Molecular mechanisms of insulin resistance in chronic kidney disease

Abstract

Insulin resistance refers to reduced sensitivity of organs to insulin-initiated biologic processes that result in metabolic defects. Insulin resistance is common in patients with end-stage renal disease but also occurs in patients with chronic kidney disease (CKD), even when the serum creatinine is minimally increased. Following insulin binding to its receptor, auto-phosphorylation of the insulin receptor is followed by kinase reactions that phosphorylate insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), and Akt. In fact, low levels of Akt phosphorylation (p-Akt) identify the presence of the insulin resistance that leads to metabolic defects in insulin-initiated metabolism of glucose, lipids, and muscle proteins. Besides CKD, other complex conditions (e.g., inflammation, oxidative stress, metabolic acidosis, aging, and excess angiotensin II) reduce p-Akt resulting in insulin resistance. Insulin resistance in each of these conditions is due to the activation of different E3 ubiquitin ligases, which specifically conjugate ubiquitin to IRS-1 marking it for degradation in the ubiquitin-proteasome system (UPS). Consequently, IRS-1 degradation suppresses insulin-induced intracellular signaling, causing insulin resistance. Understanding mechanisms of insulin resistance could lead to therapeutic strategies that improve the metabolism of patients with CKD.

Figure 1

is a pictorial representation of the intracellular insulin signaling pathway. When insulin binds to its receptor, the insulin receptor auto-phosphorylates tyrosines in the receptor. Subsequently, kinase activities phosphorylate IRS-1, PI3K and Akt which change metabolic processes including glucose uptake and lipid and protein metabolism. Interruption of this signaling pathway causes insulin resistance with impairment of insulin-stimulated metabolic functions. The insulin signaling pathway can be interrupted by chronic kidney disease inducing inflammation, excess angiotensin II, metabolic acidosis and several uremic toxins leading to defective metabolism of glucose and lipids plus reduced protein synthesis and increased protein degradation causing loss of muscle mass.

Figure 2

is a scheme that results in a reduced level of IRS-1 due to its degradation by the ubiquitin-proteasome system (UPS). In the presence of ATP, the E1 ubiquitin activating enzyme stimulates ubiquitin leading to its interaction with an E2 ubiquitin transfer protein. Subsequently, IRS-1 reacts with a specific E3 ubiquitin ligase (Elongin BC-Cullin, Fbxo40 or Cul7-Fbw8, Cblb or MG53) that are activated by individual processes (inflammation, excess insulin/IGF-1, or excess calories respectively) which then selectively transfers activated ubiquitin from the E2 ubiquitin transfer protein to IRS-1. This process is repeated until a chain of at least 5 ubiquitins is attached to IRS-1. The chain is then recognized by the 26S proteasome which removes ubiquitins and unwinds IRS-1 so it can be injected into the central core of the 26S proteasome. IRS-1 is then degraded by the 26S proteasome causing insulin resistance.