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

作者：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 Briššová, Klaus H. Kaestner, Doris A. Stoffers · 发表于：Journal of Clinical Investigation · 年份：2022 · DOI：10.1172/jci156243 · 被引用次数：67 · 研究领域：Diabetes and associated disorders、Pancreatic function and diabetes、Diabetes Management and Research

BACKGROUNDMultiple 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.METHODSHere, we functionally, histologically, and molecularly phenotyped human islets from nondiabetic GADA+ and T1D donors.RESULTSSimilar 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.CONCLUSIONWe 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.FUNDINGThis work was supported by grants from the NIH (3UC4DK112217-01S1, U01DK123594-02, UC4DK112217, UC4DK112232, U01DK123716, and P30 DK01...