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 β‐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’β‐cells unable to cope with excessive functional demands imposed by overnutrition and insulin resistance. Several laboratories have shown a reduction in β‐cell mass in type 2 diabetes and IGT, whereas others have found modest reductions and most importantly, a large overlap between β‐cell masses of diabetic and normoglycemic subjects. Therefore, at least initially, the β‐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 β‐cell apoptosis with prolonged hyperglycemia/hyperlipemia (glucolipotoxicity). β‐Cells exposed in vitro to glucolipotoxic conditions show endoplasmic reticulum (ER) and oxidative stress. ER stress mechanisms might participate in the adaptation of β‐cells to hyperglycemia, unless excessive. β‐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 β‐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)