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The role of interleukins in insulin resistance and type 2 diabetes mellitus

Abstract

In the past few years, several interleukins (ILs) attracted considerable attention as potential effectors in the pathology and physiology of insulin resistance associated with type 2 diabetes mellitus (T2DM) and obesity. IL-1, a major proinflammatory cytokine, is present at increased levels in patients with diabetes mellitus, and could promote β-cell destruction and alter insulin sensitivity. The effects of IL-1 are likely to be counteracted by IL-1 receptor antagonist protein (IL-1ra), as suggested by interventional studies in patients with T2DM who were treated with a recombinant form of this protein. However, studies in IL-1ra-deficient mice provided controversial results on the exact effect of the IL-1 signaling pathway on insulin secretion, insulin sensitivity and accumulation of adipose tissue. Likewise, IL-6 has been suggested to be involved in the development of obesity-related and T2DM-related insulin resistance. The action of IL-6 on glucose homeostasis is also complex and integrates central and peripheral mechanisms. Both experimental and clinical studies now converge to show that several ILs contribute to the pathology and physiology of T2DM through their interaction with insulin signaling pathways and β-cell function.

Key Points

  • Insulin resistance and type 2 diabetes mellitus are associated with a systemic, chronic inflammatory response that is characterized by altered cytokine production, including that of interleukins (ILs)

  • ILs are probably involved in the pathology and physiology of insulin resistance and type 2 diabetes mellitus via their effects on both insulin-signaling pathways and β-cell or α-cell function

  • Two IL systems seem to have a central role in this pathological context: IL-6 and the balance between IL-1 and IL-1 receptor antagonist

  • IL-1α and IL-1β impair insulin-signaling pathways by altering insulin-receptor substrate phosphorylation and decreasing the expression of several components of the insulin-regulated glucose transport

  • IL-1 receptor antagonist could have a complex and dual effect on insulin sensitivity and secretion

  • IL-6 is overexpressed in insulin resistance and impairs insulin action in the liver and adipose tissue; these effects depend on its concentration and duration of target tissues' exposure to IL-6

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Figure 1: Mechanisms of fatty-acid-induced and interleukin-induced insulin resistance.
Figure 2: Pleiotropic metabolic effects of the IL-1 family.
Figure 3: Metabolic effects of IL-6.

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This work was supported by grants from INSERM and Universities Paris VI and Paris XI.

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Fève, B., Bastard, JP. The role of interleukins in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol 5, 305–311 (2009). https://doi.org/10.1038/nrendo.2009.62

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