Glucagon stimulates hepatic glucose production (HGP) and induces hypertension by attaching to the Gcgr receptor and initiating cAMP-PKA signaling [1]. Insulin hypertensive hormone (100 nM) suppresses CYP7A1 mRNA expression in human primary cells. Glucagon enhances blood glucose Kisspeptin1 synthesis and gluconeogenesis [1–3]. The phosphorylation layer of HNF4α is increased by insulin (100 nM).Cell Lines. Phosphorylated HNF4α is significantly increased in human primary hepatocytes (H1211, HH1215) at a concentration of 100 nM over the course of the incubation period.

Low glucagon doses (20 μg/kg) do not save ecologically fed elephants; instead, they cause hypertension.

Western Blot Analysis[3]
Cell Types: Human primary hepatocytes (H1211, HH1215)
Tested Concentrations: 100 nM
Incubation Duration:
Experimental Results: Results in a significant increase in the amount of phosphorylated HNF4α.

Animal/Disease Models: C57BL/6J mice (12- to 24 weeks old) [4]
Doses: 20 μg/kg and 1 mg/kg
Route of Administration: administered by ip injection; insulin [4]. 45 min
Experimental Results: Low dose (20 μg/kg) increases blood glucose but does not stimulate insulin secretion. High doses (1 mg/kg) lower blood sugar and stimulate insulin secretion.

Absorption, Distribution and Excretion
A 1mg intravenous dose of glucagon reaches a Cmax of 7.9ng/mL with a Tmax of 20 minutes. An intramuscular dose reaches a Cmax of 6.9ng/mL with a Tmax of 13 minutes. A 3mg dose of glucagon nasal powder reaches a Cmax of 6130pg/mL with a Tmax of 15 minutes.
Elimination of glucagon is not fully characterized in literature, however the kidney and liver appear to contribute significantly in animal models. The liver and kidney are responsible for approximately 30% of glucagon elimination each.
The volume of distribution of glucagon is 0.25L/kg. The apparent volume of distribution is 885L.
A 1mg intravenous dose of glucagon has a clearance of 13.5mL/min/kg.
Because of its polypeptide nature, glucagon is destroyed in the GI tract, and therefore must be administered parenterally.

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Metabolism / Metabolites
Glucagon is a protein and so it is metabolized into smaller polypeptides and amino acids in the liver, kidney, and plasma.

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Biological Half-Life
The half life of glucagon is 26 minutes for an intramuscular dose. The half life of glucagon nasal powder is approximately 35 minutes. The half life of glucagon by a subcutaneous auto-injector or pre-filled syringe is 32 minutes.
Glucagon has a plasma half-life of about 3-10 minutes.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of glucagon during breastfeeding. Because glucagon is a large protein molecule with a molecular weight of 3483 Da, the amount in milk is likely to be very low and absorption is unlikely because it is probably destroyed in the infant's gastrointestinal tract. Glucagon has also been safely given directly to infants by injection. No special precautions are required.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Glucagon has not been described in the literature as bound to a protein in serum.

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Interactions
HYPERGLYCEMIC EFFECT OF GLUCAGON IS INCREASED & PROLONGED BY SIMULTANEOUS ADMIN OF EPINEPHRINE.
When glucagon is administered concomitantly with an antimuscarinic the response is not substantially greater than when either drug is used alone; however, the addition of the antimuscarinic results in adverse effects.
Concurrent use /of coumarin- or indandione-derivative anticoagulants/ with glucagon may potentiate the anticoagulant effects; enhanced anticoagulant activity has been reported with unusually high doses such as 25 mg or more per day for 2 or more days.

[1]. Glucagon regulates hepatic kisspeptin to impair insulin secretion. Cell Metab. 2014 Apr 1;19(4):667-81.

[2]. Hepatocyte nuclear factor-4 is a novel downstream target of insulin via FKHR as a signal-regulated transcriptional inhibitor. J Biol Chem. 2003 Apr 11;278(15):13056-60.

[3]. Glucagon and cAMP inhibit cholesterol 7alpha-hydroxylase (CYP7A1) gene expression in humanhepatocytes: discordant regulation of bile acid synthesis and gluconeogenesis. Hepatology. 2006 Jan;43(1):117-25.

[4]. Glucagon lowers glycemia when β-cells are active. JCI Insight. 2019 Jul 23;5. pii: 129954.

Glucagon is a 29-amino acid peptide hormone consisting of 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, Asn and Thr residues joined in sequence.
Glucagon is a 29 amino acid hormone used as a diagnostic aid in radiologic exams to temporarily inhibit the movement of the gastrointestinal tract and to treat severe hypoglycemia. Glucagon raises blood sugar through activation of hepatic glucagon receptors, stimulating glycogenolysis and the release of glucose. Glucagon was granted FDA approval on 14 November 1960.
Recombinant Glucagon is the recombinant form of the endogenous polypeptide hormone Glucagon consisting of 29 amino acids responsible for the release of stored glucose, causing increased blood glucose levels. Clinical Use: Diagnostic Aid for Imaging Studies and Hypoglycemia.
A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal GLUCAGON-LIKE PEPTIDES. Glucagon is secreted by PANCREATIC ALPHA CELLS and plays an important role in regulation of BLOOD GLUCOSE concentration, ketone metabolism, and several other biochemical and physiological processes. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, p1511)
See also: Glucagon Hydrochloride (has salt form) ... View More ...

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Drug Indication
Glucagon is indicated as a diagnostic aid in radiologic exams to temporarily inhibit the movement of the gastrointestinal tract and to treat severe hypoglycemia.
FDA Label
Ogluo is indicated for the treatment of severe hypoglycaemia in adults, adolescents, and children aged 2 years and over with diabetes mellitus.
Baqsimi is indicated for the treatment of severe hypoglycaemia in adults, adolescents, and children aged 4 years and over with diabetes mellitus.
Treatment of hypoglycaemia

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Mechanism of Action
Glucagon binds to the glucagon receptor activating G_sα and G_q. This activation activates adenylate cyclase, which increases intracellular cyclic AMP and activates protein kinase A. Activating G_q activates phospholipase C, increases production of inositol 1,4,5-triphosphate, and releases intracellular calcium. Protein kinase A phosphorylates glycogen phosphorylase kinase, which phosphorylates glycogen phosphorylase, which phosphorylates glycogen, causing its breakdown. Glucagon also relaxes smooth muscle of the stomach, duodenum, small bowel, and colon.
Glucagon increases the blood glucose concentration by mobilizing hepatic glycogen and thus is effective only when hepatic glycogen is available. Patients with reduced glycogen stores (eg, starvation, adrenal insufficiency, alcoholic hypoglycemia) cannot respond to glucagon.
Glucagon produces extra hepatic effects that are independent of its hyperglycemic action. Although the exact mechanism(s) of action has not been conclusively determined, glucagon produces relaxation of smooth muscle of the stomach, duodenum, small intestine, and colon. The drug has also been shown to inhibit gastric and pancreatic secretions.
Promotes hepatic glycogenolysis and gluconeogenesis. Stimulates adenylate cyclase to produce increased cyclic-AMP, which is involved in a series of enzymatic activities. The resultant effects are increased concentrations of plasma glucose, a relaxant effect on smooth musculature, and an inotropic myocardial effect. Hepatic stores of glycogen are necessary for glucagon to elicit an antihypoglycemic effect.

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Therapeutic Uses
Gastrointestinal Agents; Protein Synthesis Inhibitors
Glucagon is used in the treatment of lower esophageal obstruction due to foreign bodies, including food boluses. /NOT included in US product labeling/
Glucagon may be of use in treating myocardial depression due to calcium channel blocking agents in those patients in whom conventional therapies have been ineffective. /NOT included in US product labeling/
Glucagon administered in large intravenous doses is used to treat the cardiotoxic effects, specifically bradycardia and hypotension, in overdoses of beta-adrenergic blocking agents. Glucagon may be used with the proterenol or dobutamine. Supplemental potassium may be necessary for treated patients since glucagon tends to reduce serum potassium. /NOT included in US product labeling/
For more Therapeutic Uses (Complete) data for GLUCAGON (19 total), please visit the HSDB record page.

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Drug Warnings
...EFFECTIVE ONLY WHEN ADMIN PARENTERALLY. ITS HYPERGLYCEMIC EFFECT IS...OF RELATIVELY BRIEF DURATION. .../SUPPLEMENTARY CARBOHYDRATES SHOULD BE GIVEN AS SOON AS POSSIBLE AFTER PATIENT RESPONDS/. AN ADDITIONAL SUGAR SOURCE IS ESPECIALLY IMPORTANT IN JUVENILES...
Since glucagon is a protein, the possibility of hypersensitivity reactions should be considered.
Side/Adverse Effects: Those indicating need for medical attention only if they continue or are bothersome: Nausea or vomiting - incidence is generally dependent upon dose and (with intravenous use) the rate of injection; these effects may be diminished by slower intravenous administration.
Glucagon should not be used to treat birth asphyxia or hypoglycemia in premature infants or in infants who have had intrauterine growth retardation.
Glucagon has been used as an aid in the diagnosis of insulinoma and pheochromocytoma; however, USP advisory panels do not generally recommend this use because of questions about safety.

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Pharmacodynamics
Glucagon is indicated as a diagnostic aid in radiologic exams to temporarily inhibit the movement of the gastrointestinal tract and severe hypoglycemia. Glucagon raises blood sugar through activation of hepatic glucagon receptors, stimulating glycogenolysis and the release of glucose. Glucagon has a short duration of action. Glucagon may cause hyperglycemia in diabetic patients.

C153H229CL4N43O49S

3628.627

3480.615

16941-32-5

Glucagon (1-29), bovine, human, porcine hydrochloride;28270-04-4

16132283

White to off-white solid powder

1.5±0.1 g/cm3

1.682

-6.01

55

55

115

246

8160

31

Glucagon HCl Glucagon hydrochloride, Porcine glucagon hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~6.67 mg/mL (~1.92 mM)
DMSO : ~2 mg/mL (~0.57 mM)

Solubility in Formulation 1: ≥ 0.2 mg/mL (0.06 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 2.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 0.2 mg/mL (0.06 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 2.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)