Type 2 diabetes as an inflammatory disease

• Published in: Nature reviews. Immunology Vol. 11; no. 2; pp. 98 - 107
• Main Authors: Donath, Marc Y, Shoelson, Steven E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2011; Nature Publishing Group
• Subjects: 631/250/256; 631/443/319/1642/137/773; 692/420/2780; 692/700/565; Adipose tissue; Adipose tissues; Apoptosis; Biomedical and Life Sciences; Biomedicine; Blood; Body fat; Care and treatment; Cell death; Cell Hypoxia; Chemokines; Clinical trials; Clinical Trials as Topic; Complications and side effects; Cytokines; Development and progression; Diabetes; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - immunology; Diabetes Mellitus, Type 2 - metabolism; Endoplasmic reticulum; Glucose; Humans; Hyperglycemia; Immune system; Immunology; Inflammation; Inflammation - drug therapy; Inflammation - immunology; Inflammation - metabolism; Inflammatory diseases; Insulin - metabolism; Insulin - pharmacology; Insulin resistance; Interleukin-1 - antagonists & inhibitors; Interleukin-1 - metabolism; Liver; MAP Kinase Kinase 4 - metabolism; Metabolism; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Nitric oxide; Obesity; Pathogenesis; Physiological aspects; Proteins; Receptors, Interleukin-1 - antagonists & inhibitors; Receptors, Interleukin-1 - metabolism; review-article; Risk factors; Tumor necrosis factor-TNF; Type 2 diabetes; United States
• ISSN: 1474-1733; 1474-1741
• DOI: 10.1038/nri2925

Key Points Type 2 diabetes is associated with obesity, ageing and inactivity. It is due to a progressive failure of pancreatic islet β-cells to compensate for insulin resistance. The proposed mechanisms to explain impaired insulin secretion and sensitivity in type 2 diabetes include oxidative stress, endoplasmic reticulum stress, amyloid deposition in the pancreas, ectopic lipid deposition in muscle, liver and pancreas, and lipotoxicity and glucotoxicity. All these cellular stresses may induce an inflammatory response or are exacerbated by or associated with inflammation. Factors that are associated with innate immune responses are present in the circulation, insulin-sensitive tissues and pancreatic islets in type 2 diabetes, and this evidence supports the involvement of inflammation in the pathogenesis of this disease. Mechanisms thought to be responsible for the inflammatory state in type 2 diabetes include hypoxia and cell death of expanding adipose tissue, activation of the nuclear factor-κB (NF-κB) and JUN N-terminal kinase (JNK) pathways, activation of interleukin-1β (IL-1β), and recruitment and activation of immune cells. Clinical trials using IL-1 antagonists or salsalate to directly target pro-inflammatory factors in patients with type 2 diabetes show promising preliminary results and support the role of inflammation in this condition. Existing data suggest a potential role for inflammation in the pathogenesis of type 2 diabetes. The relative importance of this mechanism and the precise therapeutic consequences remain to be elucidated. The cellular stresses that are proposed to underlie impaired insulin secretion and sensitivity in type 2 diabetes can also trigger inflammation. Here, the authors explain how inflammatory mechanisms are involved in the pathogenesis of type 2 diabetes and how this knowledge is directing immunomodulatory strategies for treating the disease. 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.