Type 1 diabetes is characterized by the loss of insulin production due to beta cell dysfunction and/or destruction. The hypothesis that beta cell loss occurs early during the pre-diabetic phase has recently been challenged. Here we show, for the first time in situ that in pancreas sections from autoantibody positive donors (Ab+) insulin area and beta cell mass are maintained prior to disease onset, and that production of proinsulin increases. This suggests that beta cell destruction occurs more precipitously than previously assumed. Indeed, the pancreatic proinsulin to insulin area ratio (PI /INS area ratio) was also increased in these prediabetic donors. Using high-resolution confocal microscopy we found a high accumulation of vesicles containing proinsulin in beta cells from Ab+ donors, suggesting either a defect in proinsulin conversion or an accumulation of immature vesicles due to an increase in insulin demand and/or to a dysfunction in vesicular trafficking. In addition, islets from Ab+ donors were larger and contained a higher number of beta cells per islet. Our data indicate that beta 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 beta cell mass is still intact, could be a successful therapeutic strategy.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-1343/-/DC1.
- Received July 10, 2016.
- Accepted January 26, 2017.
- © 2017 by the American Diabetes Association.