Review Article

Type 2 diabetes as an inflammatory disease

  • Nature Reviews Immunology volume 11, pages 98107 (2011)
  • doi:10.1038/nri2925
  • Download Citation
Published:

Abstract

Components of the immune system are altered in obesity and type 2 diabetes (T2D), with the most apparent changes occurring in adipose tissue, the liver, pancreatic islets, the vasculature and circulating leukocytes. These immunological changes include altered levels of specific cytokines and chemokines, changes in the number and activation state of various leukocyte populations and increased apoptosis and tissue fibrosis. Together, these changes suggest that inflammation participates in the pathogenesis of T2D. Preliminary results from clinical trials with salicylates and interleukin-1 antagonists support this notion and have opened the door for immunomodulatory strategies for the treatment of T2D that simultaneously lower blood glucose levels and potentially reduce the severity and prevalence of the associated complications of this disease.

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Acknowledgements

The authors wish to thank their scientific collaborators who have contributed so much to these studies, in particular A. Goldfine, J. Lee, D. Mathis, K. Maedler, P. Halban, T. Mandrup-Poulsen, J. Ehses and M. Boni-Schnetzler.

Author information

Affiliations

  1. Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, CH-4031 Basel, Switzerland.  MDonath@uhbs.ch

    • Marc Y. Donath
  2. Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, Massachusetts 02215, USA.  steven.shoelson@joslin.harvard.edu

    • Steven E. Shoelson

Authors

  1. Search for Marc Y. Donath in:

  2. Search for Steven E. Shoelson in:

Competing interests

Marc Y. Donath is listed as the inventor of a patent filed in 2003 for the use of an interleukin-1 receptor antagonist for the treatment of or prophylaxis against type 2 diabetes. He is a consultant for Novartis, XOMA, Eli Lilly and Company, Cytos, Merck and AstraZeneca. Steven E. Shoelson holds patents on the use of salicylates in diabetes, prediabetes and cardiovascular disease. He has consulted for Catabasis, Amylin, AstraZeneca, Merck, Genentech, XOMA and Kowa.

Glossary

Insulin resistance

A pathological condition in which insulin becomes less effective at lowering blood glucose levels.

Endoplasmic reticulum stress

(ER stress). A response by the ER that results in the disruption of protein folding and the accumulation of unfolded proteins in the ER.

Lipotoxicity

The toxic effects of elevated levels of free fatty acids. These detrimental effects may be functional and reversible, or may lead to cell death.

Glucotoxicity

The toxic effects of hyperglycaemia. These detrimental effects may be functional and reversible, or may lead to cell death.

Autoinflammatory disease

A disease resulting from an attack by the innate immune system on the body's own tissues. By contrast, autoimmune diseases are caused by the pathological activation of adaptive immune responses. Autoimmune and autoinflammatory diseases have some characteristics in common, including shared effector mechanisms.

M1-type macrophage

A macrophage that is activated by Toll-like receptor ligands (such as lipopolysaccharide) and interferon-γ, and that expresses inducible nitric oxide synthase, which generates nitric oxide.

M2-type macrophage

A macrophage that is stimulated by interleukin-4 (IL-4) or IL-13 and that expresses arginase 1, the mannose receptor CD206 and the IL-4 receptor α-chain.

KitW–sh/W–sh mice

The KitW–sh (or sash) mutation abolishes KIT expression in mast cells, and the mutant mice are deficient in mast cells.

Insulitis

Inflammation of the pancreatic islets during the progression of diabetes. Insulitis in type 1 diabetes is caused by autoimmunity and in type 2 diabetes by metabolic stressors such as hyperglycaemia and elevated levels of free fatty acids.

Ischaemia

A condition in which the flow of blood to a tissue or organs is less than normal, and which results in injury to that tissue or organ.

Cachexia

Severe weight loss, muscle wasting and debility caused by prolonged disease. It is thought to be mediated through neuroimmunoendocrine interactions.

Leptin

A protein hormone that regulates energy intake and expenditure. It is one of the most important adipose-derived hormones and its production correlates with the mass of adipose tissue.

Inflammasome

A molecular complex of several proteins that, when activated, results in the production of active caspase 1, which cleaves pro-interleukin-1β (pro-IL-1β) and pro-IL-18 to produce the active cytokines.

Salsalate

A prodrug form of salicylic acid that has fewer side effects than sodium salicylate. Salsalate is approved for use in humans as a source of salicylic acid.