β-Cell failure in type 2 diabetes

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 beta-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' beta-cells unable to cope with excessive functional demands imposed by overnutrition and insulin resistance. Several laboratories have shown a reduction in beta-cell mass in type 2 diabetes and IGT, whereas others have found modest reductions and most importantly, a large overlap between beta-cell masses of diabetic and normoglycemic subjects. Therefore, at least initially, the beta-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 beta-cell apoptosis with prolonged hyperglycemia/hyperlipemia (glucolipotoxicity). beta-Cells exposed in vitro to glucolipotoxic conditions show endoplasmic reticulum (ER) and oxidative stress. ER stress mechanisms might participate in the adaptation of beta-cells to hyperglycemia, unless excessive. beta-Cells are not deficient in antioxidant defense, thioredoxin playing a major role. Its inhibitor, thioredoxin-interacting protein (TXNIP), might be important in leading to beta-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)