Glucagon receptor (GCGR) and Glucagon-like peptide-1 receptor (GLP-1R). Glucagon acts on hepatocytes via GCGR to stimulate hepatic glucose production and on pancreatic β-cells via both GCGR and GLP-1R (with GLP-1R being the predominant mediator) to stimulate glucose-stimulated insulin secretion (GSIS) in a glucose-dependent manner. [1, 4]
Glucagon also stimulates hepatic kisspeptin1 production via GCGR and cAMP-PKA-CREB signaling. [1]

GSK2018682 has no agonist activity toward human S1P2, S1P3, or S1P4 but is an agonist for the S1P1 and S1P5 receptors, with pEC50s of 7.7 and 7.2, respectively[1].

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In primary mouse hepatocytes, glucagon (200 pg/mL) stimulated Kiss1 expression and Pck1 expression within 2 hours. Insulin (2000 pg/mL) counter-regulated glucagon-stimulated Kiss1 and Pck1 expression. [1]
In mouse H2.35 hepatoma cells transfected with a Kiss1 promoter luciferase reporter, glucagon stimulated transcriptional activity. Mutation of CRE half-sites in the Kiss1 promoter decreased glucagon responsiveness. [1]
In isolated mouse islets, glucagon stimulated insulin secretion in a dose-dependent manner at elevated glucose concentrations (10 or 20 mM) but not at low glucose. The insulinotropic effect was primarily mediated through GLP-1R, as demonstrated using islets from β-cell-specific GLP-1R knockout mice. [4]
In perfused mouse islets, alanine (10 mM) stimulated glucagon secretion more potently than glutamine (10 mM) at both low (2.7 mM) and high (10 mM) glucose. [4]

Low-dose (20 μg/kg) glucagon increases blood glucose but does not stimulate insulin secretion in ambient-fed mice. High doses (1 mg/kg) of glucagon reduced blood glucose and stimulated insulin secretion in ambient-fed mice compared with PBS controls [4]. Animal Model: C57BL/6J mice (12 to 24 weeks old) [4] Dosage: 20 μg/kg and 1 mg/kg Administration: Administered by ip injection; 45 minutes Results: Low dose (20 μg/kg ) will increase blood sugar but will not stimulate insulin secretion. High doses (1 mg/kg) lower blood sugar and stimulate insulin secretion.

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In mice, intraperitoneal (i.p.) injection of glucagon at 16 μg/kg increased hepatic kisspeptin1 production within 30 minutes. Overnight fasting (which increases endogenous glucagon) also increased liver kisspeptin1, while refeeding reduced it. [1]
In high-fat diet (HFD)-fed and Leprᵈᵇ/ᵈᵇ diabetic mice, which are hyperglucagonemic, administration of a glucagon receptor antagonist (GAI) reduced liver kisspeptin1 expression and improved glucose tolerance. [1]
In fed mice, high-dose glucagon (1 mg/kg i.p.) decreased blood glucose and increased insulin secretion approximately 3-fold. In fasted mice, the same dose of glucagon increased blood glucose without significantly increasing insulin secretion. Co-administration of glucagon with glucose (0.5 g/kg) in fasted mice produced a net decrease in glycemia and a ~6-fold increase in insulin secretion. [4]
In mice treated with tolbutamide (100 mg/kg) to lower glucose while activating β-cells, glucagon (1 mg/kg) decreased glycemia and increased insulin secretion ~3-fold. [4]
In β-cell-specific GCGR and GLP-1R double-knockout (Gcgr:Glp1rᵝᶜᵉˡˡ⁻/⁻) mice, glucagon increased glycemia and produced only a small (~2-fold) increase in insulin secretion. Glucagon lowered glycemia in Gcgrᵝᶜᵉˡˡ⁻/⁻ mice but raised glycemia in Glp1rᵝᶜᵉˡˡ⁻/⁻ mice, demonstrating that GLP-1R is essential for the glucose-lowering effects of glucagon. [4]
In fed WT mice, i.p. alanine (0.325 g/kg) decreased glycemia and increased glucagon secretion without a detectable increase in plasma insulin. In fed Gcgr:Glp1rᵝᶜᵉˡˡ⁻/⁻ mice, alanine increased glycemia. Alanine co-administered with glucose (1.5 g/kg) increased insulin secretion beyond glucose alone in WT mice but not in Gcgr:Glp1rᵝᶜᵉˡˡ⁻/⁻ mice. [4]

Primary Mouse Hepatocyte Culture: Mouse hepatocytes were isolated and treated with vehicle (PBS), glucagon (200 pg/mL), insulin (2000 pg/mL), or glucagon + insulin. Kiss1 and Pck1 mRNA expression were measured by qRT-PCR. Kisspeptin1 protein was assessed by immunoblot. [1]
Islet Perifusion: Isolated mouse islets (100 islets/chamber) were placed into chambers containing 2.7 mM glucose KRPH buffer with Bio-Gel P-4 Media. Islets were equilibrated in 2.7 mM glucose for 48 minutes, then perfused with alanine or glutamine at concentrations indicated (2.7 mM glucose and 10 mM glucose). Effluent was collected for insulin and glucagon measurement by ELISA. [4]
Islet Static Incubation: Isolated mouse islets (20 hand-picked equal-sized islets per condition) were cultured overnight in RPMI 1640 containing 5 mM glucose. Islets were then switched to 10 or 20 mM glucose with or without kisspeptin-10 (0-100 nM, and 1 μM), exendin-4 (10 nM), or vehicle (PBS) for 30 minutes. Supernatant was taken for insulin measurement. [1]

Liver-Specific PKA Disinhibition (L-Prkarla) Mice: Mice with floxed Prkar1a alleles were treated with adenovirus expressing CRE recombinase (Adv-CRE) via tail vein injection (10⁹ PFU/mouse). Control mice received Adv-GFP. Four days later, livers were harvested for analysis. [1]
Glucagon and Alanine Tolerance Tests: Mice were fasted overnight (~16 hours) or fed ad libitum. For glucagon tests, glucagon (20 μg/kg or 1 mg/kg) was administered i.p., and blood glucose was measured at indicated times from tail blood. Serum insulin and glucagon were measured by ELISA. For alanine tests, alanine (0.325 g/kg) was administered i.p. For glucose co-administration, glucagon was prepared in PBS containing glucose (0.5 g/kg). For tolbutamide experiments, tolbutamide (100 mg/kg) was injected i.p. 1 hour before glucagon. [4]
Glucagon Receptor Antagonist (GAI) Treatment: HFD-fed or Leprᵈᵇ/ᵈᵇ mice were treated with a single dose of GAI or inactive analog GAC (dose not specified) 60 minutes before an intraperitoneal glucose tolerance test (ipGTT). Liver tissue was collected for analysis of pCREB, Kiss1, and gluconeogenic genes. [1]
Liver Kiss1 Knockdown: Adenovirus expressing Kiss1-specific shRNA (Adv-Kiss1 shRNA) or scrambled shRNA (Adv-scr shRNA) was injected via tail vein into L-Prkarla mice, HFD-fed mice, or Leprᵈᵇ/ᵈᵇ mice. Three days later, mice were subjected to ipGTT, ipITT, or ipPCT, and tissues were collected. [1]

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]. 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 secreted by pancreatic α-cells. It is a key regulator of glucose homeostasis, traditionally known for its counter-regulatory actions to raise blood glucose by stimulating hepatic glucose production. [1, 4]
Glucagon also acts as an insulinotropic hormone in the fed state, stimulating insulin secretion in a glucose-dependent manner primarily through the GLP-1 receptor on β-cells. This effect complements insulin action to maintain euglycemia during meals. [4]
Glucagon stimulates hepatic kisspeptin1 production via cAMP-PKA-CREB signaling. Kisspeptin1 in turn acts on β-cells to suppress GSIS, establishing a liver-to-islet endocrine circuit. In type 2 diabetes mellitus, hyperglucagonemia leads to increased hepatic kisspeptin1, which contributes to impaired insulin secretion. [1]

C153H226CLN43O49S

3519.20827245712

3517.6

28270-04-4

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;

16186213

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

White to off-white solid at room temperature

56

55

115

247

8160

31

C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC4=CC=CC=C4)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC5=CNC6=CC=CC=C65)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@@H](C)O)C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)NC(=O)[C@H](CC7=CN=CN7)N)O.Cl

RKGLLHCSSVJTAN-YYICOITRSA-N

InChI=1S/C153H225N43O49S.ClH/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);1H/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;hydrochloride

Glucagon HCl

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO: 25 mg/mL (7.1 mM)
H2O: 16.7 mg/mL (4.7 mM)

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.)