Conversion of the death inhibitor ARC to a killer activates pancreatic β cell death in diabetes

Dev Cell. 2021 Mar 22;56(6):747-760.e6. doi: 10.1016/j.devcel.2021.02.011. Epub 2021 Mar 4.

Abstract

Loss of insulin-secreting pancreatic β cells through apoptosis contributes to the progression of type 2 diabetes, but underlying mechanisms remain elusive. Here, we identify a pathway in which the cell death inhibitor ARC paradoxically becomes a killer during diabetes. While cytoplasmic ARC maintains β cell viability and pancreatic architecture, a pool of ARC relocates to the nucleus to induce β cell apoptosis in humans with diabetes and several pathophysiologically distinct mouse models. β cell death results through the coordinate downregulation of serpins (serine protease inhibitors) not previously known to be synthesized and secreted by β cells. Loss of the serpin α1-antitrypsin from the extracellular space unleashes elastase, triggering the disruption of β cell anchorage and subsequent cell death. Administration of α1-antitrypsin to mice with diabetes prevents β cell death and metabolic abnormalities. These data uncover a pathway for β cell loss in type 2 diabetes and identify an FDA-approved drug that may impede progression of this syndrome.

Keywords: ARC; alpha-1 antitrypsin; cell death; diabetes; serpins.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / physiology
  • Apoptosis*
  • Cell Nucleus / metabolism*
  • Cytoplasm / metabolism
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Diabetes Mellitus, Experimental / etiology
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology*
  • Diabetes Mellitus, Type 2 / etiology
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology*
  • Female
  • Humans
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Proteins / physiology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • alpha 1-Antitrypsin / chemistry*
  • alpha 1-Antitrypsin / genetics
  • alpha 1-Antitrypsin / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Cytoskeletal Proteins
  • Muscle Proteins
  • Nerve Tissue Proteins
  • Nol3 protein, mouse
  • activity regulated cytoskeletal-associated protein
  • alpha 1-Antitrypsin