Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Diabetology International

23-03-2024 | Type 1 Diabetes | Mini-Review

Advances in clinical research on glucagon

Authors: Ichiro Horie, Norio Abiru

Published in: Diabetology International

Login to get access

Abstract

We are now celebrating the 100th anniversary of the discovery of an important pancreatic hormone, glucagon. Glucagon is historically described as a diabetogenic hormone elevating glucose levels via increases in insulin resistance and hepatic gluconeogenesis. The more recently identified actions of glucagon include not only its pathophysiologic effects on glucose metabolism but also its significant roles in amino-acid metabolism in the liver. The possibility that abnormalities in α-cells’ secretion of glucagon in metabolic disorders are a compensatory adaptation for the maintenance of metabolic homeostasis is another current issue. However, the clinical research concerning glucagon has been considerably behind the advances in basic research due to the lack of suitable methodology for obtaining precise measurements of plasma glucagon levels in humans. The precise physiology of glucagon secretory dynamics in individuals with metabolic dysfunction (including diabetes) has been clarified since the development in 2014 of a quantitative measurement technique for glucagon. In this review, we summarize the advances in the clinical research concerning glucagon, including those of our studies and the relevant literature.
Literature
1.
Scheen AJ, Lefebvre PJ. Glucagon, from past to present: a century of intensive research and controversies. Lancet Diabetes Endocrinol. 2023;11:129–38.PubMedCrossRef
2.
Wewer Albrechtsen NJ, Holst JJ, Cherrington AD, Finan B, Gluud LL, et al. 100 years of glucagon and 100 more. Diabetologia. 2023;66:1378–94.PubMedCrossRef
3.
4.
Wewer Albrechtsen NJ, Hartmann B, Veedfald S, Windelov JA, Plamboeck A, et al. Hyperglucagonaemia analysed by glucagon sandwich ELISA: nonspecific interference or truly elevated levels? Diabetologia. 2014;57:1919–26.PubMedCrossRef
5.
Miyachi A, Kobayashi M, Mieno E, Goto M, Furusawa K, 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.PubMedCrossRef
6.
Katahira T, Kanazawa A, Shinohara M, Koshibu M, Kaga H, et al. Postprandial plasma glucagon kinetics in type 2 diabetes mellitus: comparison of immunoassay and mass spectrometry. J Endocr Soc. 2019;3:42–51.PubMedCrossRef
7.
Muller WA, Faloona GR, Aguilar-Parada E, Unger RH. Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion. N Engl J Med. 1970;283:109–15.PubMedCrossRef
8.
Holst JJ, Wewer Albrechtsen NJ, Pedersen J, Knop FK. Glucagon and amino acids are linked in a mutual feedback cycle: the liver-alpha-cell axis. Diabetes. 2017;66:235–40.PubMedCrossRef
9.
Kawai K, Murayama Y, Okuda Y, Yamashita K. Postprandial glucose, insulin and glucagon responses to meals with different nutrient compositions in non-insulin-dependent diabetes mellitus. Endocrinol Jpn. 1987;34:745–53.PubMedCrossRef
10.
Yabe D, Kuroe A, Watanabe K, Iwasaki M, Hamasaki A, et al. Early phase glucagon and insulin secretory abnormalities, but not incretin secretion, are similarly responsible for hyperglycemia after ingestion of nutrients. J Diabetes Complicat. 2015;29:413–21.CrossRef
11.
Matsuo T, Miyagawa J, Kusunoki Y, Miuchi M, Ikawa T, et al. Postabsorptive hyperglucagonemia in patients with type 2 diabetes mellitus analyzed with a novel enzyme-linked immunosorbent assay. J Diabetes Investig. 2016;7:324–31.PubMedCrossRef
12.
Kobayashi M, Satoh H, Matsuo T, Kusunoki Y, Tokushima M, 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.PubMedCrossRef
13.
Ichikawa R, Takano K, Fujimoto K, Kobayashi M, Kitamura T, Shichiri M, Miyatsuka T. Robust increase in glucagon secretion after oral protein intake, but not after glucose or lipid intake in Japanese people without diabetes. J Diabetes Investig. 2023;14:1172–4.PubMedPubMedCentralCrossRef
14.
Horie I, Abiru N, Eto M, Sako A, Akeshima J, et al. Sex differences in insulin and glucagon responses for glucose homeostasis in young healthy Japanese adults. J Diabetes Investig. 2018;9:1283–7.PubMedPubMedCentralCrossRef
15.
Faerch K, Borch-Johnsen K, Vaag A, Jorgensen T, Witte DR. Sex differences in glucose levels: a consequence of physiology or methodological convenience? The Inter99 study. Diabetologia. 2010;53:858–65.PubMedCrossRef
16.
Sicree RA, Zimmet PZ, Dunstan DW, Cameron AJ, Welborn TA, et al. Differences in height explain gender differences in the response to the oral glucose tolerance test—the AusDiab study. Diabet Med. 2008;25:296–302.PubMedCrossRef
17.
Rathmann W, Strassburger K, Giani G, Doring A, Meisinger C. Differences in height explain gender differences in the response to the oral glucose tolerance test. Diabet Med. 2008;25:1374–5.PubMedCrossRef
18.
Faerch K, Pacini G, Nolan JJ, Hansen T, Tura A, et al. Impact of glucose tolerance status, sex, and body size on glucose absorption patterns during OGTTs. Diabetes Care. 2013;36:3691–7.PubMedPubMedCentralCrossRef
19.
Qiao Q, Hu G, Tuomilehto J, Nakagami T, Balkau B, et al. Age- and sex-specific prevalence of diabetes and impaired glucose regulation in 11 Asian cohorts. Diabetes Care. 2003;26:1770–80.PubMedCrossRef
20.
Anderwald C, Gastaldelli A, Tura A, Krebs M, Promintzer-Schifferl M, et al. Mechanism and effects of glucose absorption during an oral glucose tolerance test among females and males. J Clin Endocrinol Metab. 2011;96:515–24.PubMedCrossRef
21.
Knop FK, Aaboe K, Vilsboll T, Volund A, Holst JJ, et al. Impaired incretin effect and fasting hyperglucagonaemia characterizing type 2 diabetic subjects are early signs of dysmetabolism in obesity. Diabetes Obes Metab. 2012;14:500–10.PubMedCrossRef
22.
Wewer Albrechtsen NJ, Junker AE, Christensen M, Haedersdal S, Wibrand F, et al. Hyperglucagonemia correlates with plasma levels of non-branched-chain amino acids in patients with liver disease independent of type 2 diabetes. Am J Physiol Gastrointest Liver Physiol. 2018;314:G91–6.PubMedCrossRef
23.
Morita Y, Ohno H, Kobuke K, Oki K, Yoneda M. Variation in plasma glucagon levels according to obesity status in Japanese Americans with normal glucose tolerance. Endocr J. 2021;68:95–102.PubMedCrossRef
24.
Junker AE, Gluud L, Holst JJ, Knop FK, Vilsboll T. Diabetic and nondiabetic patients with nonalcoholic fatty liver disease have an impaired incretin effect and fasting hyperglucagonaemia. J Intern Med. 2016;279:485–93.PubMedCrossRef
25.
Suppli MP, Lund A, Bagger JI, Vilsboll T, Knop FK. Involvement of steatosis-induced glucagon resistance in hyperglucagonaemia. Med Hypotheses. 2016;86:100–3.PubMedCrossRef
26.
Wewer Albrechtsen NJ, Pedersen J, Galsgaard KD, Winther-Sorensen M, Suppli MP, et al. The liver-alpha-cell axis and type 2 diabetes. Endocr Rev. 2019;40:1353–66.PubMedCrossRef
27.
Suppli MP, Bagger JI, Lund A, Demant M, van Hall G, et al. Glucagon resistance at the level of amino acid turnover in obese subjects with hepatic steatosis. Diabetes. 2020;69:1090–9.PubMedCrossRef
28.
Wewer Albrechtsen NJ. Glucagon receptor signaling in metabolic diseases. Peptides. 2018;100:42–7.PubMedCrossRef
29.
Wewer Albrechtsen NJ, Faerch K, Jensen TM, Witte DR, Pedersen J, et al. Evidence of a liver-alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids. Diabetologia. 2018;61:671–80.PubMedCrossRef
30.
Kjeldsen SAS, Thomsen MN, Skytte MJ, Samkani A, Richter MM, et al. Markers of glucagon resistance improve with reductions in hepatic steatosis and body weight in type 2 diabetes. J Endocr Soc. 2023;7:bvad122.PubMedPubMedCentralCrossRef
31.
Bagger JI, Knop FK, Lund A, Holst JJ, Vilsboll T. Glucagon responses to increasing oral loads of glucose and corresponding isoglycaemic intravenous glucose infusions in patients with type 2 diabetes and healthy individuals. Diabetologia. 2014;57:1720–5.PubMedCrossRef
32.
Ichikawa R, Takano K, Fujimoto K, Motomiya T, Kobayashi M, et al. Basal glucagon hypersecretion and response to oral glucose load in prediabetes and mild type 2 diabetes. Endocr J. 2019;66:663–75.PubMedCrossRef
33.
Gar C, Rottenkolber M, Sacco V, Moschko S, Banning F, et al. Patterns of plasma glucagon dynamics do not match metabolic phenotypes in young women. J Clin Endocrinol Metab. 2018;103:972–82.PubMedCrossRef
34.
Shah P, Vella A, Basu A, Basu R, Schwenk WF, et al. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2000;85:4053–9.PubMed
35.
36.
37.
38.
39.
Catalano PM, Tyzbir ED, Roman NM, Amini SB, Sims EA. Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am J Obstet Gynecol. 1991;165:1667–72.PubMedCrossRef
40.
Kuhl C. Etiology and pathogenesis of gestational diabetes. Diabetes Care. 1998;21(Suppl 2):B19–26.PubMed
41.
Grigorakis SI, Alevizaki M, Beis C, Anastasiou E, Alevizaki CC, et al. Hormonal parameters in gestational diabetes mellitus during the third trimester: high glucagon levels. Gynecol Obstet Invest. 2000;49:106–9.PubMedCrossRef
42.
Beis C, Grigorakis SI, Philippou G, Alevizaki M, Anastasiou E. Lack of suppression of plasma glucagon levels in late pregnancy persists postpartum only in women with previous gestational diabetes mellitus. Acta Diabetol. 2005;42:31–5.PubMedCrossRef
43.
Bonde L, Vilsboll T, Nielsen T, Bagger JI, Svare JA, et al. Reduced postprandial GLP-1 responses in women with gestational diabetes mellitus. Diabetes Obes Metab. 2013;15:713–20.PubMedCrossRef
44.
Horie I, Haraguchi A, Ito A, Nozaki A, Natsuda S, et al. Impaired early-phase suppression of glucagon secretion after glucose load is associated with insulin requirement during pregnancy in gestational diabetes. J Diabetes Investig. 2020;11:232–40.PubMedCrossRef
45.
Committee on Practice B-O. ACOG Practice Bulletin No. 190: Gestational diabetes mellitus. Obstet Gynecol. 2018;131:e49–64.CrossRef
46.
47.
Shigeno R, Horie I, Miwa M, Ito A, Haraguchi A, et al. Bihormonal dysregulation of insulin and glucagon contributes to glucose intolerance development at one year post-delivery in women with gestational diabetes: a prospective cohort study using an early postpartum 75-g glucose tolerance test. Endocr J. 2021;68:919–31.PubMedCrossRef
48.
Kramer CK, Borgono CA, Van Nostrand P, Retnakaran R, Zinman B. Glucagon response to oral glucose challenge in type 1 diabetes: lack of impact of euglycemia. Diabetes Care. 2014;37:1076–82.PubMedCrossRef
49.
Komada H, Hirota Y, Sakaguchi K, Okuno Y, Ogawa W, et al. Impaired glucagon secretion in patients with fulminant type 1 diabetes mellitus. Endocrine. 2019;63:476–9.PubMedCrossRef
50.
Kielgast U, Holst JJ, Madsbad S. Antidiabetic actions of endogenous and exogenous GLP-1 in type 1 diabetic patients with and without residual beta-cell function. Diabetes. 2011;60:1599–607.PubMedPubMedCentralCrossRef
51.
52.
Akturk HK, Rewers A, Joseph H, Schneider N, Garg SK. Possible ways to improve postprandial glucose control in type 1 diabetes. Diabetes Technol Ther. 2018;20:S224–32.PubMedCrossRef
53.
Hosokawa Y, Kozawa J, Nishizawa H, Kawamori D, Maeda N, et al. Positive correlation between fasting plasma glucagon and serum C-peptide in Japanese patients with diabetes. Heliyon. 2019;5: e01715.PubMedPubMedCentralCrossRef
54.
55.
Sherr J, Tsalikian E, Fox L, Buckingham B, Weinzimer S, et al. Evolution of abnormal plasma glucagon responses to mixed-meal feedings in youth with type 1 diabetes during the first 2 years after diagnosis. Diabetes Care. 2014;37:1741–4.PubMedPubMedCentralCrossRef
56.
Fredheim S, Andersen ML, Porksen S, Nielsen LB, Pipper C, et al. The influence of glucagon on postprandial hyperglycaemia in children 5 years after onset of type 1 diabetes. Diabetologia. 2015;58:828–34.PubMedCrossRef
57.
Li K, Song WJ, Wu X, Gu DY, Zang P, et al. Associations of serum glucagon levels with glycemic variability in type 1 diabetes with different disease durations. Endocrine. 2018;61:473–81.PubMedCrossRef
58.
Thivolet C, Marchand L, Chikh K. Inappropriate glucagon and GLP-1 secretion in individuals with long-standing type 1 diabetes: effects of residual C-peptide. Diabetologia. 2019;62:593–7.PubMedCrossRef
59.
Ito A, Horie I, Miwa M, Sako A, Niri T, et al. Impact of glucagon response on early postprandial glucose excursions irrespective of residual beta-cell function in type 1 diabetes: a cross-sectional study using a mixed meal tolerance test. J Diabetes Investig. 2021;12:1367–76.PubMedPubMedCentralCrossRef
60.
Takahashi N, Chujo D. Response to “preserved” glucagon secretion in fulminant type 1 diabetes. J Diabetes Investig. 2019;10:188–9.PubMedCrossRef
61.
Sayama K, Imagawa A, Okita K, Uno S, Moriwaki M, et al. Pancreatic beta and alpha cells are both decreased in patients with fulminant type 1 diabetes: a morphometrical assessment. Diabetologia. 2005;48:1560–4.PubMedCrossRef
62.
Kawamori D, Katakami N, Takahara M, Miyashita K, Sakamoto F, et al. Dysregulated plasma glucagon levels in Japanese young adult type 1 diabetes patients. J Diabetes Investig. 2019;10:62–6.PubMedCrossRef
63.
64.
65.
Pixner T, Stummer N, Schneider AM, Lukas A, Gramlinger K, et al. The relationship between glucose and the liver-alpha cell axis—a systematic review. Front Endocrinol. 2022;13:1061682.CrossRef
66.
67.
68.
Mitrakou A, Fanelli C, Veneman T, Perriello G, Calderone S, et al. Reversibility of unawareness of hypoglycemia in patients with insulinomas. N Engl J Med. 1993;329:834–9.PubMedCrossRef
69.
Arbelaez AM, Xing D, Cryer PE, Kollman C, Beck RW, et al. Blunted glucagon but not epinephrine responses to hypoglycemia occurs in youth with less than 1 yr duration of type 1 diabetes mellitus. Pediatr Diabetes. 2014;15:127–34.PubMedCrossRef
70.
Sherr J, Xing D, Ruedy KJ, Beck RW, Kollman C, et al. Lack of association between residual insulin production and glucagon response to hypoglycemia in youth with short duration of type 1 diabetes. Diabetes Care. 2013;36:1470–6.PubMedPubMedCentralCrossRef
71.
72.
Hare KJ, Vilsboll T, Asmar M, Deacon CF, Knop FK, et al. The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute equally to its glucose-lowering action. Diabetes. 2010;59:1765–70.PubMedPubMedCentralCrossRef
73.
Balas B, Baig MR, Watson C, Dunning BE, Ligueros-Saylan M, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007;92:1249–55.PubMedCrossRef
74.
Kuhadiya ND, Dhindsa S, Ghanim H, Mehta A, Makdissi A, et al. Addition of liraglutide to insulin in patients with type 1 diabetes: a randomized placebo-controlled clinical trial of 12 weeks. Diabetes Care. 2016;39:1027–35.PubMedPubMedCentralCrossRef
75.
Redondo MJ, Bacha F. GLP-1 receptor agonist as adjuvant therapy in type 1 diabetes: no apparent benefit for beta-cell function or glycemia. J Clin Endocrinol Metab. 2020;105:e3000–2.PubMedPubMedCentralCrossRef
76.
Riddle MC, Nahra R, Han J, Castle J, Hanavan K, et al. Control of postprandial hyperglycemia in type 1 diabetes by 24-hour fixed-dose coadministration of pramlintide and regular human insulin: a randomized, two-way crossover study. Diabetes Care. 2018;41:2346–52.PubMedCrossRef
77.
Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499–508.PubMedPubMedCentralCrossRef
78.
Suga T, Kikuchi O, Kobayashi M, Matsui S, Yokota-Hashimoto H, et al. SGLT1 in pancreatic alpha cells regulates glucagon secretion in mice, possibly explaining the distinct effects of SGLT2 inhibitors on plasma glucagon levels. Mol Metab. 2019;19:1–12.PubMedCrossRef
79.
Committee on the Proper Use of SI. Recommendations on the proper use of SGLT2 inhibitors. J Diabetes Investig. 2020;11:257–61.CrossRef
80.
Nakamura Y, Horie I, Tashiro S, Kobayashi M, Kitamura T, et al. Study of glucagon response and its association with glycemic control and variability after administration of ipragliflozin as an adjunctive to insulin treatment in patients with type 1 diabetes (Suglat-AID): a protocol for single-arm, multicenter, open-label, prospective exploratory trial. Med Case Rep Study Protoc. 2021;2: e0135.CrossRef
81.
Lefebvre PJ, Paquot N, Scheen AJ. Inhibiting or antagonizing glucagon: making progress in diabetes care. Diabetes Obes Metab. 2015;17:720–5.PubMedCrossRef
82.
Kazda CM, Ding Y, Kelly RP, Garhyan P, Shi C, et al. Evaluation of efficacy and safety of the glucagon receptor antagonist LY2409021 in patients with type 2 diabetes: 12- and 24-week phase 2 studies. Diabetes Care. 2016;39:1241–9.PubMedCrossRef
83.
Yabe D, Kawamori D, Seino Y, Oura T, Takeuchi M. Change in pharmacodynamic variables following once-weekly tirzepatide treatment versus dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono substudy). Diabetes Obes Metab. 2023;25:398–406.PubMedCrossRef
84.
Heise T, Mari A, DeVries JH, Urva S, Li J, et al. Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial. Lancet Diabetes Endocrinol. 2022;10:418–29.PubMedCrossRef
85.
Ambery P, Parker VE, Stumvoll M, Posch MG, Heise T, 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.PubMedCrossRef
86.
Tillner J, Posch MG, Wagner F, Teichert L, Hijazi Y, et al. A novel dual glucagon-like peptide and glucagon receptor agonist SAR425899: results of randomized, placebo-controlled first-in-human and first-in-patient trials. Diabetes Obes Metab. 2019;21:120–8.PubMedCrossRef
87.
88.
Cegla J, Troke RC, Jones B, Tharakan G, Kenkre J, et al. Coinfusion of low-dose GLP-1 and glucagon in man results in a reduction in food intake. Diabetes. 2014;63:3711–20.PubMedCrossRef
89.
Finan B, Capozzi ME, Campbell JE. Repositioning glucagon action in the physiology and pharmacology of diabetes. Diabetes. 2020;69:532–41.PubMedCrossRef
Metadata
Title
Advances in clinical research on glucagon
Authors
Ichiro Horie
Norio Abiru
Publication date
23-03-2024
Publisher
Springer Nature Singapore
Published in
Diabetology International
Print ISSN: 2190-1678
Electronic ISSN: 2190-1686
DOI
https://doi.org/10.1007/s13340-024-00705-w
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits