Incinderine is a potent dual GLP-1/GIP agonist with combined DPP-4 inhibition. This will be further explained in the writeup but there are multiple mechanisms of action with complex interactions. It cashes out as Incinderine being one of the most powerful fat burners on the market, easily as powerful as its pharma counterparts—perhaps more powerful as Incinderine is not limited to a single MOA. Let's take a look:
Myricetin is a member of the flavonoid class of polyphenolic compounds, with antioxidant properties. Common dietary sources include vegetables, fruits, nuts, berries, tea, and red wine. Myricetin is structurally similar to fisetin, luteolin, and quercetin and is reported to have many of the same functions as these other members of the flavonol class of flavonoids. Myrecetin is an exceptionally potent flavonoid with a host of beneficial effects on health but for our purposes we are specifically concerned with its ability to help us lose bodyfat.
Myricetin is a POTENT GLP-1 agonist comparable in strength and effects to the prescriprion GLP-1 agonist Liraglutide (REF 1.) And showed more potent effects on insulin and fat loss than injected GLP-1.
QUOTE"the rats injected with myricetin exhibited better glucose tolerance in this single-dose injection experiment than those treated with GLP-1. The treatment with myricetin resulted in blood glucose levels that were main-tained at 7.5–8.5 mM over 8 h, and these results were similar to those after liraglutide administration. Additionally, myricetin seemed to exhibit a similar glucoregulatory duration(0–8 h), which suggests that myricetin might possess a half-life similar to that of liraglutide (11.3 h) "
It would appear that Myricetin is an exceptionally potent GLP-1 agonist, as effective as prescription drugs of this type and more potent than GLP-1 itself at managing insulin but there is more.
Dipeptidyl-peptidase 4 (DPP4) is a glycoprotein, which is ubiquitously expressed on the surface of a variety of cells. This exopeptidase selectively cleaves N-terminal (Peptide Bond) dipeptides from a variety of substrates, including cytokines, growth factors, neuropeptides, and the incretin hormones. Expression of DPP4 is substantially dysregulated in a variety of disease states including inflammation, cancer, obesity, and diabetes. Since the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GIP), are major regulators of post-prandial insulin secretion, inhibition of DPP4 by the gliptin family of drugs has gained considerable interest for the therapy of type 2 diabetics. DPP-4 inhibitors prevent the N-terminal cleavage and the destruction of the Incretins GLP-1 and GIP. Myricetin is a potent DPP-4 inhibitor so on top of its ability to increase the secretion of GLP-1 it also prevents its destruction which is part of why Myricetin is shown to be more powerful than GLP-1 itself.
Glucose-dependent insulinotropic polypeptide (more commonly known earlier as gastric inhibitory polypeptide or gastric inhibitory peptide), abbreviated as GIP, is an inhibiting hormone of the secretin family of hormones. While it is a weak inhibitor of gastric acid secretion, its main role, being an incretin, is to stimulate insulin secretion. Recently the pharamaceutical industry has been working hard to improve on the already extremely effective GLP-1 agonist. In 2022 Eli Lily announced the next generation of these far burning drugs with Mountjaro. The first Combination GLP-1 and GIP agonist. This combination has been shown to decrease weight by significantly more than semaglutide and other GLP-1 agonists.
Weight reduction: 11.2 kg (24.7 lb., Mounjaro 15 mg), 6.9 kg (15.2 lb., injectable semaglutide 1 mg) and 0 kg (placebo), p<0.001
Fat mass reduction: 9.7 kg (21.4 lb., Mounjaro 15 mg) and 5.9 kg (13.0 lb., injectable semaglutide 1 mg), p=0.002
Keep in mind neither of these drugs have the added DDP-4 inhibitor so we have even more power in Incinderine.
ok so we have Massive potential as a GLP-1 and GIP inhibitor coupled with DPP-4 inhibition but thats just the beginning.
Myricetin also increases insulin sensitivity which further accentuates the weight loss potential of the previously discussed mechanisms as GLP-1 agonists. GIP agonists and DPP-4 inhibitors all help boost insulin.
Myricetin also activates BAT (brown adipose tissue AKA brown fat) and Beige Fat by upregulating thermogenic protein expression and activating mitochondrial biogenesis, eventually increasing heat dissipation and calorie expenditure. This is exceptionally important for those of us looking to burn body fat. In order to demonstrate why we need a bit of education regarding the different types of fat.
There are different types of fat in your body. Each type is identified by its color and function, including:
White fat: This is the type of fat we want to get rid of.
Most of the fat in your body is white fat. White fat stores energy in various places around your body. White fat insulates your organs. Too much white fat leads to obesity.
Brown fat: This is the type we want.
Brown fat is smaller than white fat. It stores energy and burns that energy to regulate your body temperature. Brown fat helps you burn calories by creating heat right before your body starts to shiver (thermogenesis). It also helps regulate sugar (glucose) and fat metabolism.
Beige fat: This type is also beneficial because it is basically white fat preparing to convert to the brown fat.
Beige fat is a combination of white and brown fat cells. These cells burn calories to regulate body temperature by converting white fat cells to brown.
Converting our white fat to brown fat is massively important to getting super us shredded. Brown fat is not fat like we would think of it. Its an absolute lean physique shredding powerhouse that instead of storing the calories we eat it burns them off like a furnace. So we want as much of this as possible. Increasing the conversion rate of white fat to beige and brown causes the body utilize excess calories and burn them off vs storing them.
For the sake of brevity I will just quickly mention some additional benefits.
Myricetin is a relatively potent aromatase inhibitor and the reduction in estrogen will assist in reducing bodyfat and water retention. Myricetin is a PDE inhibitor, reduces LDL and my favorite, increases the release of endorphins which really helps push through when you are training to failure and dieting. It also has a host of antiaging and general health benefits.
Myricetin has one drawback....it has a roughly 10% oral bioavailability. Studies indicate that complexing myricetin with specific cylodextrins can increase oral bioavailability by 900%. So our Myricetin cyclo complex is 900% more potent than plain myricetin and Incinderine also employs Biox which increases bioavailability and reduces metabolism in vivo even further.
1. Myricetin: a potent approach for the treatment of type2 diabetes as a natural class B GPCR agonist
Previous studies have shown that hyperinsulinemia is not only a marker of insulin resistance, but also the causative factor of peripheral tissue insulin resistance. It also has been suggested that prolonged high-dose insulin treatment can mimic the effects of hyperinsulinemia and exacerbate...
Oleanolic acid is a naturally occurring pentacyclic triterpenoid related to betulinic acid. It is widely distributed in food and plants where it exists as a free acid or as an aglycone of triterpenoid saponins. Oleanolic acid is an interesting fat burner that shares some of its effects with other triterpenoids like ursolic acid. For example oleanolic acid is a Takeda G protein-coupled receptor 5 (TGR5) agonist. An interesting finding for TGR5 is its role in energy metabolism. The discovery of TGR5 expression in brown adipocyte tissues (BATs) and the recent demonstration of BAT in adult human body suggest a potential approach to combat obesity by targeting TGR5 to increase thermogenesis. Endogenous TGR5, regulates glucose metabolism. In animals, TGR5 activation by a chemical agonist leads to an increase in GLP-1 which helps Oleanolic acid work together with Myricetin for GLP-1 receptor modulation.
Oleanolic acid treated obese mice exhibited a decrease in body, liver, and visceral adipose tissue weights. Oleanolic acid treatment improved glucose tolerance, insulin level, plasma lipopolysaccharide (LPS), and hepatic cholesterol and triglyceride concentrations.
Oleanolic acid increases the mRNA encoding of CD36, a fat taste receptor, in taste bud cells. This gives us a preference toward fatty foods vs sugary ones which is preferential for fat loss. Expression of CD36 is regulated at both the transcriptional and posttranslational levels, but regulation differs among different cell types. Similar to many other genes involved in lipid metabolism, CD36 expression in fat and muscle is upregulated by the nuclear hormone transcription factor PPAR-ɣ. Studies have indicated that CD36 links extracellular signals to intracellular fatty acid metabolism and redox metabolism in both innate and adaptive immune cells, impacting their fate and activation. Similar mechanisms operate in hematopoietic stem cells and tumor initiating cancer stem cells where CD36 expression promotes and maintains “stemness” by sensing extracellular ligands, including oxidized phospholipids, and by facilitating fatty acid uptake from surrounding adipose tissues to fuel fatty acid oxidation. The laymens version of this is CD36 reduces craving for sugar, increases fat metabolism and helps increase the uptake of adipose tissue specifically to be utilized for fuel. This is also part of how we see the increase in brown fat from Oleanolic acid.
Oleanolic acid also influences the expression of mRNA encoding pro-inflammatory cytokines (IL-1β and IL-6) and some lipogenic genes (PPARα, SREBP1, FAS, ChREBP, and G6Pase) in liver and adipose tissue. These are well known fat burning pathways that help contribute to the fat burning effects of this powerful ingredient. Its also very effective at reducing Reactive oxygen species which helps prevent DNA and RNA damage. In addition Oleanolic acid shows protective benefits against mitochondrial damage and activates macrophages to assist with boosting the immune systems response to exercise, helps to repair muscle faster after training and increases mineral bone density.
Unfortunately Oleanolic acid has very poor oral bioavailability with its absolute bioavailability to be approximately .7%. Not 7%... .7%. This makes it basically inert orally so we had to modify it to make it orally bioavailable. Not all compounds are suitable for all methods. Oleanolic acid tends to have a very poor bond with cyclodextrins so we opted for phospholipid complex which significantly increases bioavailability, and, Incinderine employs our bioavailability complex BioX which gives additional potency. There is no oleanolic acid product available that works this well period.
1. Oleanolic acid improves diet-induced obesity by modulating fat preference and inflammation in mice
Berberine was investigated as an inhibitor of human dipeptidyl peptidase IV (DPP IV) in an attempt to explain its anti-hyperglycemic activities. The investigation included simulated docking experiments to fit berberine within the binding pocket of DPP IV. Berberine was found to readily fit within the binding pocket. Findings suggest that DPP IV inhibition is, at least, one of the mechanisms that explain the anti-hyperglycemic activity of berberine. The fact that berberine was recently reported to potently inhibit the pro-diabetic target human protein tyrosine phosphatase 1B (h-PTP 1B) discloses a novel dual natural h-PTP 1B/DPP IV inhibitor. Berberine also increased the potency of the DPP-4 inhibitor drug sitagliptin.
Inhibition of PTP1B has been shown to cause fat specific weight loss. The ability to lose fat without also catabolizing skeletal muscle is extremely important for those of us who value our hard earned muscle tissue. Inhibition of PTP1B enhances leptin and insulin sensitivity, represses hunger, and increases browning of adipose tissue, to decrease adiposity and improve glucose metabolism. Berberine is a potent PTP1B inhbitor and has been shown in studies mimic the actions of insulin by increasing glucose uptake ability by 3T3-L1 adipocytes and L6 myocytes in an insulin-independent manner, inhibiting phosphatase activity of protein tyrosine phosphatase 1B (PTP1B), and increasing phosphorylation of IR, IRS1 and Akt in 3T3-L1 adipocytes. The insulin mimetic actions of Berberine work in tandem with the insuling release from Myricetin and Oleanolic acid by increasing the actions of insulin released though GLP-1 agonism, GIP agonism and DPP-4 inhibition. The triple threat makes this natural trio in Incinderine the most potent orally active fat burner of its kind. Easily comparable or stronger than their pharma counterparts as Incinderine has multiple MOAs and...we are not nearly done yet.
1. Berberine induces GLP-1 secretion through activation of bitter taste receptor pathways
2. Restoration of GLP-1 secretion by Berberine is associated with protection of colon enterocytes from mitochondrial overheating in diet-induced obese mice
3. Inhibition of dipeptidyl peptidase IV (DPP IV) is one of the mechanisms explaining the hypoglycemic effect of berberine
4. The therapeutic effects of berberine plus sitagliptin in a rat model of fatty liver disease
Intranasal Targeting of Hypothalamic PTP1B and TCPTP Reinstates Leptin and Insulin Sensitivity and Promotes Weight Loss in Obesity
6. Berberine inhibits PTP1B activity and mimics insulin action
1. 6-Paradol Acts as a Potential Anti-obesity Vanilloid from Grains of Paradise
Synephrine, BITTER ORANGE EXTRACT is an alkaloid, occurring naturally in some plants and animals, and also in approved drugs products as its m-substituted analog known as neo-synephrine. p-Synephrine (or formerly Sympatol and oxedrine and m-synephrine are known for their longer acting adrenergic effects compared to epinephrine and norepinephrine. Isopropylnorsynephrine is another derivative that is an exceptionally potent beta agonist and lipolytic agent providing nearly 60% of the fat loss potential of the prototypical β-adrenergic agonist isoprenaline.
The weight loss observed in consumers of extracts of Citrus aurantium (bitter orange) has been tentatively attributed to the lipolytic and thermogenic effects of the alkaloids abundant in the unripe fruit. Synephrine, octopamine, tyramine, and other alkaloids have been repeatedly identified and quantified in Citrus members of the Rutaceae family.
One study aimed at comparing the acute lipolytic activity of synephrine, octopamine, tyramine, and N-methyltyramine and other alkaloids in human adipocytes. Maximal response to the prototypical β-adrenergic agonist isoprenaline was taken as reference in both species. In rat, octopamine was slightly more active than synephrine while tyramine and N-methyl tyramine did not stimulate lipolysis. Tyramine and N-methyl tyramine induced only 20% of the maximal lipolysis and exhibited antilipolytic properties. Synephrine and octopamine were stimulatory at proper doses. Since synephrine is more abundant than octopamine in C. aurantium, it should be the main responsible for the putative lipolytic action of the extracts. Noteworthy, their common isopropyl derivative, isopropylnorsynephrine (also named isopropyloctopamine or betaphrine), is clearly lipolytic: active at 1 μg/ml and reproducing more than 60% of isoprenaline maximal effect in human adipocytes. This compound has few reported adverse effects to date and is an exceptionally effective lypolytic agent. Our bitter orange extract is exceptional as we target specific components within the plant that are not widely utilized.