Inflammation and insulin resistance

Abstract

Obesity-induced chronic inflammation is a key component in the pathogenesis of insulin resistance and the Metabolic syndrome. In this review, we focus on the interconnection between obesity, inflammation and insulin resistance. Pro-inflammatory cytokines can cause insulin resistance in adipose tissue, skeletal muscle and liver by inhibiting insulin signal transduction. The sources of cytokines in insulin resistant states are the insulin target tissue themselves, primarily fat and liver, but to a larger extent the activated tissue resident macrophages. While the initiating factors of this inflammatory response remain to be fully determined, chronic inflammation in these tissues could cause localized insulin resistance via autocrine/paracrine cytokine signaling and systemic insulin resistance via endocrine cytokine signaling all of which contribute to the abnormal metabolic state.

Figure 1. Direct interaction of insulin signaling and inflammatory pathways

The insulin signaling cascade branches into two main pathways. The PI3K/AKT pathway mediates insulin action on nutrient metabolism including glucose uptake. The Ras/MAPK pathway mediates insulin’s effect on gene expression, but also interacts with the PI3K-AKT pathway to control cell growth and differentiation. Activation of the insulin receptor leads to tyrosine phosphorylation of IRS1 thereby initiating signal transduction. Stimulation of the NFκB and AP-1 Fos/Jun inflammatory pathways results in the activation of the serine kinases, Ikkb and Jnk1, which reduce the signaling ability of IRS1. Additional inflammation-related negative regulators of IRS proteins include the Socs proteins and NO, which are induced in inflammation, and promote IRS degradation. NO also reduces PI3K/Akt activity by s-nitrosylation of Akt.

Figure 2. Obesity and the development of inflammation and insulin resistance

Obesity-induced changes in skeletal muscle, adipose tissue and the liver result in localized inflammation and insulin resistance (IR) through autocrine and paracrine signaling. Endocrine-mediated cross-talk between insulin target tissues contributes to insulin resistance in distant tissues. Systemic inflammation and insulin resistance are the net effect of these changes.