RESUMO
Interleukin-18 (IL-18), a potent and multifunctional pro-inflammatory cytokine, plays a critical role in regulating ß-cell failure, ß-cell death, insulin resistance, and various complications of diabetes mellitus (DM). It exerts its effects by triggering various signaling pathways, enhancing the production of pro-inflammatory cytokines and nitric oxide (NO), as well as promoting immune cells infiltration and ß-cells death. Abnormal alterations in IL-18 levels have been revealed to be strongly associated with the onset and development of DM and its complications. Targeting IL-18 may present a novel and promising approach for DM therapy. An increasing number of IL-18 inhibitors, including chemical and natural inhibitors, have been developed and have been shown to protect against DM and diabetic complications. This review provides a comprehensive understanding of the production, biological functions, action mode, and activated signaling pathways of IL-18. Next, we shed light on how IL-18 contributes to the pathogenesis of DM and its associated complications with links to its roles in the modulation of ß-cell failure and death, insulin resistance in various tissues, and pancreatitis. Furthermore, the therapeutic potential of targeting IL-18 for the diagnosis and treatment of DM is also highlighted. We hope that this review will help us better understand the functions of IL-18 in the pathogenesis of DM and its complications, providing novel strategies for DM diagnosis and treatment.
RESUMO
Type 2 diabetic patients are insulin resistant as a result of obesity and a sedentary lifestyle. Nevertheless, it has been known for the past five decades that insulin response to nutrients is markedly diminished in type 2 diabetes. There is now a consensus that impaired glucose regulation cannot develop without insulin deficiency. First-phase insulin response to glucose is lost very early in the development of type 2 diabetes. Several prospective studies have shown that impaired insulin response to glucose is a predictor of future impaired glucose tolerance (IGT) and type 2 diabetes. Recently discovered type 2 diabetes-risk gene variants influence ß-cell function, and might represent the molecular basis for the low insulin secretion that predicts future type 2 diabetes. We believe type 2 diabetes develops on the basis of normal but 'weak'ß-cells unable to cope with excessive functional demands imposed by overnutrition and insulin resistance. Several laboratories have shown a reduction in ß-cell mass in type 2 diabetes and IGT, whereas others have found modest reductions and most importantly, a large overlap between ß-cell masses of diabetic and normoglycemic subjects. Therefore, at least initially, the ß-cell dysfunction of type 2 diabetes seems more functional than structural. However, type 2 diabetes is a progressive disorder, and animal models of diabetes show ß-cell apoptosis with prolonged hyperglycemia/hyperlipemia (glucolipotoxicity). ß-Cells exposed in vitro to glucolipotoxic conditions show endoplasmic reticulum (ER) and oxidative stress. ER stress mechanisms might participate in the adaptation of ß-cells to hyperglycemia, unless excessive. ß-Cells are not deficient in anti-oxidant defense, thioredoxin playing a major role. Its inhibitor, thioredoxin-interacting protein (TXNIP), might be important in leading to ß-cell apoptosis and type 2 diabetes. These topics are intensively investigated and might lead to novel therapeutic approaches. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00094.x, 2011).