Impact of weight loss on GLP-1, glucagon and oxyntomodulin secretion in patients with obesity and type 2 diabetes

BACKGROUND: The effect of glucagon on metabolic processes is ambiguous: on the one hand, an excess of this hormone in the postprandial period increases glycemia, on the other hand, it can contribute to weight loss. In this regard, it is important to assess the secretion of the natural glucagon/glucagon-like peptide-1 coagonist oxyntomodulin in obese individuals with or without type 2 diabetes (T2D).

AIM: To investigate the secretion levels of GLP-1, glucagon, and the GLP-1/glucagon coagonist oxyntomodulin in patients with obesity, with or without T2D, during the weight loss process after bariatric surgery.

MATERIALS AND METHODS: The study involved participants with morbid obesity, with or without T2D, all of whom underwent bariatric surgery. Prior to the procedure, and then at 3 and 6 months post-surgery, the patients participated in hyperinsulinemic euglycemic clamp tests and OGTT. During these assessments, glucose, glucagon, GLP-1, and oxyntomodulin levels were measured at 0, 30, and 120 minutes.

RESULTS: The research included 44 obese patients without T2D and 42 with T2D. Baseline characteristics, including age, height, weight, BMI, waist circumference, and hip circumference, did not show significant differences between the two groups. Patients without T2D showed a lower degree of insulin resistance, a lower glucagon level, and greater preservation of GLP-1 secretion. Additionally, these patients initially exhibited higher levels of oxyntomodulin compared to those with T2D (area under the curve 2.08 [1.61; 2.50] ng/ml*h vs 1.64 [1.07; 1.78] ng/ml*h , p<0.00005). Following weight loss, oxyntomodulin secretion levels rose in both groups (in the T2DM (-) group: 2.35 [1.9; 3.28] ng/ml*h at 3 months, 2.55 [2.02; 3.35] ng/ml*h at 6 months, p<0.00001; in the T2DM (+) group: 2.27 [1.95; 2.61] ng/ml*h at 3 months; 2.4 [1.99; 2.72] ng/ml*h at  6 months, p<0.00001) with no significant intergroup differences at 3 and 6 months after ­surgery.

CONCLUSION: Baseline oxyntomodulin levels were significantly higher in patients with normal carbohydrate metabolism than in patients with type 2 diabetes and increased equally in both groups at 3 and 6 months after bariatric intervention. These results may indicate potential protective functions of oxyntomodulin, but further studies are needed.

1. Zhihong Y, Chen W, Qianqian Z, et al. Emerging roles of oxyntomodulin-based glucagon-like peptide-1/glucagon co-agonist analogs in diabetes and obesity. Peptides. 2023;162:170955. doi: https://doi.org/10.1016/j.peptides.2023.170955

2. Chen X, Maldonado E, DeFronzo RA, Tripathy D. Impaired Suppression of Glucagon in Obese Subjects Parallels Decline in Insulin Sensitivity and Beta-Cell Function. J Clin Endocrinol Metab. 2021;106(5):1398-1409. doi: https://doi.org/10.1210/clinem/dgab019

3. Shestakova EA, Il’in AV, Shestakova MV, Dedov II. Secretion of incretin hormones in people having risk factors for type 2 diabetes mellitus. Terapevticheskii arkhiv. 2014;86(10):10-14. (In Russ.)

4. Zheng Z, Zong Y, Ma Y, et al. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduct Target Ther. 2024;9(1):234. doi: https://doi.org/10.1038/s41392-024-01931-z

5. Ershova EV, Troshina EA. Use of bariatric surgery in patients with type 2 diabetes: help to the practitioner. Obesity and metabolism. 2016;13(1):50-56. (In Russ.) doi: https://doi.org/10.14341/omet2016150-56

6. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237(3):E214-E223. doi: https://doi.org/10.1152/ajpendo.1979.237.3.E214

7. Pickford P, Lucey M, Rujan RM, et al. Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist. Mol Metab. 2021;51:101242. doi: https://doi.org/10.1016/j.molmet.2021.101242

8. Look AHEAD Research Group. Eight-year weight losses with an intensive lifestyle intervention: the look AHEAD study. Obesity (Silver Spring). 2014;22(1):5-13. doi: https://doi.org/10.1002/oby.20662

9. Anton SD, Han H, York E, Martin CK, Ravussin E, Williamson DA. Effect of calorie restriction on subjective ratings of appetite. J Hum Nutr Diet. 2009;22(2):141-147. doi: https://doi.org/10.1111/j.1365-277X.2008.00943.x

10. Sumithran P, Prendergast LA, Delbridge E, et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011;365(17):1597-1604. doi: https://doi.org/10.1056/NEJMoa1105816

11. Wynne K, Park AJ, Small CJ, et al. Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial. Diabetes. 2005;54(8):2390-2395. doi: https://doi.org/10.2337/diabetes.54.8.2390

12. Wynne K, Park AJ, Small CJ, et al. Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial. Int J Obes (Lond). 2006;30(12):1729-1736. doi: https://doi.org/10.1038/sj.ijo.0803344

13. Alba M, Yee J, Frustaci ME, Samtani MN, Fleck P. Efficacy and safety of glucagon-like peptide-1/glucagon receptor co-agonist JNJ-64565111 in individuals with obesity without type 2 diabetes mellitus: A randomized dose-ranging study. Clin Obes. 2021;11(2):e12432. doi: https://doi.org/10.1111/cob.12432

14. Alba M, Yee J, Frustaci ME, et al. Efficacy and safety of glucagon-like peptide-1/glucagon receptor co-agonist JNJ-64565111 in individuals with obesity without type 2 diabetes mellitus: A randomized dose-ranging study. Clin Obes. 2021;11(2):e12432. doi: https://doi.org/10.1111/cob.12432

15. Winther JB, Holst JJ. Glucagon agonism in the treatment of metabolic diseases including type 2 diabetes mellitus and obesity. Diabetes Obes Metab. 2024;26(9):3501-3512. doi: https://doi.org/10.1111/dom.15693

16. Alexiadou K, Cuenco J, Howard J, et al. Proglucagon peptide secretion profiles in type 2 diabetes before and after bariatric surgery: 1-year prospective study. BMJ Open Diabetes Res Care. 2020;8(1):e001076. doi: https://doi.org/10.1136/bmjdrc-2019-001076

17. Lafferty RA, O’Harte FPM, Irwin N, Gault VA, Flatt PR. Proglucagon-Derived Peptides as Therapeutics. Front Endocrinol (Lausanne). 2021;12:689678. Published 2021 May 18. doi: https://doi.org/10.3389/fendo.2021.689678