Chemical Identity

Property	Value
Name	Glucagon
Source	Pancreatic α-cells (islets of Langerhans)
Sequence	His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Thr
Length	29 amino acids
Chemical Formula	C₁₅₃H₂₂₅N₄₃O₄₉
Molecular Weight	3482.8 Da
PDB Structures	1GCN (NMR), 2MFR (NMR)

Structure

Glucagon is a linear peptide that adopts an α-helical conformation in membrane environments:

• N-terminal residues 1-8: Receptor binding
• Residues 9-20: α-helical segment, receptor activation
• C-terminal residues 21-29: Membrane association
• Key residue: His1 is essential for receptor activation

Receptor and Signaling

Glucagon Receptor (GCGR)

• Type: Class B G-protein coupled receptor
• Gene: GCGR (chromosome 17q25)
• Expression: Liver (primary), kidney, heart, adipose, brain
• G-protein: Gαs → adenylyl cyclase → cAMP → PKA

Signal Transduction

Glucagon → GCGR → Gαs → Adenylyl cyclase → cAMP
                                              ↓
                                        PKA activation
                                              ↓
                                    Phosphorylase kinase
                                              ↓
                                    Glycogen phosphorylase
                                              ↓
                                    Glycogen → Glucose-1-P → Glucose

Physiological Effects

Glucose Metabolism

• Glycogenolysis: Breaks down liver glycogen → glucose release
• Gluconeogenesis: Synthesizes glucose from amino acids, lactate, glycerol
• Net effect: Raises blood glucose levels

Lipid Metabolism

• Lipolysis: Activates hormone-sensitive lipase in adipose tissue
• Ketogenesis: Promotes ketone body production during fasting
• Fatty acid oxidation: Enhances hepatic fatty acid catabolism

Other Effects

• Cardiac: Increases heart rate and contractility (positive inotrope)
• Renal: Increases glomerular filtration rate
• GI: Reduces GI motility

Clinical Applications

Hypoglycemia Treatment

• Glucagon emergency kit: 1 mg IM/SC for severe hypoglycemia
• Nasal glucagon (Baqsimi): 3 mg intranasal
• Stable liquid glucagon (Gvoke): Ready-to-use formulation

Dual-Hormone Artificial Pancreas

• Insulin + glucagon delivery: Mimics physiological glucose regulation
• Advantage: Reduces hypoglycemia risk vs insulin-only systems
• Status: Research and clinical trials

Diagnostic Applications

• Glucagon stimulation test: Assesses adrenal function
• Glucagon test for pheochromocytoma: Provokes catecholamine release

Manufacturing

• Recombinant: E. coli expression, refolding, purification
• SPPS: Chemical synthesis (less common)
• Formulations: Lyophilized powder + diluent, stable liquid

References

1. Jelinek LJ, et al. “Cloning and expression of the glucagon receptor.” Diabetes 46:184-190, 1997. doi:10.2337/diab.46.2.184
2. Jiang G, Zhang BB. “Glucagon: a pivotal hormone in the metabolic syndrome.” Diabetes 52:1849-1856, 2003.
3. Unger RH, Orci L. “Glucagon and the α-cell: physiology and pathophysiology.” New England Journal of Medicine 304:1518-1524, 1981.
4. D’Alessio D. “The role of glucagon in the development of diabetes.” Diabetes 58:2432-2437, 2009.
5. Unger RH, et al. “Dual hormone artificial pancreas.” Diabetes Care 37:1-9, 2014.