Oxyntomodulin was initially identified as a moiety that exhibited glucagon like immunoreactivity and was appropriately named for its ability to modulate the gastric acid secretion in the gastric oxyntic glands.1,2 Oxyntomodulin is a 37 amino acid peptide hormone secreted by the gut endocrine L-cells post-prandially3. Oxyntomodulin and Glucagon, a peptide hormone secreted by the alpha cells of the pancreas, share the identical amino acid sequence in the N-terminal 29 aa with oxyntomodulin having an additional octapeptide in the C-terminus. Upon nutrient ingestion, prohormone convertase1/3 cleaves proglucagon precursor into Oxyntomodulin, GLP-1/2 and GRPP.3

Oxyntomodulin is known to bind both the GLP-1 receptor (GLP1R) and the glucagon receptor (GCGR), but with lower affinity compared to GLP-1 and glucagon.3

Oxyntomodulin causes weight loss in obese patients via suppression of food intake and increase in energy expenditure.3 It is reported to have varied tissue-specific effects; and stimulates endocrine pancreas to secrete insulin, somatostatin and glucagon. Oxyntomodulin administration was also reported to increase heart-rate in mice.3 Besides regulating glucose homeostasis in monogastric animals, oxyntomodulin also increases the concentration of insulin and glucose in plasma of Holstein cattle under normal physiological conditions.4 Using mass-spectrometry based profiling of human plasma, it was shown that Type 2 diabetes patients have lower levels of Oxyntomodulin and levels increase more than 10-fold after gastric bypass surgery.5 Oxyntomodulin is therapeutically used to lower glucose levels and suppress appetite resulting in weight loss.

References:

1. Unger, R.H., Eisentraut,A.M.,McCall,M.S.,Keller,S.,Lanz,H.C.,Madison,L.L., 1959. Glucagon antibodies and their use for immunoassay for glucagon. Proceedings of the Society for Experimental Biology and Medicine 102:621–623.
2. Bataille, D., Tatemoto,K.,Coudray,A.M.,Rosselin,G.,Mutt,V.,1981.Bioactive ‘enteroglucagon’ (oxyntomodulin):evidence for a C-terminal extension of the glucagon molecule. Comptes Rendus des Séances de l’Académie des Sciences. Série III 293:323–328.
3. Pocai A. 2012. Unraveling oxyntomodulin, GLP1’s enigmatic brother. J Endocrinol. 215(3):335-46
4. ThanThan S, Zhao H, Yannaing S, Ishikawa T, Kuwayama H.2010. Oxyntomodulin increases the concentrations of insulin and glucose in plasma but does not affect ghrelin secretion in Holstein cattle under normal physiological conditions. Domest Anim Endocrinol. 39(3):163-70
5. Wewer Albrechtsen NJ et al; 2016. Oxyntomodulin Identified as a Marker of Type 2 Diabetes and Gastric Bypass Surgery by Mass-spectrometry Based Profiling of Human Plasma. EBioMedicine.7:112-20.
6. HHS Publication, 5th ed., 2007. Biosafety in Microbiological and Biomedical Laboratories. Available http://www.cdc.gov/biosafety/publications/bmbl5/BMBL5
7. DHHS (NIOSH) Publication No. 78–127, August 1976. Current Intelligence Bulletin 13 – Explosive Azide Hazard. Available: http:// www.cdc.gov/niosh.
8. Kricka L. Interferences in immunoassays – still a threat. Clin Chem 2000; 46: 1037–1038.

Oxyntomodulin ELISA AL-139
D’Alessio D, Kumar A, Kalra B, Mistry S, Tong J. Novel ELISA Assays Demonstrate Specificity of Islet and Intestinal Processing of Proglucagon. Volume 4, Issue Supplement_1, April May 2020, SUN-LB124, https://doi.org/10

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Fothergill LJ, Ringuet MT, Sioras E, Hunne B, Fazio Coles TE, Martins PR, Furness JB. Cellular and sub-cellular localisation of oxyntomodulin-like immunoreactivity in enteroendocrine cells of human, mouse, pig and rat. Cell Tissue Res. 2019 Feb;375(2):359-369. doi: 10.1007/s00441-018-2921-z. Epub 2018 Sep 27. PMID: 30259122.

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Fothergill LJ, Ringuet MT, Sioras E, Hunne B, Fazio Coles TE, Martins PR, Furness JB. Cellular and sub-cellular localisation of oxyntomodulin-like immunoreactivity in enteroendocrine cells of human, mouse, pig and rat. Cell Tissue Res. 2019 Feb;375(2):359-369.

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Jiang H, Pang S, Zhang Y, Yu T, Liu M, Deng H, et al. A phase 1b randomized controlled trial of a glucagon-like peptide-1 and glucagon receptor dual agonist IBI362 (LY3305677) in Chinese patients with type 2 diabetes. Nat Commun. 2022;13(3613):1-13. doi:10.1038/s41467-022-31328-x(905).

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Kim S, Abbasi F, Nachmanoff C, Kumar A, Kalra B, Savjani G, Mantzoros C. Effect of Liraglutide Treatment on Proglucagon-Derived Peptides. JESOCI, Volume 4, Abstract Supplement, 2020

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Kumar A, Kalra B, Mistry S, Patel AS, Budhavarapu V, Chatterji T, Savjani G, Krishna R, D’Alessio D. Development of Novel Specific and Sensitive ELISAs for Proglucagon-Derived Peptides. Poster presented at 69th AACC Meeting; 2017 July 30-Aug 3; San Diego, CA

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Legro R, Dodson W, Estes S, Kunselman A, Coutifaris C, Dokras A. Effect of Weight Loss and Hormonal Suppression Alone and in Combination on Bioactive Gut and Ovarian Peptide Hormones in Women with Polycystic Ovary Syndrome. Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, MON-233, https://doi.org/10.1210/js.2019-MON-233

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Perakakis N, Chen J, Ghaly W, Vamvini MT, Mantzoros CS. Effects of oral and intravenous lipid administration on hormones affecting energy balance. Poster session presented at the Obesity Week Meeting; 2017 Oct 29-Nov 2; Washington DC.

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Perakakis N, Farr OM, Mantzoros CS. Fasting oxyntomodulin, glicentin, and gastric inhibitory polypeptide levels are associated with activation of reward- and attention-related brain centres in response to visual food cues in adults with obesity: A cross-sectional functional MRI study. Diabetes Obes Metab. 2021 May;23(5):1202-1207. doi: 10.1111/dom.14315. Epub 2021 Jan 22. PMID: 33417264.

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Perakakis N, Kalra B, Angelidi AM, Kumar A, Gavrieli A, MYannakoulia M, Mantzoros CS. Methods paper: Performance characteristics of novel assays for circulating levels of proglucagon-derived peptides and validation in a placebo controlled cross-over randomized clinical trial. Metabolism, Volume 129, 2022, 155157, ISSN 0026-0495, https://doi.org/10.1016/j.metabol.2022.155157.

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Polyzos SA, Perakakis N, Boutari C, Kountouras J, Ghaly W, Anastasilakis AD, Karagiannis A, Mantzoros CS. Targeted Analysis of Three Hormonal Systems Identifies Molecules Associated with the Presence and Severity of NAFLD. J Clin Endocrinol Metab. 2020 Mar 1;105(3):e390–400. doi: 10.1210/clinem/dgz172. PMID: 31690932; PMCID: PMC7112980.

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Richard Legro, William Dodson, Stephanie Estes, Allen Kunselman, Christos Coutifaris, Anuja Dokras, MON-233 Effect of Weight Loss and Hormonal Suppression Alone and in Combination on Bioactive Gut and Ovarian Peptide Hormones in Women with Polycystic Ovary Syndrome, Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, MON–233, https://doi.org/10.1210/js.2019-

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Shah A, Dodson WC, Kris-Etherton PM, Kunselman AR, Stetter CM, Gnatuk CL, Estes SJ, Allison KC, Sarwer DB, Sluss PM, Coutifaris C, Dokras A, Legro RS. Effects of Oral Contraception and Lifestyle Modification on Incretins and TGF-ß Superfamily Hormones in PCOS. J Clin Endocrinol Metab. 2021 Jan 1;106(1):108-119. doi: 10.1210/clinem/dgaa682. PMID: 32968804; PMCID: PMC7765645

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Stefanakis K, Kokkinos A, Argyrakopoulou G, et al. Circulating levels of proglucagon derived peptides are differentially regulated by the glucagon like peptide-1 agonist liraglutide and the centrally acting naltrexone/bupropion and can predict future weight loss and metabolic improvements: A 6-month long interventional study. Diabetes Obes Metab. 023;25(9):2561‐2574. doi:10.1111/dom.15141

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Tuccinardi D, Farr OM, Upadhyay J, Oussaada SM, Klapa MI, Candela M, Rampelli S, Lehoux S, Lázaro I, Sala-Vila A, Brigidi P, Cummings RD, Mantzoros CS. Mechanisms underlying the cardiometabolic protective effect of walnut consumption in obese people: A cross-over, randomized, double-blind, controlled inpatient physiology study. Diabetes Obes Metab. 2019 Sep;21(9):2086-2095. doi: 10.1111/dom.13773. Epub 2019 Jul 2. PMID: 31087608; PMCID: PMC6684390.

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Tuccinardi D, Farr OM, Upadhyay J, Oussaada SM, Mathew H, Paschou SA, Perakakis N, Koniaris A, Kelesidis T, Mantzoros CS. Lorcasse1rin treatment decreases body weight and reduces cardiometabolic risk factors in obese adults: A six-month, randomized, placebo-controlled, double-blind clinical trial. Diabetes Obes Metab. 2019 Jun;21(6):1487-1492. doi: 10.1111/dom.13655. Epub 2019 Mar 18. PMID: 30724455; PMCID: PMC6504613.

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Upadhyay J, Panagiotou G, Anastasilakis A, Mantzoros C. Oxyntomodulin and Glucagon in Healthy Humans: Anthropometric, Hormonal, and Metabolic Predictors and Response to Glucose Load and Exercise. Abstract – ADA Supported Research, Integrated Physiology / Obesity. Not Dated

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Upadhyay J, Perakakis N, Panagiotou G, Anastasilakis AD, Mantzoros CS. Regulation of the proglucagon-derived hormones in healthy and in obese after bariatric surgery. Poster Presentation. Unknown Conference

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