Cargando…

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

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 autoant...

Descripción completa

Detalles Bibliográficos
Autores principales: Rodriguez-Calvo, Teresa, Zapardiel-Gonzalo, Jose, Amirian, Natalie, Castillo, Ericka, Lajevardi, Yasaman, Krogvold, Lars, Dahl-Jørgensen, Knut, von Herrath, Matthias G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399615/
https://www.ncbi.nlm.nih.gov/pubmed/28137793
http://dx.doi.org/10.2337/db16-1343
_version_ 1783230676947959808
author Rodriguez-Calvo, Teresa
Zapardiel-Gonzalo, Jose
Amirian, Natalie
Castillo, Ericka
Lajevardi, Yasaman
Krogvold, Lars
Dahl-Jørgensen, Knut
von Herrath, Matthias G.
author_facet Rodriguez-Calvo, Teresa
Zapardiel-Gonzalo, Jose
Amirian, Natalie
Castillo, Ericka
Lajevardi, Yasaman
Krogvold, Lars
Dahl-Jørgensen, Knut
von Herrath, Matthias G.
author_sort Rodriguez-Calvo, Teresa
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5399615
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher American Diabetes Association
record_format MEDLINE/PubMed
spelling pubmed-53996152018-05-01 Increase in Pancreatic Proinsulin and Preservation of β-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset Rodriguez-Calvo, Teresa Zapardiel-Gonzalo, Jose Amirian, Natalie Castillo, Ericka Lajevardi, Yasaman Krogvold, Lars Dahl-Jørgensen, Knut von Herrath, Matthias G. Diabetes Pathophysiology 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. American Diabetes Association 2017-05 2017-01-30 /pmc/articles/PMC5399615/ /pubmed/28137793 http://dx.doi.org/10.2337/db16-1343 Text en © 2017 by the American Diabetes Association. http://www.diabetesjournals.org/content/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
spellingShingle Pathophysiology
Rodriguez-Calvo, Teresa
Zapardiel-Gonzalo, Jose
Amirian, Natalie
Castillo, Ericka
Lajevardi, Yasaman
Krogvold, Lars
Dahl-Jørgensen, Knut
von Herrath, Matthias G.
Increase in Pancreatic Proinsulin and Preservation of β-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset
title Increase in Pancreatic Proinsulin and Preservation of β-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset
title_full Increase in Pancreatic Proinsulin and Preservation of β-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset
title_fullStr Increase in Pancreatic Proinsulin and Preservation of β-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset
title_full_unstemmed Increase in Pancreatic Proinsulin and Preservation of β-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset
title_short Increase in Pancreatic Proinsulin and Preservation of β-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset
title_sort increase in pancreatic proinsulin and preservation of β-cell mass in autoantibody-positive donors prior to type 1 diabetes onset
topic Pathophysiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399615/
https://www.ncbi.nlm.nih.gov/pubmed/28137793
http://dx.doi.org/10.2337/db16-1343
work_keys_str_mv AT rodriguezcalvoteresa increaseinpancreaticproinsulinandpreservationofbcellmassinautoantibodypositivedonorspriortotype1diabetesonset
AT zapardielgonzalojose increaseinpancreaticproinsulinandpreservationofbcellmassinautoantibodypositivedonorspriortotype1diabetesonset
AT amiriannatalie increaseinpancreaticproinsulinandpreservationofbcellmassinautoantibodypositivedonorspriortotype1diabetesonset
AT castilloericka increaseinpancreaticproinsulinandpreservationofbcellmassinautoantibodypositivedonorspriortotype1diabetesonset
AT lajevardiyasaman increaseinpancreaticproinsulinandpreservationofbcellmassinautoantibodypositivedonorspriortotype1diabetesonset
AT krogvoldlars increaseinpancreaticproinsulinandpreservationofbcellmassinautoantibodypositivedonorspriortotype1diabetesonset
AT dahljørgensenknut increaseinpancreaticproinsulinandpreservationofbcellmassinautoantibodypositivedonorspriortotype1diabetesonset
AT vonherrathmatthiasg increaseinpancreaticproinsulinandpreservationofbcellmassinautoantibodypositivedonorspriortotype1diabetesonset