title: Increase in Pancreatic Proinsulin and Preservation of β-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset.
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.
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Rodriguez-Calvo
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
authors.forename: Jose
authors.initials: J
authors.lastname: Zapardiel-Gonzalo
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Amirian
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
authors.forename: Ericka
authors.initials: E
authors.lastname: Castillo
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA.
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Lajevardi
authors.affiliation: Division of Paediatric and Adolescent Medicine, Oslo University Hospital, and Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Krogvold
authors.affiliation: Division of Paediatric and Adolescent Medicine, Oslo University Hospital, and Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Knut
authors.initials: K
authors.lastname: Dahl-Jørgensen
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA matthias@lji.org mtvh@novonordisk.com.|Novo Nordisk Diabetes Research & Development Center, Seattle, WA.
authors.forename: Matthias G
authors.initials: MG
authors.lastname: von Herrath
mesh_terms: D000328:Adult; D001323:Autoantibodies; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D011236:Prediabetic State / Q000378:metabolism* / Q000473:pathology; D011384:Proinsulin / Q000378:metabolism*; D022161:Transport Vesicles / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D011384:Proinsulin