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      Problem or solution: The strange story of glucagon

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      Author(s): * , 1 , 1
      Publication date PMC-release:
      Journal: Peptides
      Publisher: Elsevier Science Inc
      Keywords: Glucagon, Diabetes, Obesity, Energy expenditure, Incretin, Oxyntomodulin

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          Highlights

          • •

            Hyperglucagonaemia is seen in all forms of diabetes including type 2 diabetes and alloxan-induced pancreatic destruction.

          • •

            Agents that block activity at the glucagon receptor are being used in clinical trials to treat diabetes.

          • •

            Peptides are being developed which combine activation of glucagon and incretin receptors to treat obesity.

          Abstract

          Globally, 13% of the world’s adult population is obese, and more than 400 million people suffer from diabetes. These conditions are both associated with significant morbidity, mortality and financial cost. Therefore, finding new pharmacological treatments is an imperative. Relative hyperglucagonaemia is seen in all types of diabetes, and has been implicated in its pathogenesis. Consequently, clinical trials are underway using drugs which block glucagon activity to treat type 2 diabetes. Conversely, exogenous glucagon can increase energy expenditure. Therefore, researchers are designing peptides that combine activation of the glucagon receptor with further incretin properties, which will treat obesity while mitigating the hyperglycaemic effects of glucagon. This review will discuss these conflicting physiological properties of glucagon, and the attempts to harness these effects pharmacologically.

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          Most cited references105

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          Changes in energy expenditure resulting from altered body weight.

          Rudolph L. Leibel, Michael Rosenbaum, Jules Hirsch (1995)
          No current treatment for obesity reliably sustains weight loss, perhaps because compensatory metabolic processes resist the maintenance of the altered body weight. We examined the effects of experimental perturbations of body weight on energy expenditure to determine whether they lead to metabolic changes and whether obese subjects and those who have never been obese respond similarly. We repeatedly measured 24-hour total energy expenditure, resting and nonresting energy expenditure, and the thermic effect of feeding in 18 obese subjects and 23 subjects who had never been obese. The subjects were studied at their usual body weight and after losing 10 to 20 percent of their body weight by underfeeding or gaining 10 percent by overfeeding. Maintenance of a body weight at a level 10 percent or more below the initial weight was associated with a mean (+/- SD) reduction in total energy expenditure of 6 +/- 3 kcal per kilogram of fat-free mass per day in the subjects who had never been obese (P < 0.001) and 8 +/- 5 kcal per kilogram per day in the obese subjects (P < 0.001). Resting energy expenditure and nonresting energy expenditure each decreased 3 to 4 kcal per kilogram of fat-free mass per day in both groups of subjects. Maintenance of body weight at a level 10 percent above the usual weight was associated with an increase in total energy expenditure of 9 +/- 7 kcal per kilogram of fat-free mass per day in the subjects who had never been obese (P < 0.001) and 8 +/- 4 kcal per kilogram per day in the obese subjects (P < 0.001). The thermic effect of feeding and nonresting energy expenditure increased by approximately 1 to 2 and 8 to 9 kcal per kilogram of fat-free mass per day, respectively, after weight gain. These changes in energy expenditure were not related to the degree of adiposity or the sex of the subjects. Maintenance of a reduced or elevated body weight is associated with compensatory changes in energy expenditure, which oppose the maintenance of a body weight that is different from the usual weight. These compensatory changes may account for the poor long-term efficacy of treatments for obesity.
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            A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents.

            Brian Finan, Bin Yang, Nickki Ottaway … (2015)
            We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. This triple agonist demonstrates supraphysiological potency and equally aligned constituent activities at each receptor, all without cross-reactivity at other related receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. Various loss-of-function models, including genetic knockout, pharmacological blockade and selective chemical knockout, confirmed contributions of each constituent activity in vivo. We demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity. These preclinical studies suggest that, so far, this unimolecular, polypharmaceutical strategy has potential to be the most effective pharmacological approach to reversing obesity and related metabolic disorders.
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              Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice.

              R W Gelling, X Q Du, D. Dichmann … (2003)
              Glucagon, the counter-regulatory hormone to insulin, is secreted from pancreatic alpha cells in response to low blood glucose. To examine the role of glucagon in glucose homeostasis, mice were generated with a null mutation of the glucagon receptor (Gcgr(-/-)). These mice display lower blood glucose levels throughout the day and improved glucose tolerance but similar insulin levels compared with control animals. Gcgr(-/-) mice displayed supraphysiological glucagon levels associated with postnatal enlargement of the pancreas and hyperplasia of islets due predominantly to alpha cell, and to a lesser extent, delta cell proliferation. In addition, increased proglucagon expression and processing resulted in increased pancreatic glucogen-like peptide 1 (GLP-1) (1-37) and GLP-1 amide (1-36 amide) content and a 3- to 10-fold increase in circulating GLP-1 amide. Gcgr(-/-) mice also displayed reduced adiposity and leptin levels but normal body weight, food intake, and energy expenditure. These data indicate that glucagon is essential for maintenance of normal glycemia and postnatal regulation of islet and alpha and delta cell numbers. Furthermore, the lean phenotype of Gcgr(-/-) mice suggests glucagon action may be involved in the regulation of whole body composition.
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                Author and article information

                Contributors
                R.V. Scott
                S.R Bloom
                Journal
                Journal ID (nlm-ta): Peptides
                Journal ID (iso-abbrev): Peptides
                Title: Peptides
                Publisher: Elsevier Science Inc
                ISSN (Print): 0196-9781
                ISSN (Electronic): 1873-5169
                Publication date PMC-release: 1 February 2018
                Publication date (Print): February 2018
                Volume: 100
                Pages: 36-41
                Affiliations
                [0005]Imperial College London, 6th Floor, Commonwealth Building, Hammersmith Hospital, London, W12 0NN, United Kingdom
                Author notes
                [1]

                These authors planned and wrote this article.

                Article
                Publisher ID: S0196-9781(17)30359-5
                DOI: 10.1016/j.peptides.2017.11.013
                PMC ID: 5805853
                PubMed ID: 29412829
                SO-VID: 9b03ea80-6bb6-4cc0-892b-399e2e172f23
                Copyright © © 2017 The Authors
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 29 September 2017
                Date revision received : 20 November 2017
                Date accepted : 21 November 2017
                Categories
                Subject: Article

                ScienceOpen disciplines: Biochemistry
                Keywords: glucagon,diabetes,obesity,energy expenditure,incretin,oxyntomodulin
                Data availability:
                ScienceOpen disciplines: Biochemistry
                Keywords: glucagon, diabetes, obesity, energy expenditure, incretin, oxyntomodulin

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