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]

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]

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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.

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]

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

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]

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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
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]

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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.

C153H229CL4N43O49S

3628.627

3480.615

16941-32-5

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

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.)