Pancreatic β-cell failure is increasingly recognized as central to the progression of diabetes mellitus. Different causes are implicated in the onset of β-cell stress, dysfunction or death. Recent genetic and biochemical evidence both in humans and mice shows that failure in modulating the capacity and quality of the endoplasmic reticulum protein-folding machinery leads to β-cell death. The quality control of protein-folding is regulated by several signaling pathways, which are collectively termed the unfolded protein response. In β-cells proinsulin represents up to 50% of the total protein synthesis, and the rate of glucose-stimulated proinsulin translation is approximately 1 million molecules per minute per cell. When proinsulin folding is disrupted, the high burden imposed by proinsulin synthesis on the unfolded protein response is considered the leading cause of certain diabetes phenotypes. We have developed a model of the unfolded protein response to investigate the factors that can prevent misfolded protein accumulation. We also present predictions for therapeutic strategies to ameliorate pancreatic β-cell death in diabetes patients. Copyright (C) 2009 S. Karger AG, Basel