ijms-logo

Journal Browser

Journal Browser

The Biology and Pharmacology of Glucagon

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 78716

Special Issue Editors

Institute for Diabetes and Obesity (IDO), Business Campus Garching-Hochbrück, Parkring 13, 85748 Garching, Germany
Interests: obesity; diabetes; GLP-1; glucagon; GIP
Department of Medicine - Endocrinology, Diabetes & Metabolism, University of Alabama at Birmingham, BDB 783 1808 7th Avenue South, Birmingham, AL 35294-0012, USA
Interests: obesity; diabetes; glucagon; FGF21; GLP-1

Special Issue Information

Dear Colleagues,

The discovery of insulin and its pharmacology in 1921 was closely followed by that of glucagon in 1923. However, unlike insulin, glucagon action has been historically stigmatized as diabetogenic and its clinical use restricted to rescue from severe hypoglycemia. Hampered by a short half-life and poor solubility in physiological buffers, this glucocentric view of glucagon has overshadowed that glucagon is a pleiotropic hormone with broad biological action not only in the pancreas and the liver but also in the brain, the heart, the stomach and the white and brown adipose tissue. The diabetogenic reputation of glucagon is urged by reports showing that failure of glucose to suppress glucagon secretion can play a pathophysiological role in the development of type 2 diabetes, while blockade of glucagon can ameliorate hyperglycemia in diabetic patients. Ironically, the diabetogenic view of glucagon has recently been challenged by the generation of pharmacotherapies that along with insulinotropic peptides recruit glucagon receptor agonism into the same entity to treat obesity and type 2 diabetes. In this Special Issue, we describe the multifaceted nature of glucagon that goes well beyond its role on glucose metabolism.

Dr. Timo D. Müller
Assoc. Prof. Dr. Kirk Habegger
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Glucagon
  • GCGR
  • Glucagon Receptor
  • GLP-1
  • GLP-1R
  • Diabetes
  • Obesity
  • Insulin

Published Papers (11 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review

5 pages, 187 KiB  
Editorial
Revisiting the Pharmacological Value of Glucagon: An Editorial for the Special Issue “The Biology and Pharmacology of Glucagon”
by Timo D. Müller and Kirk Habegger
Int. J. Mol. Sci. 2020, 21(2), 383; https://doi.org/10.3390/ijms21020383 - 08 Jan 2020
Viewed by 2404
Abstract
In 1921, a Canadian research team led by Frederick Banting and John Macleod succeeded in the isolation of insulin from pancreatic homogenate [...] Full article
(This article belongs to the Special Issue The Biology and Pharmacology of Glucagon)

Research

Jump to: Editorial, Review

11 pages, 2450 KiB  
Article
A Dual GLP-1/GIP Receptor Agonist Does Not Antagonize Glucagon at Its Receptor but May Act as a Biased Agonist at the GLP-1 Receptor
by Noura Al-Zamel, Suleiman Al-Sabah, Yunus Luqmani, Lobna Adi, Siby Chacko, Tom Dario Schneider and Cornelius Krasel
Int. J. Mol. Sci. 2019, 20(14), 3532; https://doi.org/10.3390/ijms20143532 - 19 Jul 2019
Cited by 19 | Viewed by 4482 | Correction
Abstract
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important regulators of metabolism, making their receptors (GLP-1R and GIPR) attractive targets in the treatment of type 2 diabetes mellitus (T2DM). GLP-1R agonists are used clinically to treat T2DM but the use of GIPR [...] Read more.
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important regulators of metabolism, making their receptors (GLP-1R and GIPR) attractive targets in the treatment of type 2 diabetes mellitus (T2DM). GLP-1R agonists are used clinically to treat T2DM but the use of GIPR agonists remains controversial. Recent studies suggest that simultaneous activation of GLP-1R and GIPR with a single peptide provides superior glycemic control with fewer adverse effects than activation of GLP-1R alone. We investigated the signaling properties of a recently reported dual-incretin receptor agonist (P18). GLP-1R, GIPR, and the closely related glucagon receptor (GCGR) were expressed in HEK-293 cells. Activation of adenylate cyclase via Gαs was monitored using a luciferase-linked reporter gene (CRE-Luc) assay. Arrestin recruitment was monitored using a bioluminescence resonance energy transfer (BRET) assay. GLP-1, GIP, and glucagon displayed exquisite selectivity for their receptors in the CRE-Luc assay. P18 activated GLP-1R with similar potency to GLP-1 and GIPR with higher potency than GIP. Interestingly, P18 was less effective than GLP-1 at recruiting arrestin to GLP-1R and was inactive at GCGR. These data suggest that P18 can act as both a dual-incretin receptor agonist, and as a G protein-biased agonist at GLP-1R. Full article
(This article belongs to the Special Issue The Biology and Pharmacology of Glucagon)
Show Figures

Figure 1

Review

Jump to: Editorial, Research

10 pages, 378 KiB  
Review
Methods and Guidelines for Measurement of Glucagon in Plasma
by Jens J. Holst and Nicolai J. Wewer Albrechtsen
Int. J. Mol. Sci. 2019, 20(21), 5416; https://doi.org/10.3390/ijms20215416 - 30 Oct 2019
Cited by 32 | Viewed by 4324
Abstract
Glucagon circulates in concentrations in the low picomolar range, which is demanding regarding the sensitivity of the methods for quantification applied. In addition, the differential and tissue specific proteolytic processing of the glucagon precursor and the presence in of several glucagon-like sequences, not [...] Read more.
Glucagon circulates in concentrations in the low picomolar range, which is demanding regarding the sensitivity of the methods for quantification applied. In addition, the differential and tissue specific proteolytic processing of the glucagon precursor and the presence in of several glucagon-like sequences, not only in the precursor of glucagon, but also in a number of other peptides of the glucagon-secretin family of peptides, put special demands on the specificity of the assays. Finally, experience has shown that unspecific interference of plasma components has presented additional problems. All of these problems have resulted in a lot of diverging results concerning measured and reported glucagon responses in both humans and experimental animals that have and still are causing considerable debate and controversy. There is very solid evidence that glucagon is an important hormone in human and mammalian metabolism, but its precise physiological role in glucose and lipid metabolism and in metabolic disease has been difficult to establish, not least because of these difficulties. It was our purpose with this review to discuss the methods of glucagon quantification and discuss pitfalls and sources of error. We also reviewed some of the dogmas regarding glucagon secretion in the light of the methodological difficulties. Full article
(This article belongs to the Special Issue The Biology and Pharmacology of Glucagon)
Show Figures

Figure 1

12 pages, 658 KiB  
Review
Glucagon Regulation of Energy Expenditure
by Maximilian Kleinert, Stephan Sachs, Kirk M. Habegger, Susanna M. Hofmann and Timo D. Müller
Int. J. Mol. Sci. 2019, 20(21), 5407; https://doi.org/10.3390/ijms20215407 - 30 Oct 2019
Cited by 62 | Viewed by 7207
Abstract
Glucagon’s ability to increase energy expenditure has been known for more than 60 years, yet the mechanisms underlining glucagon’s thermogenic effect still remain largely elusive. Over the last years, significant efforts were directed to unravel the physiological and cellular underpinnings of how glucagon [...] Read more.
Glucagon’s ability to increase energy expenditure has been known for more than 60 years, yet the mechanisms underlining glucagon’s thermogenic effect still remain largely elusive. Over the last years, significant efforts were directed to unravel the physiological and cellular underpinnings of how glucagon regulates energy expenditure. In this review, we summarize the current knowledge on how glucagon regulates systems metabolism with a special emphasis on its acute and chronic thermogenic effects. Full article
(This article belongs to the Special Issue The Biology and Pharmacology of Glucagon)
Show Figures

Figure 1

18 pages, 770 KiB  
Review
The Effects of Dual GLP-1/GIP Receptor Agonism on Glucagon Secretion—A Review
by David S. Mathiesen, Jonatan I. Bagger, Natasha C. Bergmann, Asger Lund, Mikkel B. Christensen, Tina Vilsbøll and Filip K. Knop
Int. J. Mol. Sci. 2019, 20(17), 4092; https://doi.org/10.3390/ijms20174092 - 22 Aug 2019
Cited by 50 | Viewed by 8541
Abstract
The gut-derived incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion. Furthermore, GLP-1 inhibits glucagon secretion when plasma glucose concentrations are above normal fasting concentrations while GIP [...] Read more.
The gut-derived incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion. Furthermore, GLP-1 inhibits glucagon secretion when plasma glucose concentrations are above normal fasting concentrations while GIP acts glucagonotropically at low glucose levels. A dual incretin receptor agonist designed to co-activate GLP-1 and GIP receptors was recently shown to elicit robust improvements of glycemic control (mean haemoglobin A1c reduction of 1.94%) and massive body weight loss (mean weight loss of 11.3 kg) after 26 weeks of treatment with the highest dose (15 mg once weekly) in a clinical trial including overweight/obese patients with type 2 diabetes. Here, we describe the mechanisms by which the two incretins modulate alpha cell secretion of glucagon, review the effects of co-administration of GLP-1 and GIP on glucagon secretion, and discuss the potential role of glucagon in the therapeutic effects observed with novel unimolecular dual GLP-1/GIP receptor agonists. For clinicians and researchers, this manuscript offers an understanding of incretin physiology and pharmacology, and provides mechanistic insight into future antidiabetic and obesity treatments. Full article
(This article belongs to the Special Issue The Biology and Pharmacology of Glucagon)
Show Figures

Figure 1

12 pages, 1504 KiB  
Review
Glucagon Control on Food Intake and Energy Balance
by Omar Al-Massadi, Johan Fernø, Carlos Diéguez, Ruben Nogueiras and Mar Quiñones
Int. J. Mol. Sci. 2019, 20(16), 3905; https://doi.org/10.3390/ijms20163905 - 11 Aug 2019
Cited by 31 | Viewed by 7170
Abstract
Glucagon exerts pleiotropic actions on energy balance and has emerged as an attractive target for the treatment of diabetes and obesity in the last few years. Glucagon reduces body weight and adiposity by suppression of appetite and by modulation of lipid metabolism. Moreover, [...] Read more.
Glucagon exerts pleiotropic actions on energy balance and has emerged as an attractive target for the treatment of diabetes and obesity in the last few years. Glucagon reduces body weight and adiposity by suppression of appetite and by modulation of lipid metabolism. Moreover, this hormone promotes weight loss by activation of energy expenditure and thermogenesis. In this review, we cover these metabolic actions elicited by glucagon beyond its canonical regulation of glucose metabolism. In addition, we discuss recent developments of therapeutic approaches in the treatment of obesity and diabetes by dual- and tri-agonist molecules based on combinations of glucagon with other peptides. New strategies using these unimolecular polyagonists targeting the glucagon receptor (GCGR), have become successful approaches to evaluate the multifaceted nature of glucagon signaling in energy balance and metabolic syndrome. Full article
(This article belongs to the Special Issue The Biology and Pharmacology of Glucagon)
Show Figures

Graphical abstract

13 pages, 1063 KiB  
Review
Cell Autonomous Dysfunction and Insulin Resistance in Pancreatic α Cells
by Norikiyo Honzawa, Kei Fujimoto and Tadahiro Kitamura
Int. J. Mol. Sci. 2019, 20(15), 3699; https://doi.org/10.3390/ijms20153699 - 28 Jul 2019
Cited by 14 | Viewed by 9307
Abstract
To date, type 2 diabetes is considered to be a “bi-hormonal disorder” rather than an “insulin-centric disorder,” suggesting that glucagon is as important as insulin. Although glucagon increases hepatic glucose production and blood glucose levels, paradoxical glucagon hypersecretion is observed in diabetes. Recently, [...] Read more.
To date, type 2 diabetes is considered to be a “bi-hormonal disorder” rather than an “insulin-centric disorder,” suggesting that glucagon is as important as insulin. Although glucagon increases hepatic glucose production and blood glucose levels, paradoxical glucagon hypersecretion is observed in diabetes. Recently, insulin resistance in pancreatic α cells has been proposed to be associated with glucagon dysregulation. Moreover, cell autonomous dysfunction of α cells is involved in the etiology of diabetes. In this review, we summarize the current knowledge about the physiological and pathological roles of glucagon. Full article
(This article belongs to the Special Issue The Biology and Pharmacology of Glucagon)
Show Figures

Figure 1

9 pages, 226 KiB  
Review
Therapeutic Use of Intranasal Glucagon: Resolution of Hypoglycemia
by Antonio E. Pontiroli and Elena Tagliabue
Int. J. Mol. Sci. 2019, 20(15), 3646; https://doi.org/10.3390/ijms20153646 - 25 Jul 2019
Cited by 17 | Viewed by 4162
Abstract
Episodes of hypoglycemia are frequent in patients with diabetes treated with insulin or sulphonylureas. Hypoglycemia can lead to severe acute complications, and, as such, both prevention and treatment of hypoglycemia are important for the well-being of patients with diabetes. The experience of hypoglycemia [...] Read more.
Episodes of hypoglycemia are frequent in patients with diabetes treated with insulin or sulphonylureas. Hypoglycemia can lead to severe acute complications, and, as such, both prevention and treatment of hypoglycemia are important for the well-being of patients with diabetes. The experience of hypoglycemia also leads to fear of hypoglycemia, that in turn can limit optimal glycemic control in patients, especially with type 1 diabetes. Treatment of hypoglycemia is still based on administration of carbohydrates (oral or parenteral according to the level of consciousness) or of glucagon (intramuscular or subcutaneous injection). In 1983, it was shown for the first time that intranasal (IN) glucagon drops (with sodium glycocholate as a promoter) increase blood glucose levels in healthy volunteers. During the following decade, several authors showed the efficacy of IN glucagon (drops, powders, and sprays) to resolve hypoglycemia in normal volunteers and in patients with diabetes, both adults and children. Only in 2010, based on evaluation of patients’ beliefs and patients’ expectations, a canadian pharmaceutical company (Locemia Solutions, Montreal, Canada) reinitiated efforts to develop glucagon for IN administration. The project has been continued by Eli Lilly, that is seeking to obtain registration in order to make IN glucagon available to insulin users (children and adolescents) worldwide. IN glucagon is as effective as injectable glucagon, and devoid of most of the technical difficulties associated with administration of injectable glucagon. IN glucagon appears to represent a major breakthrough in the treatment of severe hypoglycemia in insulin-treated patients with diabetes, both children and adults. Full article
(This article belongs to the Special Issue The Biology and Pharmacology of Glucagon)
16 pages, 693 KiB  
Review
Glucagon, GLP-1 and Thermogenesis
by Ismael González-García, Edward Milbank, Carlos Diéguez, Miguel López and Cristina Contreras
Int. J. Mol. Sci. 2019, 20(14), 3445; https://doi.org/10.3390/ijms20143445 - 13 Jul 2019
Cited by 30 | Viewed by 9618
Abstract
Brown adipose tissue (BAT) thermogenesis is a conserved mechanism to maintain body temperature in mammals. However, since BAT contribution to energy expenditure can represent a relevant modulator of metabolic homeostasis, many studies have focused on the nervous system and endocrine factors that control [...] Read more.
Brown adipose tissue (BAT) thermogenesis is a conserved mechanism to maintain body temperature in mammals. However, since BAT contribution to energy expenditure can represent a relevant modulator of metabolic homeostasis, many studies have focused on the nervous system and endocrine factors that control the activity of this tissue. There is long-established evidence that the counter-regulatory hormone glucagon negatively influences energy balance, enhances satiety, and increases energy expenditure. Despite compelling evidence showing that glucagon has direct action on BAT thermogenesis, recent findings are questioning this conventional attribute of glucagon action. Glucagon like peptide-1 (GLP-1) is an incretin secreted by the intestinal tract which strongly decreases feeding, and, furthermore, improves metabolic parameters associated with obesity and diabetes. Therefore, GLP-1 receptors (GLP-1-R) have emerged as a promising target in the treatment of metabolic disorders. In this short review, we will summarize the latest evidence in this regard, as well as the current therapeutic glucagon- and GLP-1-based approaches to treating obesity. Full article
(This article belongs to the Special Issue The Biology and Pharmacology of Glucagon)
Show Figures

Figure 1

27 pages, 2511 KiB  
Review
Glucagon Receptor Signaling and Glucagon Resistance
by Lina Janah, Sasha Kjeldsen, Katrine D. Galsgaard, Marie Winther-Sørensen, Elena Stojanovska, Jens Pedersen, Filip K. Knop, Jens J. Holst and Nicolai J. Wewer Albrechtsen
Int. J. Mol. Sci. 2019, 20(13), 3314; https://doi.org/10.3390/ijms20133314 - 05 Jul 2019
Cited by 99 | Viewed by 15942
Abstract
Hundred years after the discovery of glucagon, its biology remains enigmatic. Accurate measurement of glucagon has been essential for uncovering its pathological hypersecretion that underlies various metabolic diseases including not only diabetes and liver diseases but also cancers (glucagonomas). The suggested key role [...] Read more.
Hundred years after the discovery of glucagon, its biology remains enigmatic. Accurate measurement of glucagon has been essential for uncovering its pathological hypersecretion that underlies various metabolic diseases including not only diabetes and liver diseases but also cancers (glucagonomas). The suggested key role of glucagon in the development of diabetes has been termed the bihormonal hypothesis. However, studying tissue-specific knockout of the glucagon receptor has revealed that the physiological role of glucagon may extend beyond blood-glucose regulation. Decades ago, animal and human studies reported an important role of glucagon in amino acid metabolism through ureagenesis. Using modern technologies such as metabolomic profiling, knowledge about the effects of glucagon on amino acid metabolism has been expanded and the mechanisms involved further delineated. Glucagon receptor antagonists have indirectly put focus on glucagon’s potential role in lipid metabolism, as individuals treated with these antagonists showed dyslipidemia and increased hepatic fat. One emerging field in glucagon biology now seems to include the concept of hepatic glucagon resistance. Here, we discuss the roles of glucagon in glucose homeostasis, amino acid metabolism, and lipid metabolism and present speculations on the molecular pathways causing and associating with postulated hepatic glucagon resistance. Full article
(This article belongs to the Special Issue The Biology and Pharmacology of Glucagon)
Show Figures

Graphical abstract

20 pages, 1748 KiB  
Review
Glucagon-Induced Acetylation of Energy-Sensing Factors in Control of Hepatic Metabolism
by Li Zhang, Weilei Yao, Jun Xia, Tongxin Wang and Feiruo Huang
Int. J. Mol. Sci. 2019, 20(8), 1885; https://doi.org/10.3390/ijms20081885 - 16 Apr 2019
Cited by 20 | Viewed by 4724
Abstract
The liver is the central organ of glycolipid metabolism, which regulates the metabolism of lipids and glucose to maintain energy homeostasis upon alterations of physiological conditions. Researchers formerly focused on the phosphorylation of glucagon in controlling liver metabolism. Noteworthily, emerging evidence has shown [...] Read more.
The liver is the central organ of glycolipid metabolism, which regulates the metabolism of lipids and glucose to maintain energy homeostasis upon alterations of physiological conditions. Researchers formerly focused on the phosphorylation of glucagon in controlling liver metabolism. Noteworthily, emerging evidence has shown glucagon could additionally induce acetylation to control hepatic metabolism in response to different physiological states. Through inducing acetylation of complex metabolic networks, glucagon interacts extensively with various energy-sensing factors in shifting from glucose metabolism to lipid metabolism during prolonged fasting. In addition, glucagon-induced acetylation of different energy-sensing factors is involved in the advancement of nonalcoholic fatty liver disease (NAFLD) to liver cancer. Here, we summarize the latest findings on glucagon to control hepatic metabolism by inducing acetylation of energy-sensing factors. Finally, we summarize and discuss the potential impact of glucagon on the treatment of liver diseases. Full article
(This article belongs to the Special Issue The Biology and Pharmacology of Glucagon)
Show Figures

Graphical abstract

Back to TopTop