GLP-1 + GIP 5 mg

GLP-1 + GIP is a polypeptide closely similar to the recently known drug tirzepatide (Gastric Inhibitory Polypeptide; Gastric Inhibitory Peptide), created for individuals dealing with type 2 diabetes and non-alcoholic fatty liver disease.

It consists of a chain of 39 amino acids, with a molecular mass of 4813.527 g/mol, making it a relatively large peptide, which limits its stability under higher temperatures. GLP-1 + GIP-1 stimulates insulin release by binding to GIP and GLP-1 receptors in the pancreas. Over time, its use increases adiponectin levels (a protein that regulates metabolic processes) by up to 26% [1].

GLP-1 suppresses hunger, reduces insulin levels, and enhances insulin sensitivity. This results in significant weight loss, improved glucose tolerance, and a reduced risk of cardiovascular diseases.

HOW GLP-1 ANALOGS WORK

In the simplest terms, they increase insulin release from the pancreas, thereby regulating blood glucose levels. Studies show that individuals with type 2 diabetes, after using GLP-1 + GIP for a 6-month period, experience a 2.4% decrease in glycated hemoglobin HbA1c levels. HbA1c reflects average blood sugar levels over recent months and is directly proportional to the administered dose, also affecting body weight (body fat levels) in tirzepatide users. The higher the dose, the greater the weight loss [2].

The mechanism of action of GLP-1 analogs (such as tirzepatide or ozempic) is not solely based on improving insulin production. Research indicates that these agents enhance the functioning of pancreatic beta cells, responsible for insulin production. Importantly, studies show that GLP-1 analogs can increase the efficiency of insulin processing by beta cells. Additionally, this affects their workload (which is crucial when considering the transition from type 2 diabetes to type 1 diabetes) and slows down the progression of type 2 diabetes.

It is significant that GLP-1 analogs increase insulin production in a glycemic state-dependent manner. This results in fasting GLP-1 analogs lowering insulin levels, thereby contributing to improved insulin sensitivity in peripheral tissues. Another positive aspect of using GLP-1 analogs is the reduction in fasting glucagon levels, which also promotes glycemic stability [3].

Advantage of GLP-1 + GIP over other GLP-1 analogs

The product is a dual agonist of the GIP receptor and the GLP-1 receptor (glucagon-like peptide-1). These receptors appear to interact synergistically in terms of metabolic disorders more effectively than GLP-1 agonists alone, which are already approved as a therapy for type 2 diabetes and obesity. GLP-1 has a higher affinity for the GIP receptor than for the GLP-1 receptor.

GIP, also known as an insulinotropic polypeptide, is endogenously synthesized in the small intestine. It binds to the GIP receptor and reduces the production of gastric acid while stimulating insulin production. This secondary function is the main reason why the body increases insulin production after a meal. GLP-1 receptors are not only found in the pancreas but also in the brain. Similar to GIP, GLP-1 stimulates insulin production. Activation of the GLP-1 receptor increases both insulin synthesis and its release, which has been the basis of interest in GLP-1 analogs and their development. In the brain, stimulation of the GLP-1 receptor reduces appetite.

The dual nature of GLP-1, as mentioned earlier, in terms of receptor stimulation – GIP and GLP-1 – is what gives it an advantage over other GLP-1 analogs. Stimulation of the GLP-1 receptor at a genetic level increases the survival time of pancreatic beta cells. This leads to more efficient insulin secretion [4]. Studies show that GLP-1 GIP exerts a similar strength of stimulation as GIP at the GIP receptor level. However, in the case of the GLP-1 receptor, it favors cAMP production over beta-arrestin, which translates into GLP-1 exhibiting an even higher level of GLP-1 receptor activation compared to other GLP-1 agonists – both endogenous and synthetic [5]. These differences result in GLP-1 significantly improving insulin production. It increases the feeling of fullness and reduces the production of pro-inflammatory cytokines by adipocytes.

GLP-1 GIP regulates insulin levels through multiple mechanisms, including increasing adiponectin levels [6]. Adiponectin is a protein that significantly influences the metabolism of fatty acids, glucose, and has a protective effect on blood vessels. Its reduced levels are observed in individuals with metabolic disorders, non-alcoholic fatty liver disease, hypertension, coronary artery disease, and atherosclerosis. Elevated adiponectin levels reduce adipocyte proliferation and increase energy expenditure through a beneficial impact on cellular mitochondria.

APPETITE SUPPRESSION

In addition to GLP-1 GIP suppressing appetite by interacting with the GLP-1 receptor in the brain, it also does so by delaying gastric emptying. However, this effect diminishes with increasing dosage. This is due to a phenomenon called tachyphylaxis, which is partial adaptation to a substance due to its continuous administration without breaks. A way to bypass this is to maintain a low dose for 4 weeks and then gradually increase it. By prolonging gastric emptying, GLP-1 – as well as other GLP-1 analogs – intensify the feeling of satiety with food. By inhibiting appetite in this manner and contributing to reduced food consumption, it leads to weight loss.

EFFECTIVENESS OF GLP-1 + GIP FOR WEIGHT LOSS VS. OTHER GLP-1 ANALOGS

Comparing the effectiveness of GLP-1 GIP to other GLP-1 analogs has revealed significant differences. This is especially noticeable in their long-term comparison of their impact on body weight. GLP-1 GIP clearly allowed for the maintenance of reduced body weight. Other GLP-1 analogs, on the other hand, resulted in weight gain overall [2] (which may be due to desensitization of GLP-1 receptors in the brain and increased hunger after discontinuing GLP-1 analogs). Weight loss with GLP-1 use depended on the dosage.

It appears that the GIP mechanism is associated with the effectiveness of GLP-1 in terms of weight loss and its long-term maintenance. GIP directly modulates the insulin sensitivity of adipocytes, leading to increased adiponectin activity. This, in turn, reduces the production of pro-inflammatory cytokines by adipocytes (which is important in various diseases, such as the activation of mast cells leading to increased histamine release).

Activation of GIP pathways in the central nervous system regulates hypothalamic centers responsible for post-meal satiety, resulting in a reduction in perceived hunger and food consumption. This, in turn, contributes to better glucose control and weight reduction. It appears that the advantage of GLP-1 GIP over other GLP-1 analogs comes from its property of regulating adiponectin in adipose tissue and suppressing appetite by stimulating the GIP receptor in the hypothalamus [10].

PROTECTIVE EFFECTS ON THE CARDIOVASCULAR SYSTEM

GLP-1 + GIP, through their influence on adiponectin, have a beneficial impact on the cardiovascular system. A decreased level of this protein is associated with atherosclerosis, obesity (obesity reduces adiponectin), and heart diseases. Studies on individuals with type 2 diabetes who used GLP-1 showed improvements in lipid parameters, such as a reduction in triglycerides and apoC-III [11]. This translated into a reduced risk of cardiovascular diseases. Additionally, adiponectin has the property of increasing HDL cholesterol levels and decreasing triglyceride levels, contributing to a lower risk of heart diseases.

Increased adiponectin activity may also result from improved dietary quality, increased physical activity, and is a characteristic of lipid-lowering drugs [12]. GLP-1 + GIP show similar benefits. GLP-1 analogs reduce the risk of cardiovascular diseases in two ways. Firstly, by the aforementioned effect on reducing blood pressure, improving the lipid profile, and reducing body fat. Secondly, through adiponectin, which reduces inflammation and improves endothelial parameters [13].

Regarding the improvement of endothelial function, GLP-1 analogs have an effect on blood vessel relaxation. This action reduces blood pressure [13]. This effect appears to be achieved through the expression of the eNOS gene responsible for nitric oxide production. Interestingly, this effect is likely even stronger in individuals with heart diseases or metabolic disorders.

In terms of reducing inflammation, GLP-1 analogs have a broad spectrum of action. They contribute to this state of affairs, among other things, by limiting NF-kB signaling, reducing MMP-9 activity, suppressing the production of pro-inflammatory cytokines, or decreasing macrophage activity. Interestingly, these effects seem to persist even 3 months after a single dose [13]. For this reason, tirzepatide is being considered as a therapeutic agent for individuals after a heart attack, and further research is currently being conducted to determine its effectiveness in this regard [14].

SUMMARY of peptide actions:

• Suppresses appetite
• Very effective in reducing body weight
• Weight loss is directly proportional to the dosage used
• Its use leads to weight loss, mainly through a significant reduction in appetite
• It stands out among other GLP-1 analogs due to its activity on the GIP receptor
• Unlike other GLP-1 analogs, it leads to long-term weight loss
• Improves metabolic properties
• Significantly improves glucose tolerance and insulin production
• Enhances the function of pancreatic beta cells
• Reduces triglycerides and increases HDL cholesterol levels
• Gradually exerts protective effects on the cardiovascular system
• Increases nitric oxide production
• A single dose reduces inflammatory processes for up to 3 months
• GLP-1 + GIP can be stored for up to 24 months at temperatures between 2 to 8 degrees Celsius

DOSAGE USED IN STUDIES:

• Start with the minimum effective dose to determine the body’s tolerance.
• Continue using a dose that helps control appetite.
• Suggested dosages: 1 or 1.25 mg, 2 or 2.5 mg, 4 or 5 mg, 8 or 10 mg, max 15 mg.
• Frequency of doses and route of administration: subcutaneously every 7 days (injections), T 1/2 = 5 days.
• Gradually reduce the dose in the last weeks is recommended.
• The frequent combination with johimbine

SIDE EFFECTS OF GLP-1 + GIP AS SHOWN BY STUDIES:

• Nausea (can be avoided by starting with a smaller dose)
• Vomiting (can be avoided by starting with a smaller dose)
• Diarrhea (can be avoided by starting with a smaller dose)
• Reduced appetite
• Weight loss
• Rarely leads to hypoglycemia.

BIBLIOGRAPHY
1. https://pubmed.ncbi.nlm.nih.gov/33236115/
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843845/
3. https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.13979
4. https://www.medscape.org/viewarticle/544820
5. https://insight.jci.org/articles/view/140532
6. https://pubmed.ncbi.nlm.nih.gov/32291277/
7. https://pubmed.ncbi.nlm.nih.gov/32519795/
8. https://pubmed.ncbi.nlm.nih.gov/34370970/
9. https://pubmed.ncbi.nlm.nih.gov/33571454/
10. https://pubmed.ncbi.nlm.nih.gov/32603429/
11. https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.14174
12. https://www.mdpi.com/1422-0067/20/5/1190
13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301685/
14. GLP work

GLP-1 with GIP PRODUCT INTENDED FOR RESEARCH PURPOSES ONLY!

All properties mentioned above are observed in laboratory tests, not done on humans, and are for informational purposes only. All information contained in the descriptions is not approved by GIS, GIF or EFSA. The substance is not a medicine, food product or dietary supplement and is not suitable for human consumption. The product qualifies as a chemical reagent/reference material authorised for marketing in the EU. It can only be used for scientific research. Other information about the product is contained in the safety data sheet of the chemical, which we make available for inspection. Products are only available to institutions or individuals who are associated with research or laboratory activities.