative stress (14), which could promote renal injury via decreased production and availability of nitric oxide (15) and accelerated formation of glycoxidation and lipid peroxidation products (16 -18).…”