The β-cell in human type 2 diabetes

Abstract

β-cell dysfunction is central to the onset and progression of type 2 diabetes. Reduced islet number and/or diminished β-cell mass/volume in the pancreas of type 2 diabetic subjects have been reported by many authors, mainly due to increased apoptosis not compensated for by adequate regeneration. In addition, ultrastructural analysis has shown reduced insulin granules and morphological changes in several β-cell organelles, including mitochondria and endoplasmic reticulum. Several quantitative and qualitative defects of β-cell function have been described in human type 2 diabetes using isolated islets, including alterations in early phase and glucose-stimulated insulin release. These survival and functional changes are accompanied by modifications of islet gene and protein expression. The impact of genotype in affecting β-cell function and survival has been addressed in a few studies, and a number of gene variants have been associated with β-cell dysfunction. Among acquired factors, the role of glucotoxicity and lipotoxicity could be of particular importance, due to the potential deleterious impact of elevated levels of glucose and/or free fatty acids in the natural history of β-cell damage. More recently, it has been proposed that inflammation might also play a role in the dysfunction of the β-cell in type 2 diabetes. Encouraging, although preliminary, data show that some of these defects might be directly counteracted, at least in part, by appropriate in vitro pharmacological intervention.