Alpha cell dysfunction in type 1 diabetes is independent of a senescence program

Front Endocrinol (Lausanne). 2022 Oct 7:13:932516. doi: 10.3389/fendo.2022.932516. eCollection 2022.


Type 1 Diabetes (T1D) is caused by insulin deficiency, due to progressive autoimmune destruction of pancreatic β cells. Glucagon-secreting α cells become dysfunctional in T1D and contribute to pathophysiology, however, the mechanisms involved are unclear. While the majority of β cells are destroyed in T1D, some β cells escape this fate and become senescent but whether α cell dysfunction involves a senescence program has not been explored. Here we addressed the question of whether α cells become senescent during the natural history of T1D in the non-obese diabetic (NOD) mouse model and humans. NOD mice had several distinct subpopulations of α cells, but none were defined by markers of senescence at the transcriptional or protein level. Similarly, α cells of human T1D donors did not express senescence markers. Despite the lack of senescence in α cells in vivo, using a human islet culture model, we observed that DNA damage-induced senescence led to alterations in islet glucagon secretion, which could be rescued by inhibiting the senescence-associated secretory phenotype (SASP). Together our results suggest that α cell dysfunction in T1D is not due to activation of a senescence program, however, senescent β cell accumulation in the islet microenvironment may have a negative effect on α cell function.

Keywords: DNA damage response (DDR); Type 1 diabetes (T1D); alpha cells of pancreatic islet; glucagon secretion; senescence.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Diabetes Mellitus, Type 1* / metabolism
  • Glucagon / metabolism
  • Glucagon-Secreting Cells* / metabolism
  • Humans
  • Insulin / metabolism
  • Mice
  • Mice, Inbred NOD


  • Glucagon
  • Insulin
  • Biomarkers