Peptide hormone; Glucagon receptor (GCGR) and Glucagon-like peptide-1 receptor (GLP-1R).

Glucagon exerts its effects by binding to G-protein-coupled glucagon receptors (GCGR) predominantly expressed in hepatocytes . This binding activates adenylate cyclase, increasing intracellular cyclic AMP (cAMP) levels, which in turn stimulates glycogenolysis and gluconeogenesis to release glucose from liver glycogen stores . Glucagon has also been shown to stimulate adipose lipolysis and myocardial contractility, though some evidence suggests these effects may require pharmacological concentrations above 0.1 nM .

In Vivo Activity
When administered for severe hypoglycemia, glucagon typically raises blood glucose within 10 minutes, with time to maximum glucose concentration ranging from 5-20 minutes (IV) to 30 minutes (IM) . The median glucose excursion ranges from 2.6 to 6.2 mmol/L depending on dose and baseline glucose levels . Glucagon also relaxes gastrointestinal smooth muscle within 1 minute (IV) or 5-15 minutes (IM), with duration of 5-40 minutes . The intranasal formulation (3 mg) is also effective, with over 99% of hypoglycemic patients achieving treatment success .

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Pharmacokinetics
Glucagon has a very short half-life of approximately 3-6 minutes in blood, with a metabolic clearance rate of about 10 mL/kg/min . After subcutaneous administration, peak plasma concentration is reached within 10-20 minutes, and the half-life is approximately 42 minutes (SC) or 26 minutes (IM) . The liver and kidney are the major sites of clearance, each contributing about 30% to overall metabolic clearance . The absolute bioavailability of intranasal glucagon is approximately 16% relative to injectable formulations . After intraperitoneal administration, time to peak concentration is approximately 11 minutes, with an elimination half-life of about 19 minutes .

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Toxicity
The most common adverse effect of glucagon is nausea, occurring in up to 35% of patients . Hypertension may occur for up to 2 hours following administration, particularly during gastrointestinal procedures . Less common adverse reactions include vomiting, headache, and rare hypersensitivity reactions (including anaphylaxis) due to its protein structure . Glucagon is contraindicated in patients with pheochromocytoma and those with known hypersensitivity . It is pregnancy category B, with no special precautions needed during breastfeeding due to its high molecular weight .

Absorption, Distribution and Excretion
Following intravenous injection of 1 mg glucagon, the peak plasma concentration (Cmax) was 7.9 ng/mL, and the time to peak concentration (Tmax) was 20 minutes. Following intramuscular injection of 1 mg glucagon, the peak plasma concentration (Cmax) was 6.9 ng/mL, and the time to peak concentration (Tmax) was 13 minutes. Following nasal administration of 3 mg glucagon powder, the peak plasma concentration (Cmax) was 6130 pg/mL, and the time to peak concentration (Tmax) was 15 minutes. The elimination pathway of glucagon is not fully elucidated in the literature, but animal models show that the kidneys and liver play significant roles in its clearance. The liver and kidneys are each responsible for clearing approximately 30% of glucagon. The volume of distribution of glucagon is 0.25 L/kg. The apparent volume of distribution is 885 liters. The clearance rate of 1 mg intravenously administered glucagon is 13.5 mL/min/kg.
Because glucagon is a polypeptide, it is destroyed in the gastrointestinal tract and must therefore be administered via parenteral route.

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

Biological Half-Life
The half-life of intramuscularly administered glucagon is 26 minutes. The half-life of nasal glucagon powder is approximately 35 minutes. The half-life of glucagon administered via subcutaneous auto-injector or pre-filled syringe is 32 minutes.
The plasma half-life of glucagon is approximately 3–10 minutes.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Currently, there is no clinical information regarding the use of glucagon during lactation. Because glucagon is a large protein molecule with a molecular weight of 3483 Da, its concentration in breast milk is likely very low, and it is unlikely to be absorbed as it is likely to be destroyed in the infant's gastrointestinal tract. Glucagon can also be safely administered directly to the infant by injection. No special precautions are required.
◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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Protein Binding
The binding of glucagon to proteins in serum is not described in the literature.

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Interactions
Concurrent administration of adrenaline can enhance and prolong the hyperglycemic effect of glucagon.
When glucagon is used concurrently with anticholinergic drugs, the response is not significantly enhanced compared to using either drug alone; however, the addition of an anticholinergic drug can lead to adverse reactions.
Concurrent use of coumarin or indanedione derivative anticoagulants and glucagon may enhance anticoagulation; it has been reported that abnormally high doses (e.g., 25 mg or more daily for 2 days or longer) can enhance anticoagulant activity.

[1]. Bromer WW, Chance RE. Zinc glucagon depression of blood amino acids in rabbits. Diabetes. 1969 Nov;18(11):748-54.

Glucagon is a peptide hormone composed of 29 amino acids, with the following amino acid residues in order: 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. Glucagon is a hormone composed of 29 amino acids that can be used as an adjunct diagnostic agent in radiological examinations, temporarily inhibit gastrointestinal motility, and treat severe hypoglycemia. Glucagon raises blood glucose levels by activating hepatic glucagon receptors, stimulating glycogenolysis and glucose release. Glucagon was approved by the U.S. Food and Drug Administration (FDA) on November 14, 1960.
Recombinant glucagon is a recombinant form of the endogenous polypeptide hormone glucagon, composed of 29 amino acids. It is responsible for releasing stored glucose, thereby raising blood glucose levels. Clinical applications: imaging examinations and auxiliary diagnosis of hypoglycemia.
Glucagon is a pancreatic peptide composed of 29 amino acids, derived from proglucagon, and is also a precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic α cells and plays an important role in regulating blood glucose concentration, ketone body metabolism, and many other biochemical and physiological processes. (Excerpt from Gilman et al., Goodman and Gilman's Pharmacological Basis, 9th ed., p. 1511)
See also: Glucagon hydrochloride (salt form)...see more...

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Drug Indications
Glucagon is suitable for auxiliary diagnosis in radiological examinations, can temporarily inhibit gastrointestinal motility, and is used to treat severe hypoglycemia.
FDA Label
Ogluo is indicated for the treatment of severe hypoglycemia in adults, adolescents, and children aged 2 years and older with diabetes.
Baqsimi is indicated for the treatment of severe hypoglycemia in adults, adolescents, and children aged 4 years and older with diabetes.
Treatment of Hypoglycemia
Mechanism of Action

Glucagon binds to glucagon receptors, activating… Activation of G_sα and G_q activates adenylate cyclase, thereby increasing intracellular levels of cyclic adenosine monophosphate (cAMP) and activating protein kinase A. Activation of G_q activates phospholipase C, increasing the production of inositol 1,4,5-triphosphate and releasing intracellular calcium ions. Protein kinase A phosphorylates glycogen phosphorylase kinase, which in turn phosphorylates glycogen phosphorylase, leading to glycogenolysis. Glucagon also relaxes the smooth muscle of the stomach, duodenum, small intestine, and colon.
Glucagon increases blood glucose levels by mobilizing liver glycogen, and is therefore only effective when liver glycogen is adequate. Patients with depleted glycogen reserves (e.g., starvation, adrenal insufficiency, alcoholic hypoglycemia) do not respond to glucagon.
In addition to its blood glucose-raising effect, glucagon also produces extrahepatic effects. Although its exact mechanism of action is not fully understood, glucagon relaxes the smooth muscle of the stomach, duodenum, small intestine, and colon. The drug has also been shown to inhibit the secretion of gastric and pancreatic juices.
It promotes liver glycogenolysis and gluconeogenesis. It stimulates adenylate cyclase to produce more cyclic adenosine monophosphate (cAMP), which participates in a series of enzymatic reactions. Ultimately, this leads to increased plasma glucose levels, smooth muscle relaxation, and myocardial contractility. Glycogen stored in the liver is essential for glucagon to exert its antihyperglycemic effect.
Therapeutic Uses

Gastrointestinal drug; protein synthesis inhibitor
Glucagon is used to treat lower esophageal obstruction caused by foreign bodies (including food boluses). /Not included in US product label/
For patients unresponsive to conventional therapy, glucagon may be used to treat myocardial depression caused by calcium channel blockers. /Not included in US product label/
High-dose intravenous glucagon is used to treat cardiotoxicity caused by overdose of beta-adrenergic blockers, particularly bradycardia and hypotension. Glucagon may be used in combination with isoproterenol or dobutamine. Because glucagon lowers serum potassium levels, patients receiving treatment may require potassium supplementation. /Not included in US product label/
For more complete data on the therapeutic uses of glucagon (19 in total), please visit the HSDB record page.

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Drug Warnings
…Effective only with parenteral administration. Its hyperglycemic effect is relatively short-lived. …/Patients should be given carbohydrates as soon as possible after a reaction/. Sugar supplementation is especially important for adolescents…
Because glucagon is a protein, the possibility of allergic reactions should be considered. Side effects/adverse reactions: Medical attention is only necessary if symptoms persist or are bothersome: nausea or vomiting—incidence usually depends on the dose and (when administered intravenously) the rate of injection; slowing the rate of intravenous injection can reduce these reactions. Glucagon should not be used to treat birth asphyxia or hypoglycemia in premature infants or infants with intrauterine growth restriction. Glucagon has been used as an adjunct in the diagnosis of insulinomas and pheochromocytomas; however, due to safety concerns, the United States Pharmacopeia (USP) Advisory Panel generally does not recommend this use. Pharmacodynamics: Glucagon is indicated for adjunctive diagnosis during radiological examinations and may temporarily suppress gastrointestinal motility and cause severe hypoglycemia. Glucagon raises blood glucose levels by activating hepatic glucagon receptors, stimulating glycogenolysis and glucose release. The duration of action of glucagon is short. Glucagon may cause hyperglycemia in diabetic patients.

C153H225N43O49S

3482.74729999998

3516.59

9007-92-5

Glucagon HCl; 28270-04-4; Glucagon (Human) (Glukagon; Hyperglycemic-glycogenolytic factor); 9007-92-5; Glucagon 4HCl; 16941-32-5; Glucagon (1-29), bovine, human, porcine; 16941-32-5;

16132283

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-Thr

HSQGTFTSDYSKYLDSRRAQDFVQWLMNT

FINE, WHITE OR FAINTLY COLORED, CRYSTALLINE POWDER

230ºC at 760 mm Hg

-15ºC

0.391

55

55

115

246

8160

31

C12C=CC=CC=1NC=C2C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@H](C(=O)O)[C@H](O)C)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](NC(=O)[C@H]([C@H](O)C)NC(=O)CNC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1N=CNC=1)CC1C=CC=CC=1)CC1C=CC(O)=CC=1)CC1=CC=C(O)C=C1)CC1=CC=CC=C1.Cl

MASNOZXLGMXCHN-ZLPAWPGGSA-N

InChI=1S/C153H225N43O49S/c1-72(2)52-97(133(226)176-96(47-51-246-11)132(225)184-104(60-115(159)209)143(236)196-123(78(10)203)151(244)245)179-137(230)103(58-83-64-167-89-29-19-18-28-87(83)89)183-131(224)95(43-46-114(158)208)177-148(241)120(74(5)6)194-141(234)101(54-79-24-14-12-15-25-79)182-138(231)105(61-117(211)212)185-130(223)94(42-45-113(157)207)171-124(217)75(7)170-127(220)91(31-22-49-165-152(160)161)172-128(221)92(32-23-50-166-153(162)163)174-146(239)110(69-199)191-140(233)107(63-119(215)216)186-134(227)98(53-73(3)4)178-135(228)99(56-81-33-37-85(204)38-34-81)180-129(222)90(30-20-21-48-154)173-145(238)109(68-198)190-136(229)100(57-82-35-39-86(205)40-36-82)181-139(232)106(62-118(213)214)187-147(240)111(70-200)192-150(243)122(77(9)202)195-142(235)102(55-80-26-16-13-17-27-80)188-149(242)121(76(8)201)193-116(210)66-168-126(219)93(41-44-112(156)206)175-144(237)108(67-197)189-125(218)88(155)59-84-65-164-71-169-84/h12-19,24-29,33-40,64-65,71-78,88,90-111,120-123,167,197-205H,20-23,30-32,41-63,66-70,154-155H2,1-11H3,(H2,156,206)(H2,157,207)(H2,158,208)(H2,159,209)(H,164,169)(H,168,219)(H,170,220)(H,171,217)(H,172,221)(H,173,238)(H,174,239)(H,175,237)(H,176,226)(H,177,241)(H,178,228)(H,179,230)(H,180,222)(H,181,232)(H,182,231)(H,183,224)(H,184,225)(H,185,223)(H,186,227)(H,187,240)(H,188,242)(H,189,218)(H,190,229)(H,191,233)(H,192,243)(H,193,210)(H,194,234)(H,195,235)(H,196,236)(H,211,212)(H,213,214)(H,215,216)(H,244,245)(H4,160,161,165)(H4,162,163,166)/t75-,76+,77+,78+,88-,90-,91-,92-,93-,94-,95-,96-,97-,98-,99-,100-,101-,102-,103-,104-,105-,106-,107-,108-,109-,110-,111-,120-,121-,122-,123-/m0/s1

(3S)-3-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]amino]-5-oxopentanoyl]amino]-4-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-amino-1-[[(1S,2R)-1-carboxy-2-hydroxypropyl]amino]-1,4-dioxobutan-2-yl]amino]-4-methylsulfanyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-oxobutanoic acid

Glucagon

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: 25 mg/mL

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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