Content area
Full Text
REVIEWS
REVIEWS
Type 2 diabetes as an inflammatory disease
Marc Y. Donath* and Steven E. Shoelson
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 interleukin1 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.
Insulin resistanceA 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.
LipotoxicityThe toxic effects of elevated levels of free fatty acids. These detrimental effects may be functional and reversible, or may lead to cell death.
Major advances have been made in understanding the mechanisms that are involved in the pathogenesis of type 2 diabetes (T2D)15. A decrease in insulin-stimulated glucose uptake (insulin resistance) is associated with obesity, ageing and inactivity. The pancreatic islets respond to insulin resistance by enhancing their cell mass and insulin secretory activity. However, when the functional expansion of islet -cells fails to compensate for the degree of insulin resistance, insulin deficiency and ultimately T2D develop. The onset of T2D leads in turn to the development of its long-term consequences: macrovascular complications (including athero sclerosis and amputations) and microvascular complications (including retinopathy, nephropathy and neuro pathy). Insulin resistance is typically present throughout the progression from prediabetes to the later stages of overt T2D. By contrast, the onset of T2D and its progression are largely determined by the progressive failure of -cells to produce sufficient levels of insulin. Interestingly, many insulin-resistant individuals do not become diabetic, because their -cells are able to compensate for the increased demand for insulin. Only about one-third of obese, insulin-resistant individuals actually...