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

Diabetes. 2017 May;66(5):1334-1345. doi: 10.2337/db16-1343. Epub 2017 Jan 30.


Type 1 diabetes is characterized by the loss of insulin production caused by β-cell dysfunction and/or destruction. The hypothesis that β-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 β-cell mass are maintained before disease onset and that production of proinsulin increases. This suggests that β-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 β-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 β-cells per islet. Our data indicate that β-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 β-cell mass is still intact, could be a successful therapeutic strategy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Autoantibodies
  • Case-Control Studies
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetes Mellitus, Type 1 / pathology
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Male
  • Microscopy, Confocal
  • Middle Aged
  • Pancreas / metabolism*
  • Pancreas / pathology
  • Prediabetic State / metabolism*
  • Prediabetic State / pathology
  • Proinsulin / metabolism*
  • Transport Vesicles / metabolism
  • Transport Vesicles / pathology
  • Young Adult


  • Autoantibodies
  • Proinsulin