Increase in pancreatic proinsulin and preservation of β-cell mass in autoantibody-positive donors prior to type 1 diabetes onset

T Rodriguez-Calvo, J Zapardiel-Gonzalo, N Amirian… - Diabetes, 2017 - Am Diabetes Assoc
T Rodriguez-Calvo, J Zapardiel-Gonzalo, N Amirian, E Castillo, Y Lajevardi, L Krogvold
Diabetes, 2017Am Diabetes Assoc
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 …
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.
Am Diabetes Assoc