Endocrinol Metab.  2024 Feb;39(1):33-39. 10.3803/EnM.2024.1911.

Glucagon: Physiological and Pharmacological Functions and Pathophysiological Significance in Type 2 Diabetes

• Kitamura T

• KMID: 2552793
• DOI: http://doi.org/10.3803/EnM.2024.1911

Abstract

Glucagon has many functions, including the promotion of hepatic glucose production, fatty acid oxidation, thermogenesis, energy consumption, lipolysis, and myocardial contraction, as well as the suppression of lipogenesis, appetite, and gastrointestinal motility. However, it remains unclear which of these functions are physiological and which are pharmacological. Research on glucagon has lagged behind research on insulin because cross-reactivity with glucagon-related peptides in plasma has hindered the development of an accurate measurement system for glucagon. We recently developed a new glucagon sandwich enzyme-linked immunosorbent assay (ELISA) that is more specific and more sensitive to glucagon than the currently used measurement systems. The new sandwich ELISA is expected to contribute to personalized medicine for diabetes through its use in clinical examinations, the diagnosis of the pathophysiological condition of individual diabetes patients, and the choice of a treatment strategy. Efforts are continuing to develop glucagon/glucagon-like peptide-1 receptor dual agonists to improve obesity and fatty liver by enhancing glucagon’s appetite-suppressing and lipolysis- and thermogenesis-promoting effects. Thus, glucagon is expected to be applied to new diagnostic and therapeutic strategies based on a more accurate understanding of its functions.

Keyword

Glucagon; Sandwich enzyme-linked immunosorbent assay; Diabetes

Figure

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  Fig. 1. Diagram of glucagon’s various physiological and pharmacological effects in multiple organs.

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  Fig. 2. The concentration-dependent effects of glucagon on lipolysis, myocardial contraction, hepatic gluconeogenesis, and the cyclic adenosine monophosphate (cAMP) concentration in each tissue. The gray bar in each graph indicates the physiological range of the plasma glucagon concentration. Modified from Rodgers [1], with permission from Bentham Science Publishers.

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  Fig. 3. (A) Various glucagon-related peptides produced from proglucagon. (B) Comparison of the plasma glucagon values obtained by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) to those obtained by conventional competitive radioimmunoassay (RIA) or Mercodia sandwich enzyme-linked immunosorbent assay (ELISA). Modified from Miyachi et al. [5], with permission from Springer Nature. GLP, glucagon-like peptide; IP, intervening peptide; GRPP, glicentin-related pancreatic polypeptide.

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  Fig. 4. Plasma glucagon levels measured by the Mercodia sandwich enzyme-linked immunosorbent assay (ELISA; left) or conventional competitive radioimmunoassay (RIA; right) during the (A) glucose tolerance test or (B) meal tolerance test in type 2 diabetes patients (red) and healthy people (blue). Modified from Kobayashi et al. [6]. aP<0.05; bP<0.001.

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  Fig. 5. Schematic diagram showing (A) the newly developed glucagon sandwich enzyme-linked immunosorbent assay (ELISA) and (B) the results of cross-reactivity tests in the Mercodia sandwich ELISA and new sandwich ELISA. Plasma glucagon values after bariatric surgery measured by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) and compared to the values obtained by (C) the Mercodia sandwich ELISA or (D) the new sandwich ELISA. Modified from Kobayashi et al. [8]. HRP, horseradish peroxidase; IgG, immunoglobulin G; RIA, radioimmunoassay; ND, not detected.

Reference

1. Rodgers RL. Glucagon and cyclic AMP: time to turn the page? Curr Diabetes Rev. 2012; 8:362–81.

2. Bak MJ, Albrechtsen NW, Pedersen J, Hartmann B, Christensen M, Vilsboll T, et al. Specificity and sensitivity of commercially available assays for glucagon and oxyntomodulin measurement in humans. Eur J Endocrinol. 2014; 170:529–38.

3. Wewer Albrechtsen NJ, Hartmann B, Veedfald S, Windelov JA, Plamboeck A, Bojsen-Moller KN, et al. Hyperglucagonaemia analysed by glucagon sandwich ELISA: nonspecific interference or truly elevated levels? Diabetologia. 2014; 57:1919–26.

4. Matsuo T, Miyagawa J, Kusunoki Y, Miuchi M, Ikawa T, Akagami T, et al. Postabsorptive hyperglucagonemia in patients with type 2 diabetes mellitus analyzed with a novel enzymelinked immunosorbent assay. J Diabetes Investig. 2016; 7:324–31.

5. Miyachi A, Kobayashi M, Mieno E, Goto M, Furusawa K, Inagaki T, et al. Accurate analytical method for human plasma glucagon levels using liquid chromatography-high resolution mass spectrometry: comparison with commercially available immunoassays. Anal Bioanal Chem. 2017; 409:5911–8.

6. Kobayashi M, Satoh H, Matsuo T, Kusunoki Y, Tokushima M, Watada H, et al. Plasma glucagon levels measured by sandwich ELISA are correlated with impaired glucose tolerance in type 2 diabetes. Endocr J. 2020; 67:903–22.

7. Kobayashi M, Waki H, Nakayama H, Miyachi A, Mieno E, Hamajima H, et al. Pseudo-hyperglucagonemia was observed in pancreatectomized patients when measured by glucagon sandwich enzyme-linked immunosorbent assay. J Diabetes Investig. 2021; 12:286–9.

8. Kobayashi M, Maruyama N, Yamamoto Y, Togawa T, Ida T, Yoshida M, et al. A newly developed glucagon sandwich ELISA is useful for more accurate glucagon evaluation than the currently used sandwich ELISA in subjects with elevated plasma proglucagon-derived peptide levels. J Diabetes Investig. 2023; 14:648–58.

9. Suga T, Kikuchi O, Kobayashi M, Matsui S, Yokota-Hashimoto H, Wada E, et al. SGLT1 in pancreatic α cells regulates glucagon secretion in mice, possibly explaining the distinct effects of SGLT2 inhibitors on plasma glucagon levels. Mol Metab. 2019; 19:1–12.

10. Day JW, Ottaway N, Patterson JT, Gelfanov V, Smiley D, Gidda J, et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol. 2009; 5:749–57.

11. Ambery P, Parker VE, Stumvoll M, Posch MG, Heise T, Plum-Moerschel L, et al. MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet. 2018; 391:2607–18.

12. Alba M, Yee J, Frustaci ME, Samtani MN, Fleck P. Efficacy and safety of glucagon-like peptide-1/glucagon receptor coagonist JNJ-64565111 in individuals with obesity without type 2 diabetes mellitus: a randomized dose-ranging study. Clin Obes. 2021; 11:e12432.

13. Romero-Gomez M, Lawitz E, Shankar RR, Chaudhri E, Liu J, Lam RLH, et al. A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease. J Hepatol. 2023; 79:888–97.