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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.

Author information

1
Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
2
Division of Paediatric and Adolescent Medicine, Oslo University Hospital, and Faculty of Medicine, University of Oslo, Oslo, Norway.
3
Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA matthias@lji.org mtvh@novonordisk.com.
4
Novo Nordisk Diabetes Research & Development Center, Seattle, WA.

Abstract

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.

PMID:
28137793
PMCID:
PMC5399615
DOI:
10.2337/db16-1343
[Indexed for MEDLINE]
Free PMC Article

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