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

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 alpha cells in the T1D islets, GADA(+) donor islets demonstrated a preserved insulin secretory response. By contrast, alpha cell glucagon secretion was dysregulated in both GADA(+) and T1D islets, with impaired glucose suppression of glucagon secretion. Single-cell RNA-Seq of GADA(+) alpha cells revealed distinct abnormalities in glycolysis and oxidative phosphorylation pathways and a marked downregulation of cAMP-dependent protein kinase inhibitor alpha (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 alpha cell dysfunction was present during the early stages of islet autoimmunity at a time when alpha cell mass was still normal, raising important questions about the role of early alpha cell dysfunction in the progression of T1D.