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The Biology and Pharmacology of Glucagon

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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 93510

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Special Issue Editors

Dr. Timo D. Müller

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Guest Editor

Institute for Diabetes and Obesity (IDO), Business Campus Garching-Hochbrück, Parkring 13, 85748 Garching, Germany
Interests: obesity; diabetes; GLP-1; glucagon; GIP

Assoc. Prof. Dr. Kirk Habegger

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Guest Editor

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

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Keywords

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

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

5 pages, 187 KiB

Open AccessEditorial

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 - 8 Jan 2020

Viewed by 2879

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

Open AccessArticle

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 20 | Viewed by 5398 | 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 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 Gα_s 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)

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Review

Jump to: Editorial, Research

10 pages, 378 KiB

Open AccessReview

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 38 | Viewed by 5302

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 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)

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12 pages, 658 KiB

Open AccessReview

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 78 | Viewed by 8579

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 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)

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18 pages, 770 KiB

Open AccessReview

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 56 | Viewed by 10581

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 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)

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12 pages, 1504 KiB

Open AccessReview

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 44 | Viewed by 8617

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, 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)

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13 pages, 1063 KiB

Open AccessReview

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 17 | Viewed by 10402

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, 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)

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9 pages, 226 KiB

Open AccessReview

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 4706

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 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

Open AccessReview

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 34 | Viewed by 11466

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 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)

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27 pages, 2511 KiB

Open AccessReview

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 - 5 Jul 2019

Cited by 121 | Viewed by 19198

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 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)

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20 pages, 1748 KiB

Open AccessReview

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 23 | Viewed by 5396

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 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)

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