Studies exploring the impact of the peptide also indicate that it may slow gastric emptying, leading to increased satiety and decreased food intake, which may contribute to weight loss observed in test models. It may stimulate the proliferation and differentiation of pancreatic beta cells, potentially promoting their regeneration.(1)
The discovery and development of Liraglutide initially broke ground by identifying GLP-1, an incretin hormone that is considered to induce glycemic control and weight regulation. This discovery prompted efforts to enhance GLP-1’s potential in weight control and insulin resistance.
Studies in Liraglutide have been associated with potential influence on weight and cardiovascular risk factors such as blood pressure and lipid profile. While still under exploratory research conditions, its multifaceted proposed mechanism of action appears to encompass glucose regulation, weight loss, and potential beta cell regeneration.
Research Studies on Liraglutide Peptide
Liraglutide and the Incretin Effect
As posited by Dr. Holst, the incretin effect represents one of the primary physiological impacts of glucagon-like peptide-1 (GLP-1).(3) Incretins encompass a group of metabolic hormones released by the gastrointestinal (GI) tract that are considered to contribute to the reduction of blood glucose levels.
In rodent models, GLP-1, alongside glucose-dependent insulinotropic polypeptide (GIP), has been identified as one of the possible key hormones stimulating the incretin effect. Despite GIP circulating at levels approximately tenfold higher than GLP-1, research teams suggest that GLP-1 may exhibit greater potency, particularly when blood glucose levels are elevated.
Notably, Liraglutide peptide may be potentiated when combined with specific similar compounds. In a study conducted in 2007, the presentation of Liraglutide peptide was investigated in rat pancreases that were pretreated with sulfonylurea compounds. The study results suggested that “GLP-1 administration to isolated perfused rat pancreases at low perfusate glucose concentrations normally does not affect insulin secretion, but resulted in dramatic stimulation of insulin secretion after pre-treatment with sulfonylurea drugs (40, 89). Indeed, 30–40% of patients treated with both sulfonyl urea compounds and a GLP-1 agonist (exendin 4, see below) experience, usually mild, hypoglycemia” (3)
Liraglutide and the Beta Cells
Studies conducted in animal models have suggested that glucagon-like peptide-1 (GLP-1), and similar peptides, such as Liraglutide, may exhibit stimulatory action on the growth and proliferation of pancreatic beta cells. Furthermore, GLP-1-like peptides such as Liraglutide may promote the differentiation of new beta cells from progenitor cells present in the epithelium of the pancreatic duct. They may exert an inhibitory action on beta cell apoptosis.(4) These findings indicate a shift in the balance between beta cell growth and death, favoring growth.
Notably, a compelling trial theorized that Liraglutide may inhibit the death of beta cells induced by elevated levels of inflammatory cytokines. Mouse models of type 1 diabetes have appeared to indicate that GLP-1 may act as a protective agent for islet cells.(4)
Liraglutide and the Cardiovascular System
GLP-1 receptors are widely distributed throughout the heart and are considered by researchers to exert positive actions on cardiac function in specific contexts. These proposed actions include increased heart rate and reduced left ventricular end-diastolic pressure – all of which may potentially help prevent left ventricular hypertrophy, cardiac remodeling, and heart failure.(5)
Emerging scientific research suggests that GLP-1 (and similar peptides such as Liraglutide) may mitigate damage induced via heart dysfunctions. The peptide appears to enhance glucose uptake in cardiac muscle, thereby aiding ischemic myocardial cells in obtaining the necessary nutrients to sustain their function and prevent programmed cell death. Notably, this increase in glucose uptake appears to occur independently of insulin.
Studies involving large infusions of GLP-1 in dogs have indicated improved left ventricular performance and reduced systemic vascular resistance.(6) As per Nikolaidis and team, “rGLP-1 dramatically improved LV and systemic hemodynamics in conscious dogs with advanced DCM induced by rapid pacing. rGLP-1 has insulinomimetic and glucagonostatic properties, with resultant increases in myocardial glucose uptake. rGLP-1 may be a useful metabolic adjuvant in decompensated heart failure.” (6)
Liraglutide and Obesity
Studies conducted in mouse models have indicated that the presentation of GLP-1 and its analog GLP-1Ras, such as Liraglutide, may reduce appetite drive and decrease food intake.(7) Recent clinical investigations have suggested that the twice-daily introduction of GLP-1 receptor agonists in mice may lead to gradual and consistent weight loss. This sustained weight loss may lead to significant improvements in cardiovascular risk factors and a reduction in hemoglobin A1C levels.
Liraglutide and Neuroprotection
Emerging research suggests that GLP-1 may positively improve learning and protect neurons from neurodegenerative impact. Studies have suggested that Liraglutide (GLP-1) may enhance associative and spatial learning in mice and may ameliorate learning deficits in mice with specific genetic abnormalities. In rats with elevated expression of GLP-1 receptors in specific brain regions, learning and memory performance appeared notably enhanced compared to normal controls.(8)
Furthermore, research conducted in mice has suggested that GLP-1 analogs such as Liraglutide may exert neuroprotective action against excitotoxic neuronal damage, which may provide complete protection against glutamate-induced apoptosis in rat models of neurodegeneration. Scientists also theorize that the peptide may promote neurite outgrowth in cultured cells.(9)
- National Center for Biotechnology Information (2022). PubChem Compound Summary for CID 16134956, Liraglutide. https://pubchem.ncbi.nlm.nih.gov/compound/Liraglutide.
- Knudsen LB, Lau J. The Discovery and Development of Liraglutide and Semaglutide. Front Endocrinol (Lausanne). 2019 Apr 12;10:155. doi: 10.3389/fendo.2019.00155. PMID: 31031702; PMCID: PMC6474072. https://pubmed.ncbi.nlm.nih.gov/31031702/
- Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007 Oct;87(4):1409-39. doi: 10.1152/physrev.00034.2006. PMID: 17928588. https://pubmed.ncbi.nlm.nih.gov/17928588/
- Tandong Yang, Meng Chen, Jeffrey D. Carter, Craig S. Nunemaker, James C. Garmey, Sarah D. Kimble, Jerry L. Nadler, Combined treatment with lisofylline and exendin-4 reverses autoimmune diabetes, Biochemical and Biophysical Research Communications, Volume 344, Issue 3, 2006, Pages 1017-1022, ISSN 0006-291X, https://www.sciencedirect.com/science/article/pii/S0006291X06007066
- Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes. 2005. https://pubmed.ncbi.nlm.nih.gov/15616022/
- Nikolaidis LA, Elahi D, Hentosz T, Doverspike A, Huerbin R, Zourelias L, Stolarski C, Shen YT, Shannon RP. Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation. 2004 Aug 24;110(8):955-61. https://pubmed.ncbi.nlm.nih.gov/15313949/
- Blonde L, Klein EJ, Han J, Zhang B, Mac SM, Poon TH, Taylor KL, Trautmann ME, Kim DD, Kendall DM. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. https://pubmed.ncbi.nlm.nih.gov/16776751/
- During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003 Sep; https://pubmed.ncbi.nlm.nih.gov/12925848
- Perry T, Haughey NJ, Mattson MP, Egan JM, Greig NH. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharmacol Exp Ther. 2002 Sep;302(3):881-8. doi: 10.1124/jpet.102.037481. PMID: 12183643. https://pubmed.ncbi.nlm.nih.gov/12183643/
Dr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.