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

Area of Science:

• Endocrinology
• Cell Biology
• Diabetes Research

Background:

• Diabetes is characterized by abnormal glucagon secretion and insufficient beta cell mass.
• Glucagon receptor (GCGR) antagonism shows promise for diabetes treatment by reducing hyperglycemia and promoting beta cell regeneration.
• However, GCGR antagonism can lead to alpha and delta cell hyperplasia, necessitating further investigation into its effects on non-alpha islet cells.

Purpose of the Study:

• To investigate how blocking glucagon action influences pancreatic islet non-alpha cells.
• To assess the relevance of these mechanisms in human islets.
• To explore the potential of targeting non-alpha cell proliferation for diabetes therapies.

Main Methods:

• Utilized zebrafish, rodents, and transplanted human islets across six models of disrupted glucagon signaling.
• Examined the impact on delta and beta cell proliferation and mass.
• Employed models with global deficiency of cationic amino acid transporter SLC7A2 and mTORC1 inhibition with rapamycin to assess nutrient sensing requirements.

Main Results:

• Glucagon signaling inhibition stimulated delta cell proliferation in mouse and human islets, dependent on rapamycin and SLC7A2.
• GCGR deficiency enhanced beta cell proliferation via SLC7A2 and mTORC1 in zebrafish and promoted cell cycle entry in rodent beta cells.
• Despite promoting proliferation, GCGR deficiency did not significantly increase beta cell mass in mice.

Conclusions:

• Interruption of glucagon signaling increases islet non-alpha cell proliferation across species, mediated by SLC7A2 and mTORC1.
• The observed increase in delta cell mass presents a potential avenue for future beta cell regeneration strategies through delta cell reprogramming.