Fig. 8: Working model for glucagon receptor blockade resulting in hyperglucagonemia.
From: Blockade of glucagon receptor induces α-cell hypersecretion by hyperaminoacidemia in mice
a Upon glucagon receptor blockade, the organism increases its demand for glucagon. Several factors (particularly elevated amino acids), arise from the GCGR-deficient liver and act on pancreatic islets, leading to α cell hyperplasia and enhanced α cell secretion. All these changes collectively contribute to hyperglucagonemia. b Increased circulating amino acids (especially glutamine and alanine) activate the mTOR-STAT3 and ERK-CREB signaling pathways. STAT3 enhances VGF transcription, while CREB promotes both VGF and GCG expression. Consequently, glucagon granule biogenesis and glucagon secretion are significantly increased. Conversely, blocking amino acid-induced VGF expression by inhibiting mTOR or STAT3 activation reduces levels of the glucagon granule component VGF, thereby decreasing glucagon granule biogenesis and glucagon secretion.
