Interruption of glucagon signaling augments islet non-alpha cell proliferation in SLC7A2- and mTOR-dependent manners

Mol Metab. 2024 Dec:90:102050. doi: 10.1016/j.molmet.2024.102050. Epub 2024 Oct 20.

Abstract

Objective: Dysregulated glucagon secretion and inadequate functional beta cell mass are hallmark features of diabetes. While glucagon receptor (GCGR) antagonism ameliorates hyperglycemia and elicits beta cell regeneration in pre-clinical models of diabetes, it also promotes alpha and delta cell hyperplasia. We sought to investigate the mechanism by which loss of glucagon action impacts pancreatic islet non-alpha cells, and the relevance of these observations in a human islet context.

Methods: We used zebrafish, rodents, and transplanted human islets comprising six different models of interrupted glucagon signaling to examine their impact on delta and beta cell proliferation and mass. We also used models with global deficiency of the cationic amino acid transporter, SLC7A2, and mTORC1 inhibition via rapamycin, to determine whether amino acid-dependent nutrient sensing was required for islet non-alpha cell growth.

Results: Inhibition of glucagon signaling stimulated delta cell proliferation in mouse and transplanted human islets, and in mouse islets. This was rapamycin-sensitive and required SLC7A2. Likewise, gcgr deficiency augmented beta cell proliferation via SLC7A2- and mTORC1-dependent mechanisms in zebrafish and promoted cell cycle engagement in rodent beta cells but was insufficient to drive a significant increase in beta cell mass in mice.

Conclusions: Our findings demonstrate that interruption of glucagon signaling augments islet non-alpha cell proliferation in zebrafish, rodents, and transplanted human islets in a manner requiring SLC7A2 and mTORC1 activation. An increase in delta cell mass may be leveraged for future beta cell regeneration therapies relying upon delta cell reprogramming.

Keywords: Beta cell; Delta cell; Glucagon receptor; Pancreatic islet; Proliferation; mTOR.

MeSH terms

  • Animals
  • Cell Proliferation*
  • Glucagon* / metabolism
  • Glucagon-Secreting Cells / metabolism
  • Humans
  • Insulin-Secreting Cells* / metabolism
  • Islets of Langerhans / metabolism
  • Islets of Langerhans Transplantation
  • Large Neutral Amino Acid-Transporter 1 / genetics
  • Large Neutral Amino Acid-Transporter 1 / metabolism
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Rats
  • Receptors, Glucagon / antagonists & inhibitors
  • Receptors, Glucagon / metabolism
  • Signal Transduction*
  • TOR Serine-Threonine Kinases* / metabolism
  • Zebrafish*

Substances

  • Glucagon
  • TOR Serine-Threonine Kinases
  • Large Neutral Amino Acid-Transporter 1
  • Receptors, Glucagon
  • Mechanistic Target of Rapamycin Complex 1