The impact of insulin resistance on the kidney and vasculature

Abstract

Insulin resistance is a systemic disorder that affects many organs and insulin-regulated pathways. The disorder is characterized by a reduced action of insulin despite increased insulin concentrations (hyperinsulinaemia). The effects of insulin on the kidney and vasculature differ in part from the effects on classical insulin target organs. Insulin causes vasodilation by enhancing endothelial nitric oxide production through activation of the phosphatidylinositol 3-kinase pathway. In insulin-resistant states, this pathway is impaired and the mitogen-activated protein kinase pathway stimulates vasoconstriction. The action of insulin on perivascular fat tissue and the subsequent effects on the vascular wall are not fully understood, but the hepatokine fetuin-A, which is released by fatty liver, might promote the proinflammatory effects of perivascular fat. The strong association of salt-sensitive arterial hypertension with insulin resistance indicates an involvement of the kidney in the insulin resistance syndrome. The insulin receptor is expressed on renal tubular cells and podocytes and insulin signalling has important roles in podocyte viability and tubular function. Renal sodium transport is preserved in insulin resistance and contributes to the salt-sensitivity of blood pressure in hyperinsulinaemia. Therapeutically, renal and vascular insulin resistance can be improved by an integrated holistic approach aimed at restoring overall insulin sensitivity and improving insulin signalling.

Soluble epoxide hydrolase in podocytes is a significant contributor to renal function under hyperglycemia

“…It is worth noting that podocyte sEH deficiency partially preserved renal function under hyperglycemia. Indeed, it is likely that additional contributing factors modulate podocyte dysfunction during DN given the complex molecular mechanisms underlying disease pathogenesis (reviewed in [40, 41]).…”

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

“…All these possible mechanisms could destroy the structure or activity of pathway molecules, hence inducing signaling insensitivity [137]. Patients with insulin resistance often suffer from hyperinsulinemia, hyperglycemia, hyperuricemia and dysfunctional lipid metabolism, which may evolve into metabolic disorders such as type 2 diabetes mellitus (T2DM), polycystic ovary syndrome (PCOS) and atherosclerosis [138, 139]. …”

(‐)‐Epicatechin and the Colonic 2,3‐Dihydroxybenzoic Acid Metabolite Regulate Glucose Uptake, Glucose Production, and Improve Insulin Signaling in Renal NRK‐52E Cells

“…The main site for glucose reabsorption is the early S1 segment of the proximal tubule and this process is largely mediated by the high‐capacity transporter sodium‐glucose co‐transporter‐2 (SGLT‐2) . In this regard, inhibitors of SGLT‐2 have been demonstrated to increase glycosuria and reduce hyperglycemia in type 2 diabetes . Importantly, the gluconeogenesis is a differentiated function of the renal cortex that also contributes to the glucose homeostasis, as well as to the insulin modulatory effects .…”

“…Importantly, the gluconeogenesis is a differentiated function of the renal cortex that also contributes to the glucose homeostasis, as well as to the insulin modulatory effects . In diabetes, there is a marked increase in renal glucose uptake, which might be accompanied by the upregulation of SGLT‐2 and glucose transporter‐2 (GLUT‐2) levels, and the renal gluconeogenesis is enhanced because of the deregulation of rate‐limiting gluconeogenic enzymes . Additionally, defects in the insulin signaling are thought to affect the renal glucose homeostasis and, therefore, contribute to the hyperglycemia .…”