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Cell dysfunction in islets from nondiabetic, glutamic acid decarboxylase autoantibody-positive individuals
- Source :
- Journal of Clinical Investigation. June 1, 2022, Vol. 132 Issue 11
- Publication Year :
- 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.sup.+] state may represent an early stage of T1D. METHODS. Here, we functionally, histologically, and molecularly phenotyped human islets from nondiabetic [GADA.sup.+] and T1D donors. RESULTS. Similar to the few remaining [beta] cells in the T1D islets, [GADA.sup.+] donor islets demonstrated a preserved insulin secretory response. By contrast, [alpha] cell glucagon secretion was dysregulated in both [GADA.sup.+] and T1D islets, with impaired glucose suppression of glucagon secretion. Single-cell RNA-Seq of [GADA.sup.+] [alpha] cells revealed distinct abnormalities in glycolysis and oxidative phosphorylation pathways and a marked downregulation of cAMP-dependent protein kinase inhibitor p (PKIB), providing a molecular basis for the loss of glucose suppression and the increased effect of 3-isobutyl-1-methylxanthine (IBMX) observed in [GADA.sup.+] donor islets. CONCLUSION. We found that [alpha] cell dysfunction was present during the early stages of islet autoimmunity at a time when p cell mass was still normal, raising important questions about the role of early [alpha] 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).<br />Introduction Longitudinal studies have shown that individuals who are at high genetic risk for or have a family history of type 1 diabetes (T1D), who later develop diabetes, progress through [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 132
- Issue :
- 11
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.706296497
- Full Text :
- https://doi.org/10.1172/JCI156243