Glucose regulation of β-cell stress in type 2 diabetes

In type 2 diabetes, the beta-cell is exposed to chronic hyperglycaemia, which increases its metabolic activity, with excess generation of reactive oxygen species (ROS) as a consequence. ROS accumulation induces both oxidative and endoplasmic reticulum (ER) stress, which may lead to beta-cell dysfunction and apoptosis. Recent data suggest that oxidative and ER stress are interconnected, although the mechanisms involved in nutrient regulation of the different stress pathways are dissimilar. Several components of the oxidative and ER stress machineries have important roles in the physiological response to glucose and are thus necessary for normal beta-cell function. Glucose stimulates signalling pathways that provide crucial messages for beta-cell adaptation to metabolic stress; however, the same pathways may eventually lead to apoptosis. Dynamic, temporally fluctuating activation of stress signalling is probably required for the maintenance of beta-cell survival, whereas its persistent activation results in beta-cell dysfunction and apoptosis. Thus, stress signalling is a 'double-edged sword' that may promote adaptation or apoptosis according to the balance between the divergent outputs of the various pathways. Developing new strategies for beta-cell protection based on inhibition of oxidative and/or ER stress requires comprehensive understanding of the switch from beta-cell adaptation to beta-cell apoptosis under conditions of metabolic stress, such as occurs under hyperglycaemic conditions.