The Journal of Clinical Investigation (Jun 2022)

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

  • 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

Journal volume & issue
Vol. 132, no. 11

Abstract

Read online

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).

Keywords