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α Cell dysfunction in islets from nondiabetic, glutamic acid decarboxylase autoantibody–positive individuals

Authors :
Nicolai M. Doliba
Andrea V. Rozo
Jeffrey Roman
Wei Qin
Daniel Traum
Long Gao
Jinping Liu
Elisabetta Manduchi
Chengyang Liu
Maria L. Golson
Golnaz Vahedi
Ali Naji
Franz M. Matschinsky
Mark A. Atkinson
Alvin C. Powers
Marcela Brissova
Klaus H. Kaestner
Doris A. Stoffers
for the HPAP Consortium
Source :
The Journal of Clinical Investigation, Vol 132, Iss 11 (2022)
Publication Year :
2022
Publisher :
American Society for Clinical Investigation, 2022.

Abstract

BACKGROUND Multiple islet autoantibodies (AAbs) predict the development of type 1 diabetes (T1D) and hyperglycemia within 10 years. By contrast, T1D develops in only approximately 15% of individuals who are positive for single AAbs (generally against glutamic acid decarboxylase [GADA]); hence, the single GADA+ state may represent an early stage of T1D.METHODS Here, we functionally, histologically, and molecularly phenotyped human islets from nondiabetic GADA+ and T1D donors.RESULTS Similar to the few remaining β cells in the T1D islets, GADA+ donor islets demonstrated a preserved insulin secretory response. By contrast, α cell glucagon secretion was dysregulated in both GADA+ and T1D islets, with impaired glucose suppression of glucagon secretion. Single-cell RNA-Seq of GADA+ α cells revealed distinct abnormalities in glycolysis and oxidative phosphorylation pathways and a marked downregulation of cAMP-dependent protein kinase inhibitor β (PKIB), providing a molecular basis for the loss of glucose suppression and the increased effect of 3-isobutyl-1-methylxanthine (IBMX) observed in GADA+ donor islets.CONCLUSION We found that α cell dysfunction was present during the early stages of islet autoimmunity at a time when β cell mass was still normal, raising important questions about the role of early α cell dysfunction in the progression of T1D.FUNDING This work was supported by grants from the NIH (3UC4DK112217-01S1, U01DK123594-02, UC4DK112217, UC4DK112232, U01DK123716, and P30 DK019525) and the Vanderbilt Diabetes Research and Training Center (DK20593).

Subjects

Subjects :
Endocrinology
Medicine

Details

Language :
English
ISSN :
15588238
Volume :
132
Issue :
11
Database :
Directory of Open Access Journals
Journal :
The Journal of Clinical Investigation
Publication Type :
Academic Journal
Accession number :
edsdoj.4642c42951458c9cba96f40f54dcec
Document Type :
article
Full Text :
https://doi.org/10.1172/JCI156243