Blockade of glucagon receptor induces α-cell hypersecretion by hyperaminoacidemia in mice

Area of Science:

• Endocrinology
• Molecular Biology
• Cell Biology

Background:

• Glucagon receptor (GCGR) blockade improves glycemic control but causes adverse effects like alpha-cell hyperplasia and hyperglucagonemia.
• The molecular mechanisms driving these side effects remain unclear.

Purpose of the Study:

• To investigate the mechanisms underlying hyperglucagonemia in mice lacking functional glucagon receptors.
• To identify molecular players involved in the side effects of glucagon receptor blockade therapy.

Main Methods:

• Single-cell transcriptomic sequencing of islets from glucagon receptor knockout (GCGR-KO) mice.
• Analysis of gene expression, specifically Gcg and Vgf, in alpha cells.
• Investigating the role of VGF in glucagon secretion and maturation.
• Examining the involvement of mTOR-STAT3 and ERK-CREB signaling pathways.

Main Results:

• GCGR-KO mice exhibit elevated Gcg expression and enhanced single-cell glucagon secretion.
• Vgf (nerve growth factor inducible) is significantly upregulated in alpha cells of GCGR-KO mice.
• VGF inhibition impairs glucagon granule formation and maturation, reducing hypersecretion.
• Elevated amino acids activate mTOR-STAT3 and ERK-CREB pathways, upregulating Vgf and Gcg expression.

Conclusions:

• Vgf plays a critical role in mediating hyperglucagonemia following glucagon receptor blockade.
• The mTOR-STAT3 and ERK-CREB pathways, activated by amino acids, contribute to Vgf and Gcg upregulation.
• These findings elucidate key molecular mechanisms contributing to hyperglucagonemia in GCGR blockade therapy.