Recent Progress in the Use of Glucagon and Glucagon Receptor Antago-nists in the Treatment of Diabetes Mellitus

Glucagon is an important pancreatic hormone, released into blood circulation by alpha cells of the islet of Langerhans. Glucagon induces gluconeogenesis and glycogenolysis in hepatocytes, leading to an increase in hepatic glucose production and subsequently hyperglycemia in susceptible individuals. Hyperglucagonemia is a constant feature in patients with T2DM. A number of bioactive agents that can block glucagon receptor have been identified. These glucagon receptor antagonists can reduce the hyperglycemia associated with exogenous glucagon administration in normal as well as diabetic subjects. Glucagon receptor antagonists include isoserine and beta-alanine derivatives, bicyclic 19-residue peptide BI-32169, Des-His1-[Glu9] glucagon amide and related compounds, 5-hydroxyalkyl-4-phenylpyridines, N-[3-cano-6- (1,1 dimethylpropyl)-4,5,6,7-tetrahydro-1-benzothien-2-yl]-2-ethylbutamide, Skyrin and NNC 250926. The absorption, dosage, catabolism, excretion and medicinal chemistry of these agents are the subject of this review. It emphasizes the role of glucagon in glucose homeostasis and how it could be applied as a novel tool for the management of diabetes mellitus by blocking its receptors with either monoclonal antibodies, peptide and non-peptide antagonists or gene knockout techniques.

• Publication year

  2014

• Venue

  Open Medicinal Chemistry Journal

• Publication date

  2014-12-31

• Fields of study

  Medicine

• Identifiers
  DOI 10.2174/1874104501408010028PMID 25674162PMCID 4321206
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Seven-transmembrane receptors

  2015influential reference
• Efficacy and tolerance of urea compared with vaptans for long-term treatment of patients with SIADH.

  2012cited by this paper
• Targeting the glucagon receptor family for diabetes and obesity therapy.

  2012influential reference
• Glucagon Receptor Knockout Prevents Insulin-Deficient Type 1 Diabetes in Mice

  2011influential reference
• Sentinel Surveillance of Influenza-Like-Illness in Two Cities of the Tropical Country of Ecuador: 2006–2010

  2011cited by this paper
• Discovery of cyclic guanidines as potent, orally active, human glucagon receptor antagonists.

  2011cited by this paper
• Discovery of novel, potent, selective, and orally active human glucagon receptor antagonists containing a pyrazole core.

  2011cited by this paper
• Histone Deacetylase (HDAC) Inhibition as a Novel Treatment for Diabetes Mellitus

  2011cited by this paper
• The impact of epigenomics on future drug design and new therapies.

  2011cited by this paper
• Epigenetic mechanisms in the development of type 2 diabetes.

  2010cited by this paper
• Nucleosome dynamics and histone variants.

  2010cited by this paper
• The glucagon receptor antagonist BI‐32169 constitutes a new class of lasso peptides

  2010cited by this paper
• Peroxisome Proliferator-Activated Receptor γ Activation Restores Islet Function in Diabetic Mice through Reduction of Endoplasmic Reticulum Stress and Maintenance of Euchromatin Structure

  2009cited by this paper
• Human DNA methylomes at base resolution show widespread epigenomic differences

  2009cited by this paper
• Synthetic linear and cyclic glucagon antagonists.

  2009cited by this paper
• DNA hypomethylation in the origin and pathogenesis of human diseases

  2009cited by this paper
• Benefits and limitations of reducing glucagon action for the treatment of type 2 diabetes.

  2009cited by this paper
• Non-coding RNAs, epigenetics and complexity.

  2008cited by this paper
• Novel glucagon receptor antagonists with improved selectivity over the glucose-dependent insulinotropic polypeptide receptor.

  2008cited by this paper
• Physiology of the pancreatic alpha-cell and glucagon secretion: role in glucose homeostasis and diabetes.

  2008cited by this paper
• Discovery of potent, orally active benzimidazole glucagon receptor antagonists.

  2008cited by this paper
• The glucagon receptor is required for the adaptive metabolic response to fasting.

  2008cited by this paper
• REVIEW Physiology of the pancreatic a -cell and glucagon secretion: role in glucose homeostasis and diabetes

  2008cited by this paper
• New beta-alanine derivatives are orally available glucagon receptor antagonists.

  2007cited by this paper
• A Novel Glucagon Receptor Antagonist, NNC 25-0926, Blunts Hepatic Glucose Production in the Conscious Dog

  2007cited by this paper
• New β-Alanine Derivatives Are Orally Available Glucagon Receptor Antagonists

  2007cited by this paper
• Design and synthesis of conformationally constrained tri-substituted ureas as potent antagonists of the human glucagon receptor.

  2007cited by this paper
• Biology of incretins: GLP-1 and GIP.

  2007cited by this paper
• Glucagon‐mediated internalization of serine‐phosphorylated glucagon receptor and Gsα in rat liver

  2006cited by this paper
• Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system.

  2006cited by this paper
• Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated beta cell loss and hyperglycaemia

  2006influential reference
• Vitamin E Decreases the Hyperglucagonemia of Diabetic Rats

  2006cited by this paper
• Immunoneutralization of Endogenous Glucagon Reduces Hepatic Glucose Output and Improves Long-Term Glycemic Control in Diabetic ob/ob Mice

  2006cited by this paper
• Discovery of novel, potent, and orally active spiro-urea human glucagon receptor antagonists.

  2005cited by this paper
• Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor.

  2005cited by this paper
• BI-32169, a bicyclic 19-peptide with strong glucagon receptor antagonist activity from Streptomyces sp.

  2004cited by this paper
• Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells

  2004cited by this paper
• Biaryl amide glucagon receptor antagonists.

  2004cited by this paper
• Reduction in glucagon receptor expression by an antisense oligonucleotide ameliorates diabetic syndrome in db/db mice.

  2004cited by this paper
• A novel glucagon receptor antagonist inhibits glucagon-mediated biological effects.

  2004cited by this paper
• Synthesis, biological activity, QSAR and QSPR study of 2-aminobenzimidazole derivatives as potent H3-antagonists.

  2004cited by this paper
• Hepatic glucagon receptor binding and glucose-lowering in vivo by peptidyl and non-peptidyl glucagon receptor antagonists.

  2004cited by this paper
• Hepatic and glucagon-like peptide-1-mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors.

  2004cited by this paper
• Glucagon and regulation of glucose metabolism.

  2003cited by this paper
• Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice

  2003cited by this paper
• Discovery of 5-hydroxyalkyl-4-phenylpyridines as a new class of glucagon receptor antagonists.

  2002cited by this paper
• Discovery of 5‐Hydroxyalkyl‐4‐phenylpyridines as a New Class of Glucagon Receptor Antagonists.

  2002cited by this paper
• Human glucagon receptor antagonists based on alkylidene hydrazides.

  2002cited by this paper
• Glycemic control in mice with targeted disruption of the glucagon receptor gene.

  2002cited by this paper
• Signalling: Seven-transmembrane receptors

  2002cited by this paper
• Identification of alkylidene hydrazides as glucagon receptor antagonists.

  2001cited by this paper
• Low Level Cyclic Adenosine 3’,5’-Monophosphate Accumulation Analysis of [des-His’,des-Phe’,Glu’]Glucagon-NH, Identifies Glucagon Antagonists from Weak Partial Agonists/Antagonists*

  2001cited by this paper
• Development of potent glucagon antagonists: structure-activity relationship study of glycine at position 4.

  2001cited by this paper
• Effects of a novel glucagon receptor antagonist (Bay 27–9955) on glucagon-stimulated glucose production in humans

  2001cited by this paper
• Distribution of NPY and SP and their effects on glucagon secretion from the in vitro normal and diabetic pancreatic tissues.

  2000cited by this paper
• New approaches in the treatment of type 2 diabetes.

  2000cited by this paper
• Effects of skyrin, a receptor-selective glucagon antagonist, in rat and human hepatocytes.

  2000cited by this paper
• Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus.

  2000cited by this paper
• Impact of lack of suppression of glucagon on glucose tolerance in humans.

  1999cited by this paper
• Characterization of a Novel, Non-peptidyl Antagonist of the Human Glucagon Receptor*

  1999cited by this paper
• Generation of mice expressing the human glucagon receptor with a direct replacement vector

  1999cited by this paper
• Low level cyclic adenosine 3',5'-monophosphate accumulation analysis of [des-His1, des- Phe6, Glu9] glucagon-NH2 identifies glucagon antagonists from weak partial agonists/antagonists.

  1996cited by this paper
• Molecular and cellular aspects of the glucagon receptor: role in diabetes and metabolism.

  1996cited by this paper
• Evidence for a Major Role for Glucagon in Regulation of Plasma Glucose in Conscious, Nondiabetic, and Alloxan-Induced Diabetic Rabbits

  1996cited by this paper
• Glucagon receptor mRNA distribution in rat tissues.

  1995cited by this paper
• Role of glucagon in maintenance of euglycemia in fed and fasted rats.

  1995cited by this paper
• The human glucagon receptor encoding gene: structure, cDNA sequence and chromosomal localization.

  1994cited by this paper
• Immunoneutralization of endogenous glucagon with monoclonal glucagon antibody normalizes hyperglycaemia in moderately streptozotocin-diabetic rats

  1994cited by this paper
• New glucagon analogues with conformational restrictions and altered amphiphilicity: effects on binding, adenylate cyclase and glycogenolytic activities.

  1993cited by this paper
• Biological activities of des-His1[Glu9]glucagon amide, a glucagon antagonist.

  1989cited by this paper
• A comparative study on cytotoxicities and biochemical properties of anthraquinone mycotoxins emodin and skyrin from Penicillium islandicum Sopp.

  1984cited by this paper
• A comparative study on cytotoxicities and biochemical properties of anthraquinone mycotoxins emodin and skyrin from Penicillium islandicum Sopp.

  1984cited by this paper
• Structure-conformation-activity studies of glucagon and semi-synthetic glucagon analogs

  1982cited by this paper
• Hyperglycemia of diabetic rats decreased by a glucagon receptor antagonist.

  1982cited by this paper
• Regulation of hepatic fatty acid oxidation and ketone body production.

  1980cited by this paper
• The glucagon-sensitive adenylate cyclase system in plasma membranes of rat liver. VII. Hormonal stimulation: reversibility and dependence on concentration of free hormone.

  1972cited by this paper
• The glucagon-sensitive adenyl cyclase system in plasma membranes of rat liver. IV. Effects of guanylnucleotides on binding of 125I-glucagon.

  1971cited by this paper
• The Glucagon Receptor Is Required for the Adaptive Metabolic Response to Fasting

  year unknowncited by this paper

• Lasso peptides: A focus on therapeutic index

  2025cites this paper
• Proglucagon-derived Peptides: Human Physiology and Therapeutic Potential.

  2025cites this paper
• Evaluation of Four Semi‐Mechanistic Models for Predicting Glycemic Control With a Glucagon Receptor Antagonist in People With Type 2 Diabetes

  2025cites this paper
• Opportunities and challenges of RiPP-based therapeutics.

  2024cites this paper
• Hepatic Glucagon Action - Beyond Glucose Mobilization.

  2024cites this paper
• Fasting Glucagon Level in Type 2 Diabetes and Impaired Glucose Tolerance and Its Association With Diabetes-Associated Clinical Parameters: A Study From Karachi, Pakistan

  2021cites this paper
• The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror

  2021cites this paper
• Effect of glucagon on ischemic heart disease and its risk factors: A Mendelian randomization study.

  2020cites this paper
• Glucagon and Glucagon-like Peptide-1 Receptors: Promising Therapeutic Targets for an Effective Management of Diabetes Mellitus.

  2020cites this paper
• Advances and complications of regenerative medicine in diabetes therapy

  2020cites this paper
• A Recent Achievement In the Discovery and Development of Novel Targets for the Treatment of Type-2 Diabetes Mellitus

  2020cites this paper
• Antagonistic Glucagon Receptor Antibody Promotes α-Cell Proliferation and Increases β-Cell Mass in Diabetic Mice

  2019cites this paper
• Glucagon receptor antagonism increases mouse pancreatic δ-cell mass through cell proliferation and duct-derived neogenesis.

  2019cites this paper
• The Role of Glucagon in the Pathophysiology and Treatment of Type 2 Diabetes

  2018influential citation
• Studies on Glucagon Receptor and Antagonists of Glucagon Receptor for the Management of Diabetes Mellitus

  2018cites this paper
• Regulation of hepatic glucose metabolism in health and disease

  2017cites this paper
• An investigation into glucagon receptor pharmacology

  2017cites this paper
• Investigational glucagon receptor antagonists in Phase I and II clinical trials for diabetes

  2017cites this paper
• Rôle de l'apeline dans le contrôle de l'axe "intestin-hypothalamus-périphérie" : conséquences sur le métabolisme glucidique chez la souris normale et obèse/diabétique

  2016cites this paper
• Regulation of Pancreatic α-Cell Function and Proliferation by Bone Morphogenetic Protein 4 (BMP4) In Vitro.

  2016cites this paper
• Glucosensing in the gastrointestinal tract: Impact on glucose metabolism.

  2016cites this paper
• Glucagon receptor antagonist and GIP agonist combination for diet-induced obese mice.

  2016cites this paper
• In Silico Identification of Novel Glucagon Receptor Antagonist for the Treatment of Type 2 Diabetes Mellitus

  2015cites this paper