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

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

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Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
Division of Paediatric and Adolescent Medicine, Oslo University Hospital, and Faculty of Medicine, University of Oslo, Oslo, Norway.
Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA
Novo Nordisk Diabetes Research & Development Center, Seattle, WA.


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.

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