▎GLP-3 Research
What is the research background of GLP-3?
Obesity has become one of the prominent public health challenges in contemporary society. It can give rise to numerous health problems such as type 2 metabolism mellitus, cardiovascular diseases, hypertension, dyslipidemia, and non-alcoholic fatty liver disease. With the continuous increase in the incidence of obesity, there is an increasingly urgent need for new therapies that can effectively manage body weight and improve health conditions [1]. Although lifestyle interventions, such as increased physical activity and dietary control, are the core measures for weight mnagement, it is extremely difficult for many adult obese patients to maintain long-term weight loss.
GLP-3, as a novel triple receptor agonist, can act on the glucagon-like peptide-1 receptor (
GLP-1R), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon receptor (GCGR). This multi-receptor mechanism of action endows it with significant advantages in the field of weight loss. Compared with weight loss drugs that act on only a single receptor, GLP-3 can more comprehensively regulate the body's metabolic processes[1]. GLP-3 achieves weight loss by regulating multiple hormone receptors, not only showing remarkable efficacy but also having relatively mild gastrointestinal side effects. In addition, as a triple receptor agonist, GLP-3 has a more powerful weight loss effect and a wider range of applicable populations compared with other new weight loss drugs.
What is GLP-3?
GLP-3 is a novel long-acting glucagon-like peptide-1 (GLP-1) receptor agonist. It is modified and optimized based on the structure of natural GLP-1, and it can specifically bind to and activate the GLP-1 receptor, exerting physiological functions similar to those of natural GLP-1, such as promoting insulin secretion, inhibiting glucagon secretion, delaying gastric emptying, reducing appetite, etc. It has broad application prospects in the treatment of metabolism and weight management.
What is the mechanism of action of GLP-3?
The mechanism of action of GLP-3 stems from its agonistic effects on multiple receptors. Firstly, its agonistic effect on the glucagon-like peptide-1 receptor (GLP-1R) can increase insulin secretion, inhibit glucagon secretion, lower blood glucose levels, and at the same time delay gastric emptying, increase satiety, and reduce food intake [2]. Secondly, its agonistic effect on the glucose-dependent insulinotropic polypeptide receptor (GIPR) can promote insulin secretion, enhance glucose utilization, and affect fat metabolism, inhibiting lipolysis and promoting fat synthesis[2]. Moreover, the agonistic effect of GLP-3 on the glucagon receptor (GCGR) usually promotes glycogenolysis and gluconeogenesis in the liver, increasing blood glucose levels. However, under the action of GLP-3, this glucose-raising effect is offset by the effects of the other two receptors, while promoting lipolysis and reducing fat accumulation [2]. This multi-target mode of action may be more effective in treating obesity than single receptor agonists.
By simultaneously activating these three receptors, GLP-3 can exert a variety of metabolic regulatory effects and produce therapeutic effects on obesity and related diseases. In terms of regulating blood glucose levels, since the activation of GLP-1R and GIPR promotes insulin secretion and inhibits glucagon secretion, and the activation of GCGR is offset by the effects of the other two receptors, GLP-3 can effectively regulate blood glucose levels, which is of great significance for the treatment of type 2 metabolism mellitus [1, 2]. In terms of reducing fat accumulation, the activation of GCGR promotes lipolysis and reduces fat accumulation, while the activation of GLP-1R increases satiety and reduces food intake, further reducing fat synthesis [1]. In addition, GLP-3 also has an improving effect on non-alcoholic fatty liver disease. It can reduce the fat content in the liver and improve liver function.
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HbA1c, bodyweight, blood pressure, and lipids Data are least-squares means (with error bars showing SEs) from the efficacy analysis set, unless otherwise noted.
Source:PubMed[4]
In what aspects does GLP-3 show its effects?
GLP-3 exhibits significant effects in multiple aspects
Significant weight loss effect: GLP-3 has demonstrated significant weight loss effects in multiple clinical trials. For example, in a clinical study involving 338 adults (Jastreboff A M M, 2023), patients treated with different doses of GLP-3 experienced significant weight loss at 48 weeks. Among them, patients in the 12mg dose group lost 24.2% of their body weight, and a high proportion of patients achieved weight loss to varying degrees. For instance, among patients receiving 4mg, 8mg, and 12mg doses, 92%, 100%, and 100% of the patients, respectively, lost 5% or more of their body weight. In another study [3], two randomized controlled trials involving 353 patients with type 2 metabolism mellitus showed that compared with the placebo, GLP-3 could significantly reduce the body weight of patients by 11.89kg, and also reduce glycated hemoglobin (HbA1C). In addition, in trials of adult patients with obesity without metabolism, GLP-3 caused a 24.2% weight loss in patients, and 83% of the patients lost 15% or more of their body weight at 48 weeks. These results indicate that GLP-3 has great potential in weight loss.
Treatment of type 2 metabolism mellitus: GLP-3 also shows certain potential in the treatment of type 2 metabolism mellitus. In some clinical trials, GLP-3 has shown a reduction in glycated hemoglobin (HbA1c) and dose-dependent weight loss. For example, in one study, in patients with type 2 metabolism mellitus, GLP-3 demonstrated significant blood glucose control effects. Compared with the placebo, glycated hemoglobin decreased by 1.64% [3]. Additionally, in a randomized, double-blind, placebo and active-controlled parallel-group phase 2 trial, animal models with type 2 metabolism mellitus, after receiving GLP-3 treatment, showed a significant decrease in glycated hemoglobin levels, and their body weight also decreased in a dose-dependent manner [4]. This can be attributed to the comprehensive effects of the drug on GLP-1, GCGR, and GIPR, which improve glucose metabolism and energy balance.
Improvement of cardiovascular risk factors: GLP-3 can not only reduce body weight but also improve cardiovascular risk factors, such as the serum lipid profile and glycated hemoglobin levels. This indicates a close pathophysiological link between obesity and cardiovascular diseases, and GLP-3 may improve the cardiovascular health of obese patients through multiple pathways. For example, reducing non-HDL-C, apoB, and LDLP levels can reduce the risk of atherosclerosis; reducing glycated hemoglobin levels can improve blood glucose control in patients with metabolism, thereby reducing the risk of cardiovascular complications [3, 5, 6].
Treatment of non-alcoholic fatty liver disease (NAFLD): GLP-3 is a novel triple receptor agonist peptide that targets the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). Studies have shown that GLP-3 has the potential to treat non-alcoholic fatty liver disease. In one study, a randomized, double-blind, placebo-controlled trial was conducted for 48 weeks on participants with metabolic dysfunction-associated fatty liver disease and a liver fat content of ≥10%. The results showed that at 24 weeks, the average relative changes in liver fat from the baseline in participants treated with different doses of GLP-3 (1mg, 4mg, 8mg, and 12mg) were -42.9%, -57.0%, -81.4%, and -82.4%, respectively, while that in the placebo group was +0.3%[7]. This indicates that GLP-3 may have a significant therapeutic effect on non-alcoholic fatty liver disease.
In conclusion, as a novel triple receptor agonist, GLP-3 shows great potential in the treatment of obesity and related diseases. It can regulate human metabolism from multiple dimensions by activating the glucagon receptor, glucose-dependent insulinotropic polypeptide receptor, and glucagon-like peptide-1 receptor, improving blood glucose control, reducing body weight, and regulating lipid metabolism. The emergence of GLP-3 has brought new treatment options for patients with obesity, type 2 metabolism mellitus, etc. It is expected to break through the limitations of traditional single receptor agonist drugs, provide a more powerful weapon for solving the increasingly serious problems of obesity and metabolic diseases, promote the further development of related medical fields, improve the quality of life of patients, and reduce the social medical burden.
About The Author
The above-mentioned materials are all researched, edited and compiled by Cocer Peptides.
Scientific Journal Author
Rosenstock J is a highly influential scholar in the medical field, closely collaborating with institutions such as the University of Texas Southwestern Medical Center and the University of Texas Dallas. He also conducts research at centers like the Canadian VIGOUR Center and Veloc Clin Res Ctr Med City.
His research spans endocrinology and metabolism, cardiovascular system and cardiology, pharmacology, and experimental medicine, with a focus on metabolism, obesity, and related treatments and drug development. J Rosenstock has achieved significant success in clinical medicine, being named a Highly Cited Researcher from 2017 to 2024. This highlights the high impact and broad recognition of his work. Through collaboration with multiple research institutions, he has successfully translated basic research findings into clinical applications, benefiting patients with metabolic and cardiovascular diseases and advancing medical science. Rosenstock J is listed in the reference of citation [4].
