Unlocking the Power of GLP-1: Transforming Metabolic Health and Weight Management

Unlocking the Power of GLP-1: Transforming Metabolic Health and Weight Management

Glucagon-like peptide 1 (GLP-1) has emerged as a key player in metabolic health. This naturally occurring hormone, secreted by the small intestine, regulates blood sugar levels, appetite, and weight. Its synthetic counterparts, GLP-1 receptor agonists (GLP-1RAs), have revolutionized the treatment of Type 2 Diabetes Mellitus (T2DM) and obesity.¹,² This article explores the roles of GLP-1 and GLP-1RAs, their clinical applications, and the potential for dietary supplements to support their activity.

Understanding GLP-1 and Its Functions

GLP-1 is a naturally occurring peptide hormone that plays a crucial role in regulating – among other things – blood sugar levels. It is produced in the small intestines and released into the bloodstream after eating.¹

Functions: 

• Stimulates insulin secretion:

GLP-1 increases insulin release from the pancreas, which helps lower blood sugar levels.¹

• Inhibits glucagon secretion:

GLP-1 prevents the pancreas from releasing glucagon, a hormone that raises blood sugar levels.¹

• Slows gastric emptying:

GLP-1 delays the stomach from emptying its contents into the small intestine, which helps regulate appetite and reduce calorie intake.¹

• Promotes beta-cell growth and survival:

GLP-1 helps protect and increase the number of insulin-producing cells in the pancreas.¹

Therapeutic Uses: 

Over the last two years, GLP-1 and, of more interest, Glucagon-Like Peptide 1 Receptor Agonists, which are sometimes called Glucagon-Like Peptide 1 Receptor Analogs (both are referred to as GLP-1RAs), have been all over print and digital media. These compounds have become globally famous and are in high demand for what they can do. Let us look at what these GLP-1RAs are precisely and why there is so much interest and demand for them.

The Rise of GLP-1 Receptor Agonists

GLP-1RAs, all synthetic and slightly altered versions of GLP-1, are used to treat Type 2 Diabetes Mellitus or Non-Insulin Dependent Diabetes Mellitus. (T2DM). They help improve blood sugar control, elicit weight reduction, and lower the risk of cardiovascular events. GLP-1RAs are available as subcutaneous injectable medications or oral pills.²

GLP-1RAs mimic the endogenous peptide hormone GLP-1, which is produced in the small intestine. They have a similar pharmacological effect as GLP-1, and they can cause or increase weight loss by:

• Increasing insulin production when blood sugar rises after eating.
• Slowing the movement of food from the stomach to the small intestine.

GLP-1RAs and GLP-1: What Differentiates them?

While GLP-1RAs are very similar to actual GLP-1, some significant differences exist between the two categories worth reviewing.

GLP-1 and GLP-1RAs are peptide medications used to treat T2DM and obesity. While they share similarities, the differences between the two are highlighted below:

Structure: 

• GLP-1 is a naturally occurring hormone found in the small intestines, while GLP-1RAs are synthetic variations of GLP-1 that differ, albeit only slightly, from natural GLP-1.
• The modified chemical structure of GLP-1RAs allows them to remain pharmacologically active in the body for longer than GLP-1. The half-lives of GLP-1RAs are several orders of magnitude longer than that of GLP-1, which has a plasma half-life of only 1.5-5.0 minutes when secreted by the small intestines.³ This short duration of action represents a significant limitation for the use of GLP-1 in a clinical setting, and the result is that often, GLP-1 must be administered twice per day while most GLP-1RAs are administered only once weekly. However, commercially available GLP1-RAs have an impressively extended elimination half-life of 5.7 to 6.7 days.⁴

Mechanism of Action: 

• GLP-1 and GLP-1RAs stimulate insulin release from the pancreas, suppress glucagon secretion, and slow gastric emptying.
• GLP-1RAs are usually significantly more potent than actual GLP-1 and may have additional or more desirable effects, such as much greater appetite reduction and substantially greater promotion of weight loss.⁵

Dosage and Formulations: 

Currently, in the USA, GLP-1 and the listed GLP-1RAs are approved for use by the US FDA, and only a subscription from a medical physician or similarly credentialed healthcare provider is required. Not all of them are approved for treating obesity or inducing weight loss (even if they do cause such). Most are approved for use in treating T2DM.

Efficacy and Safety: 

• Studies have shown that GLP-1RAs are generally much more effective than GLP-1 at lowering blood sugar levels and promoting weight loss.⁶
• GLP-1RAs have a significantly higher risk of gastrointestinal side effects, such as nausea, vomiting, and diarrhea. There have also been serious adverse events (SAEs) reported with the use of GLP-1RAs, such as pancreatitis.⁷ GLP-1RAs have been linked to the release of calcitonin and the potential formation of thyroid tumors.⁸
• As GLP-1RAs are polypeptide in nature (proteinaceous), antibody formation against the drug could potentially occur, resulting in injection-site reactions, loss of efficacy, and anaphylaxis. Evidence from several head-to-head trials indicates that antibodies indeed form in some people against GLP-1RA drugs.^{9, 10, 11}
• The most common side effects of GLP-1RAs include nausea, vomiting, diarrhea, and abdominal pain.¹²

Some Other Notes of Interest:

• GLP-1 levels are generally higher in people who have undergone bariatric surgery, which may contribute to the weight-loss benefits of the surgery.¹³
• Oddly, GLP-1 is also being investigated as a potential treatment for Alzheimer’s disease.¹⁴

Dietary Supplements and GLP-1 Modulation

It is important to preface that under current federal law, the US FDA has stringent and mandatory requirements related to Structure/Function Claims and the Dietary Ingredients/Supplements label. Most of the readers are quite familiar with the boxed compulsory statement that, by law, must appear on EVERY label of EVERY Dietary Supplement:

So, while it would be egregiously irresponsible as well as illegal to make any claim that any nutritional supplement is going to cause a “drug-like” effect, it is certainly within the realm of science to ask if any dietary ingredients affect plasma GLP-1 levels, specifically if any may lead to an increase in plasma GLP-1 levels.

Such questions have already been asked and, to varying degrees, answered (at least in part).

The following dietary ingredients have been correlated with an increase in GLP-1 levels. Please note that many of these citations refer to preclinical research done in petri dishes or animal models such as mice or rats. Claims that these ingredients will lead to the same results in humans cannot be made responsibly at this time.

Curcumin This study demonstrated substantial GLP-1 increases in mouse STC1-Cell Culture lines in the petri dish when exposed to substantial concentrations of curcuminoids – from 4.5mM/mL to over 100mM/mL.¹⁵

Berberine has been correlated in rats to cause a transient rise in GLP-1 levels. The oral dose of berberine given in this study was relatively high, at 120mg/kg body weight per day over five weeks.¹⁶

Probiotics A 2022 meta-analysis studied the changes in GLP-1 levels, suggesting there may be a link between various probiotics and GLP-1 levels.¹⁷

Ginseng. A meta-analysis published in Nutrients reviewing non-human, human, and rodent studies showed a connection between some extracts of ginseng and GLP-1 levels. Data from animal and in vitro studies have shown that ginseng extract and specific ginsenosides may benefit various aspects of glucose and lipid metabolism. More research is needed on the effects of ginseng and GLP-1 levels.¹⁸

Butyrate A 2018 study was performed on mice on a high-fat diet (HFD), biopsies of people with non-alcoholic fatty liver disease (NAFLD), and human hepatoma cell lines to assess the effects of Sodium Butyrate on GLP-1. The study also examined in vitro cell cultures of human hepatoma cells/NAFLD cells exposed to moderate amounts of Sodium Butyrate (5 uM) for 24 hours. The results showed an increase in the number of GLP-1 receptors in vitro.¹⁹ 

In the HFD murine models, adding sodium butyrate to the diet substantially increased the number of GLP-1 receptors and overall serum GLP-1 levels over 8 and 16 weeks. The study authors concluded that the effects of Sodium Butyrate on histone deacetylase (HDAC) may be primarily responsible for these results. More research is needed in this area before any correlative conclusions can be made in humans.¹⁹

The Future of GLP-1 in Metabolic Health

In conclusion, Glucagon-Like Peptide 1 (GLP-1) and its receptor agonists (GLP-1RAs) have emerged as powerful tools in the management of Type 2 Diabetes Mellitus and obesity, with their ability to regulate blood sugar, reduce weight, and lower cardiovascular risks. While GLP-1 is a naturally occurring hormone with a short half-life, GLP-1RAs are engineered to overcome these limitations, offering extended activity and greater efficacy. The blog explores the critical roles of GLP-1 and GLP-1RAs, including their mechanisms of action, benefits, and associated risks, providing a comprehensive overview of their potential and limitations.

Notably, butyrate—a short-chain fatty acid known for its gut health benefits—stands out among dietary components that may influence GLP-1 levels. Preclinical studies suggest that butyrate can increase GLP-1 secretion and receptor activity, potentially enhancing its metabolic benefits. These findings highlight butyrate’s unique position as a promising adjunct in metabolic health interventions. While other ingredients like curcumin, berberine, and probiotics have been associated with GLP-1 modulation, the evidence surrounding butyrate is particularly compelling due to its direct impact on GLP-1 receptor activity and its broader implications for managing glucose regulation and weight control.

This connection between butyrate and GLP-1 exemplifies the potential for innovative dietary and therapeutic strategies to improve metabolic health. As research progresses, this nexus of nutrition and endocrinology offers exciting opportunities for developing more effective and accessible interventions for metabolic disorders.

References

1. Drucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell metabolism. United States: Elsevier Inc; 2018;27(4):740–756. PMID: 29617641

2. Gupta V. Glucagon-like peptide-1 analogues: An overview. Indian journal of endocrinology and metabolism. India: Medknow Publications; 2013;17(3):413–421. PMID: 23869296

3. Hui H, Farilla L, Merkel P, Perfetti R. The short half-life of glucagon-like peptide-1 in plasma does not reflect its long-lasting beneficial effects. European Journal of Endocrinology. Colchester: European Society of Endocrinology; 2002;146(6):863–869. PMID: 12039708

4. Marx N, Husain M, Lehrke M, Verma S, Sattar N. GLP-1 Receptor Agonists for the Reduction of Atherosclerotic Cardiovascular Risk in Patients With Type 2 Diabetes. Circulation. 2022 Dec 13;146(24):1882-1894. doi: 10.1161/CIRCULATIONAHA.122.059595. Epub 2022 Dec 12. PMID: 36508493.

5. Nauck MA, Quast DR, Wefers J, Pfeiffer AFH. The evolving story of incretins (GIP and GLP‐1) in metabolic and cardiovascular disease: A pathophysiological update. Diabetes, obesity & metabolism. Oxford, UK: Blackwell Publishing Ltd; 2021;23(S3):5–29. PMID: 34310013

6. Zheng Z, Zong Y, Ma Y, Tian Y, Pang Y, Zhang C, Gao J. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal transduction and targeted therapy. London: Nature Publishing Group UK; 2024;9(1):234–29. PMID: 39289339

7. Egan AG, Blind E, Dunder K, de Graeff PA, Hummer BT, Bourcier T, Rosebraugh C. Pancreatic safety of incretin-based drugs–FDA and EMA assessment. N Engl J Med. 2014 Feb 27;370(9):794-7. doi: 10.1056/NEJMp1314078. Erratum in: N Engl J Med. 2014 Jun 5;370(23):2253. PMID: 24571751.

8. Fonseca VA, Devries JH, Henry RR, Donsmark M, Thomsen HF, Plutzky J. Reductions in systolic blood pressure with liraglutide in patients with type 2 diabetes: insights from a patient-level pooled analysis of six randomized clinical trials. J Diabetes Complications. 2014 May-Jun;28(3):399-405. doi: 10.1016/j.jdiacomp.2014.01.009. Epub 2014 Jan 21. PMID: 24561125; PMCID: PMC4231710.

9. Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, Porter L; DURATION-1 Study Group. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008 Oct 4;372(9645):1240-50. doi: 10.1016/S0140-6736(08)61206-4. Epub 2008 Sep 7. PMID: 18782641.

10. Blevins T, Pullman J, Malloy J, Yan P, Taylor K, Schulteis C, Trautmann M, Porter L. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011 May;96(5):1301-10. doi: 10.1210/jc.2010-2081. Epub 2011 Feb 9. PMID: 21307137.

11. Buse JB, Garber A, Rosenstock J, Schmidt WE, Brett JH, Videbæk N, Holst J, Nauck M. Liraglutide Treatment Is Associated with a Low Frequency and Magnitude of Antibody Formation with No Apparent Impact on Glycemic Response or Increased Frequency of Adverse Events: Results from the Liraglutide Effect and Action in Diabetes (LEAD) Trials. The journal of clinical endocrinology and metabolism. Bethesda, MD: Endocrine Society; 2011;96(6):1695–1702. PMID: 21450987

12. Shami D, Sousou JM, Batarseh E, Alazrai L. The Roles of Glucagon-Like Peptide 1 (GLP-1) Receptor Agonists and Sodium-Glucose Cotransporter 2 (SGLT-2) Inhibitors in Decreasing the Occurrence of Adverse Cardiorenal Events in Patients With Type 2 Diabetes. Cureus. 2023 Jan 7;15(1):e33484. doi: 10.7759/cureus.33484. PMID: 36751181; PMCID: PMC9901266.

13. Müller TD, Finan B, Bloom SR, D’Alessio D, Drucker DJ, Flatt PR, Fritsche A, Gribble F, Grill HJ, Habener JF, Holst JJ, Langhans W, Meier JJ, Nauck MA, Perez-Tilve D, Pocai A, Reimann F, Sandoval DA, Schwartz TW, Seeley RJ, Stemmer K, Tang-Christensen M, Woods SC, DiMarchi RD, Tschöp MH. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019 Dec;30:72-130. doi: 10.1016/j.molmet.2019.09.010. Epub 2019 Sep 30. PMID: 31767182; PMCID: PMC6812410.

14. Hamilton A, Hölscher C. Receptors for the incretin glucagon-like peptide-1 are expressed on neurons in the central nervous system. NeuroReport. Hagerstown, MD: Ovid Technologies (Wolters Kluwer Health); 2009;20(13):1161–1166. PMID: 19617854

15. Alli-Oluwafuyi AM, Luis PB, Nakashima F, Giménez-Bastida JA, Presley SH, Duvernay MT, Iwalewa EO, Schneider C. Curcumin induces secretion of glucagon-like peptide-1 through an oxidation-dependent mechanism. Biochimie. 2019 Oct;165:250-257. doi: 10.1016/j.biochi.2019.08.013. Epub 2019 Aug 27. PMID: 31470039; PMCID: PMC6746602.

16. Yu Y, Liu L, Wang X, Liu X, Liu X, Xie L, Wang G. Modulation of glucagon-like peptide-1 release by berberine: in vivo and in vitro studies. Biochem Pharmacol. 2010 Apr 1;79(7):1000-6. doi: 10.1016/j.bcp.2009.11.017. Epub 2009 Nov 27. PMID: 19945441.

17. Liang T, Xie X, Wu L, Li L, Yang L, Gao H, Deng Z, Zhang X, Chen X, Zhang J, Ding Y, Wu Q. Comparative analysis of the efficacies of probiotic supplementation and glucose-lowering drugs for the treatment of type 2 diabetes: A systematic review and meta-analysis. Frontiers in nutrition (Lausanne). Frontiers Media S.A; 2022;9:825897–825897. PMID: 35923194

18. Naseri K, Saadati S, Sadeghi A, Asbaghi O, Ghaemi F, Zafarani F, Li HB, Gan RY. The Efficacy of Ginseng (Panax) on Human Prediabetes and Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. Nutrients. 2022 Jun 9;14(12):2401. doi: 10.3390/nu14122401. PMID: 35745129; PMCID: PMC9227417.

19. Da Zhou, Yuan-Wen Chen, Ze-Hua Zhao, Rui-Xu Yang, Feng-Zhi Xin, Xiao-Lin Liu, Qin Pan, Huiping Zhou, Jian-Gao Fan. Sodium butyrate reduces high-fat diet-induced non-alcoholic steatohepatitis through upregulation of hepatic GLP-1R expression. Experimental & Molecular Medicine. Springer Science and Business Media LLC; 2018;50(12):1–12.