For a new paradigm of diabetes

The main beta cell function is that of pre-proinsulin synthesis and of insulin exocytosis in a regulated manner. After the detachment of a small signal peptide, the remaining proinsulin molecule is transferred in the endoplasmic reticulum. During the emergence of the secretory vesicles and their maturation, proinsulin is split into insulin and C peptide. Diabetes mellitus is characterized by a poor maturation of secretory vesicles explaining the higher levels of proinsulin both in beta cells and in the plasma. The defect is associated to alterations in the exocytosis machinery, initially minor (disappearance of oscillatory pattern of insulin release, and/or the amputation of early phase of insulin response) and later major (a progressive decrease of the overall insulin response). Because the increase in plasma glucose levels is a late indicator of the diabetogenic process (a decrease with more than 50% of beta cell mass/function), we propose as marker of the prehyperglycaemia the high levels of plasma proinsulin or of the proinsulin/insulin ratio. In type 1 diabetes, the autoimmune destruction of beta cell mass will have a fast evolution, while in the type 2 phenotype, the same process takes a slower, but also progressive evolution. In both cases, the decrease in beta cell mass will be induced by an increased apoptosis and the decreased regeneration reaction.