Increase in Pancreatic Proinsulin and Preservation of ?-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset.

ABSTRACT: Type 1 diabetes is characterized by the loss of insulin production caused by ?-cell dysfunction and/or destruction. The hypothesis that ?-cell loss occurs early during the prediabetic phase has recently been challenged. Here we show, for the first time in situ, that in pancreas sections from autoantibody-positive (Ab+) donors, insulin area and ?-cell mass are maintained before disease onset and that production of proinsulin increases. This suggests that ?-cell destruction occurs more precipitously than previously assumed. Indeed, the pancreatic proinsulin-to-insulin area ratio was also increased in these donors with prediabetes. Using high-resolution confocal microscopy, we found a high accumulation of vesicles containing proinsulin in ?-cells from Ab+ donors, suggesting a defect in proinsulin conversion or an accumulation of immature vesicles caused by an increase in insulin demand and/or a dysfunction in vesicular trafficking. In addition, islets from Ab+ donors were larger and contained a higher number of ?-cells per islet. Our data indicate that ?-cell mass (and function) is maintained until shortly before diagnosis and declines rapidly at the time of clinical onset of disease. This suggests that secondary prevention before onset, when ?-cell mass is still intact, could be a successful therapeutic strategy.

SUBMITTER: Rodriguez-Calvo T 

PROVIDER: S-EPMC5399615 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature