Mapping Glucagon Resistance Beyond the Pancreas: A Multi-Organ Transcriptomic Characterization of the GCGR–cAMP–PKA–CREB Axis

Introduction Glucagon dysregulation is increasingly recognized as a contributor to metabolic disease, yet glucagon resistance has been investigated predominantly as a hepatic phenomenon. However, whether the molecular architecture of glucagon signaling extends across multiple metabolic organs remains incompletely characterized. Objective To map the tissue-expression architecture of the glucagon receptor–cyclic AMP–protein kinase A–cAMP response element-binding protein (GCGR–cAMP–PKA–CREB) axis across the pancreas, liver, kidney, adipose tissue, and skeletal muscle and to explore its implications for multi-organ glucagon resistance. Methods This in silico systems-biology study analyzed publicly available human transcriptomic resources. Eighteen genes representing receptor, proximal transducer, intermediate effector, and downstream transcriptional components of the GCGR–cAMP–PKA–CREB pathway were curated from the KEGG glucagon signaling pathway. Tissue-level expression patterns were examined using GTEx data across five metabolically relevant tissues and interpreted alongside published protein-expression evidence. Results GCGR displayed the most tissue-restricted expression pattern, with high expression in liver, moderate-to-high expression in kidney cortex, and low expression in subcutaneous adipose tissue and skeletal muscle. Whole-pancreas GCGR expression was comparatively low, consistent with dilution of endocrine transcripts by the predominant exocrine compartment. In contrast, GNAS, adenylate cyclases, PKA subunits, CREB1, and CRTC2 were broadly expressed across tissues. PPARGC1A showed a distinct terminal-effector distribution, being relatively prominent in kidney and skeletal muscle but lower in liver and pancreas. Conclusion The GCGR–cAMP–PKA–CREB axis exhibits a receptor-centered, asymmetric multi-organ expression architecture. These findings support receptor availability and tissue-specific transcriptional output as potential determinants of susceptibility to glucagon resistance and provide a framework for future donor-matched and cell-resolved validation of a pancreatic-to-peripheral molecular continuum.