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).
Endocrine Services, Department of Medicine, Hebrew University Hadassah Medical Center, Jerusalem, Israel.
Gil
G
Leibowitz
Endocrine Services, Department of Medicine, Hebrew University Hadassah Medical Center, Jerusalem, Israel.
Nurit
N
Kaiser
Endocrine Services, Department of Medicine, Hebrew University Hadassah Medical Center, Jerusalem, Israel.
Erol
E
Cerasi
Insulin resistance; Insulin secretion; β‐Cell failure