Uptake spill the beans.

[Vitruvian]

This product is really, really, really, really good.... I'm excited for you guys to try it! There might even be some at the Olympia!

 

[Cary K]

Just got the email from App Nutt, HGH-Up and Uptake are being shipped!!!
Holy cow, I'm sooo excited!!!

 

[bolt10]

Just got the email from App Nutt, HGH-Up and Uptake are being shipped!!!
Holy cow, I'm sooo excited!!!

Used to get App Nut e-mails but haven't seen any recently. Hopefully I am still on the mailing list.

 

[Dewey99]

Used to get App Nut e-mails but haven't seen any recently. Hopefully I am still on the mailing list.

I had you removed since you never want to try any of our stuff. :joke:

 

[bolt10]

I had you removed since you never want to try any of our stuff. :joke:

Guess I'll toss out this bottle of Drive I have sitting here that I was going to run soon.

But ya idk if I should be happy or curse you all if you have a nice deal right now as I get paid again and make my monthly decision on my supplement purchases.

 

[drooks10]

This product is really, really, really, really good.... I'm excited for you guys to try it! There might even be some at the Olympia!

There won't be any left after I leave the booth. Haha!

Just got the email from App Nutt, HGH-Up and Uptake are being shipped!!!
Holy cow, I'm sooo excited!!!

Awesome. Can't wait to hear what you think of the products!

David
Team APPNUT

 

[Bolanrox]

lol

 

[Dewey99]

Guess I'll toss out this bottle of Drive I have sitting here that I was going to run soon.

But ya idk if I should be happy or curse you all if you have a nice deal right now as I get paid again and make my monthly decision on my supplement purchases.

Send me said money and I will make your decisions for you. Trying to be a good friend here and take some stuff off your plate.

Still looking forward to that coming log....

 

[OrganicShadow]

^ yeah sure! The check is in the mail.

 

[rms80]

Here is the whole thing

N.O. Uptake™- Technical Write-Up
Product Description
N.O Uptake™ is a revolutionary new product from Applied Nutriceuticals® that uses cutting-edge science to bring forth an innovative formula that can help users get stronger, gain lean muscle mass, recover faster, and generate an around-the-clock muscular fullness (pump). N.O. Uptake™ utilizes several different complex pathways in a pharma-strength formulation to deliver nutrients to hard-working skeletal muscle- providing an optimal environment for recovery and lean muscle enhancement. N.O. Uptake™ is a unique product, in that it can be used successfully in multiple situations- N.O. Uptake™ can be taken pre-workout (along with RPM™ and/or Drive™) to enhance Testosterone levels and supply an awesome pump, post-workout to enhance hormonal recovery and glycogen re-composition, intra-workout to stave off muscle catabolism, or even before bed with HGH-Up™ to provide a boost of GH and testosterone for overnight nutritional “dead time.”
N.O. Uptake™ Main Mechanisms of Action
-Up-regulates multiple synergistic pathways to allow for enhanced recovery, hormonal stimulation, and muscular nutrient uptake (hence the name “Uptake”)
-Facilitates nutrient transport into skeletal muscle through up-regulating glycogen synthase (GS) and GLUT4 translocation. GS is an enzyme converts that converts glucose to glycogen, while GLUT4 is a transport protein that pulls glucose across cellular membranes; both mechanisms allow for enhanced muscular fullness
-Increases GH and Testosterone levels, through a complex hypothalamic co-liganded pathway, triggering a major skeletal muscle hypertrophy signaling pathway and allowing for maximal hormonal stimulation during recovery
-Targets anabolism through the Mammalian Target of Rapamycin (mTOR), a strong biochemical trigger for recovery and growth
-Offers ingredients that enhance both the nitric oxide (NO) pathway, actual NO itself (through nitrates), as well as hydrogen sulfide (H²S)- an effect which can act synergistically to increase testosterone levels, as well as supplying a massive pump during a hard workout- you can literally “feel” your muscles growing!!!
How N.O. Uptake™ is Different from Conventional NO-Boosters

• Most conventional “pump” products simply increase Nitric Oxide (NO) levels, but add little additional benefit. They are ingested pre-workout, either as part of a pre-workout stim blend, or as a stand-alone product. Unfortunately, either in combination or as a standalone, there isn’t going to be much, if any, benefit from this type of product, especially when it comes to increasing lean muscle or recovery.
• N.O. Uptake™ allows for targeted enhancement of GLUT4 translocation of glucose into skeletal muscle- this targeted enhancement of glucose into skeletal muscle allows for greater muscle glycogen to be achieved, which ultimately speeds recovery- can your “average” NO product do this?
• N.O. Uptake™ allows for stellar pumps during a workout (more so than many of the products that are focused on this effect), but has multiple effects that will actually contribute to long-term gains through testosterone and GH enhancement. This function, and the pathways that it utilizes, makes N.O. Uptake™ unique from other Nitric Oxide-enhancers. N-Methyl D-,L-Aspartate (NMA), is a fundamental component of this lean tissue-generating group of ingredients. NMA interacts with specific receptors that are found on neurons in the pituitary gland, the hypothalamus, and the testes, allowing for wholesale increases in testosterone and GH from N.O. Uptake™.

How N.O. Uptake™ Increases Testosterone and GH Levels Through the NMDA Receptor: The Role of N-Methyl D-,L-Aspartate, DHEA, and N,N,N-Methylglycine (TMG)

• The first mechanism of action in N.O. Uptake™ has to do with three entities: the NMDAR (N-Methyl D-Aspartate) receptor, the biochemical pathway concerning SAM-e production and methylation which also acts as a co-ligand for the NMDAR, and the action of DHEA in priming NMDAR stimulation; creating a distinct and complex synergistic effect created by both direct stimulation and interaction of the three.
• NMDAR are found through the nervous system, and have a role in learning, memory, and the endocrine system. When NMDAR receptors are bound by their specific ligands and co-ligands in the hypothalamus, a hormonal cascade begins, ultimately allowing for the release of GH and Testosterone downstream.
• The SAM-e / methylation pathway is responsible for a variety of different biochemical reactions in the body. In Uptake™ the SAM-e pathway is responsible for the de-methylation of TMG to sarcosine (n-methylglycine, an important co-ligand of the NMDAR), plus the formation of H²S, both of which allow for greater NMDAR activity, greater NO activity (and H²S synergism), leading to ultimately greater initiation of hormonal release (1,37,52,53).
• The NMDAR is pretty tricky, in that it requires more than one component to activate the receptor (called ligands). Ligands are molecules that act as a trigger on a target entity (receptor) to activate a biological process. There are two crucial binding sites on NMDA receptors where ligands can exert strong activity: the glycine binding site (NR-1), and the NMDA binding site (NR-2) (39,40,41,47).

• The ligand with the strongest affinity (ability to bind to) for the NR-2 site in the hypothalamus is D-Aspartic Acid, while the ligand with the strongest affinity for the NR-1 binding site is n-methyl glycine (also known as sarcosine). To recap, the ligand with the strongest ability to bind the NMDA binding site (NR-2) in the hypothalamus is D-Aspartic Acid (followed by N-Methyl D-,L-Aspartic Acid, which is in N.O. Uptake™), and the ligand with the strongest ability to bind the glycine binding site (NR-1) is n-methyl glycine (34,36,38).

• This is noteworthy, in that the type of ligand that binds to the NR-1 binding site determines the response of the receptor. L-Glycine binds to the site quite well, but is not a good choice for our task, because it is rapidly removed from the binding site by glycine transporter 1 (GT1), a transport protein that regulates the re-uptake of glycine from the synapse (the space between nerve cells). GT1 determines the amount of glycine present between nerve endings; greater GT1 activity allows for less glycine buildup in the synapse, and the more glycine that is removed from the synapse, the less effective it can be as a co-agonist in activating the NMDA receptor. Since NMDA reception must be co-activated by two separate ligands, if one is ineffective or removed too quickly there will be little or no activation occurring, which would lead to a less effective product (33,34,64).
• Therefore, the goal is to find another ligand that can bind the GT1 and block or slow the action of the transporter protein. Blocking or slowing the action of GT1 allows greater amounts of glycine build-up in and around the synapse, which will allow for increased activation of the NR-1 binding site. This, along with the docking of N-Methyl D-Aspartic Acid on the NR-2 binding site, is essential for attaining the strongest activation of the NMDAR. D-Serine, D-Alanine, D-Cycloserine, and Sarcosine (N-Methyl Glycine, or demethylated TMG) are compounds that come to mind for this purpose; each of these compounds can act as a decent ligand of the NR-1 binding site. N-Methyl Glycine (Sarcosine) is the best choice for this job, because it limits GT1 action, slowing the removal of glycine from the synapse. Another reason sarcosine is a good choice has to do with its’ ability to act as a ligand/co-agonist of the NR-1 binding site. This means that N-Methyl Glycine can also act on the NR-1 glycine receptor as well as GT1, making it a very effective co-agonist to the NMDAR. When both NR-1 and NR-2 have been successfully bound with lower glycine transporter (GT1) activity, better overall stimulation of the NMDAR will happen, which can allow for a maximal physiological response and optimal product effectiveness (65,66).
• However, yet another compound, N,N,N-trimethylglycine (TMG) serves a multi-faceted function in a similar way to N-Methyl Glycine, D-Alanine, and D-Serine. TMG can be directly converted by the liver to the NR-1 agonist N-Methyl Glycine (Sarcosine), meaning that N.O. Uptake™ effectively allows for a co-agonist of the NMDAR to be present. However, TMG must first undergo a simple enzymatic conversion In becoming sarcosine (n-methylglycine), which is accomplished by acting as a methyl donor. (See Figure 4 below). This means that TMG donates extra methyl groups to other molecules through the methylation pathway and offers some additional benefits to N.O. Uptake™, as the methylation pathway is responsible for the production of neurotransmitters, the structure and function of DNA, and the metabolism of fats. The conversion of TMG to N-Methyl Glycine (sarcosine) is very efficient, giving N.O. Uptake™ excellent co-ligand enhancement for the NMDAR to work in conjunction with N-Methyl D-Aspartic Acid on NR-1 and NR-2 (35,38,47,56,62,63,65,66).
• When the NMDAR binding sites are triggered in the hypothalamus by NMDA and its co-agonist (in this case N-Methyl Glycine), there is an increase in cyclic guanosine monophosphate (cGMP) activity in the pituitary. cGMP is classified as a second messenger, meaning that it exerts its effects by acting in a manner secondary and in response to a first messenger signaling molecule. When the first messenger signaling molecules bind to a receptor (in this case, NMDA and its co-agonist bind to NR-1 and NR-2), the secondary pathway is activated that increases cGMP production. The heightened levels of cGMP in the pituitary correspond to an increased production of gonadotropin releasing hormone (GnRH), and growth hormone releasing hormone (GHRH). The resulting increase in GHRH from stimulation of the NMDA receptor also allows increased amounts of growth hormone (GH) to be secreted from the pituitary (5,54,55,67).
• As aforementioned, GnRH release also occurs, signaling the pituitary to release luteinizing hormone (LH), and follicle stimulating hormone (FSH) (see figure 2). Certain neurosteroids such as Pregnenolone Sulfate and DHEA have been shown to have significant positive influence on the N-Methyl D-Aspartate receptor. DHEA can further potentiate the release of GnRH through the NMDA receptor, as the effect of DHEA on the release of GnRH induced by glutamate is consistent with the identity of DHEA as a positive modulator of the NMDAR. This increase in GnRH activity, and the resultant increase in LH and FSH release, allows for an upregulation of steroidogenesis by the testes, which subsequently allows for the production of increased amounts of testosterone, as explained below (5,67,140),
• Luteinizing Hormone, through receptors found on the Leydig cells (a type of cell that helps produce testosterone) in the testes, has control over the production and secretion of testosterone. The subsequent binding of LH with its receptor on the Leydig cell allows a signal to be sent through the cyclic AMP (cAMP, another type of second messenger) pathway. Once this signaling occurs, the protein kinase A pathway is then activated, and this ultimately allows for the release of testosterone after 30-60 minutes of LH stimulation (2,3,34-36,72,73).
• Similarly, increases in cGMP from N.O. Uptake™ also enhance phosphorylation (a fancy word for activation via attachment of a phosphate group) of the steroidogenic acute regulatory protein (StAR), a Leydig cell cholesterol transfer protein that provides the building blocks for testosterone synthesis. This is important for increasing endogenous testosterone production, in that StAR activation is necessary for the stimulation of steroidogenic enzymes involved in the transfer of cholesterol to testosterone. These results suggest that increases in cGMP correlate to increases in basal steroidogenesis in the Leydig cells of the testes through the protein kinase G (PKG, or a type of enzyme that cGMP interacts with)-dependent modification of the StAR protein and interaction with LH. To summarize N.O. Uptake™ increases LH, cGMP, and StAR activity, all of which can significantly up the amount of testosterone produced in the body (72,73).

• As you can see in Figure 5 (below), TMG functions within the pathway SAM-e, albeit in different segments and capacities; each of which add to product effectiveness. TMG has been shown have positive effects on muscular strength it can increase creatine storage and synthesis, as well as having the ability to be transformed into sarcosine (an NMDAR co-ligand) and act as a methyl donor to fuel SAM-e formation and ultimately increase H²S levels (a synergistic donor gas similar to NO). TMG acts in the following fashion as a methyl donor and in the SAM-e pathway (57,59,60,61,84-87):
  • TMG donates a methyl group during the formation of SAM-e, and becomes DMG (N-N-dimethylglycine).
  • The donated methyl group can then form SAM-e, or be used for the production of neurotransmitters, the production of DNA, or the metabolism of fats
  • The remaining DMG is then converted readily by the liver to the NR-1 agonist N-Methyl Glycine via glycine N-methyltransferase.

• An increase in Hydrogen Sulfide (H²S) Production from activation of the SAM-e cycle by TMG increases NMDA receptor activity and has been shown to be synergistic with Nitric Oxide (NO) in terms of vasodilation. Enhancement of NO from leucine nitrate, L-Norvaline, and AAKG also enhance this synergistic effect significantly, and a large proportion of the most recent research on erectile dysfunction drugs is focusing on these two pathways (115-117,133-135).

• The metabolism SAM-e can go one of several directions:
  • It has the ability to form Hydrogen Sulfide (H²S) or glutathione via conversion to cysteine, which is then converted to H²S via Cystathione Beta Synthase (CBS), where it can be converted into glutathione. H²S also has strong positive effects on upregulating GLUT4 proteins in skeletal muscle, and producing increased glucose uptake through this mechanism.
  • The conversion of cysteine to glutathione during the SAM-e cycle is relevant to the product, in that glutathione is a strong testicular anti-oxidant that has been shown to have the ability to increase protein synthesis and detoxify the testes. This results in conditions that are extremely favorable for optimal testosterone production.
  • The formation of H²S from cysteine is largely dependent on Vitamin B-6 and SAM-e levels. Both components act to increase CBS activity, allowing for a greater formation of H²S. When H²S is formed, it allows for intracellular increases in cyclic AMP (cAMP) and increased NMDA receptor activity, both of which are considered strong signals for increasing testosterone levels as well, as discussed earlier.
  • Similarly, due to the inclusion of folic acid and cobalamin (Vitamin B12) in N.O. Uptake™, the formulation has the ability to complete the cycle when SAM-e levels become depleted, allowing the body to re-form methionine. Once methionine is reformed, the cycle can begin again with the substrates provided within N.O. Uptake™.
  • The SAM-e molecule has the ability to complete the cycle when tissue SAM-e levels become depleted, allowing the body to re-form methionine, and restart the cycle (6,7,11,13,14,25,27,32,41,43-45,46,56-58,135,136).

 

[rms80]

The Role of Nitric Oxide and GLUT4 Translocation: L-Norvaline, Leucine Nitrate, Arginine Alpha-Ketoglutarate, and Uridine: The Process of Increased Glucose Uptake, Priming for the Formation of Glycogen , and the Generation of Higher ATP Levels

• Carbohydrates (especially glucose) are a source of energy for the majority of tissues and skeletal muscle. Because it is very inefficient for the body to store large amounts of glucose, carbohydrates are deposited in human tissue as long-chained polysaccharides (which are repeating units held together by chemical bonds) called glycogen. So glycogen essentially consists of multiple glucose molecules held together by glycoside bonds- how does this relate to muscle? These long-chained polysaccharides are deposited within the skeletal muscle cell (myofiber), and play an important role in the structure and function of the cell. During training, when a glycogen-containing myofiber needs glucose for fuel, glucose monomers (a monomer is a small molecule that can bind to other monomers) are removed one at a time from glycogen molecules (76-80).

• This is the basic process of glycogen formation from glucose (glycogenesis) and glycogen breakdown to glucose (glycolysis) - it is very efficient, and it is localized for a reason- over 65% of total body glycogen stores are located in skeletal muscle. The other 35% or so (this varies amongst individuals) is located in the liver, and liver glycogen is the main element of maintaining proper blood sugar levels and other processes in the body that require glucose. The reason for this is straightforward- myofibers contain an enzyme called phosphoglucomutase, which can convert glucose to a usable form for glycolysis. Because glucose contains an attached phosphate group, none of the glucose produced from glycogen hydrolysis in myofibers are able to leave the cell in which it was created. However, cells in the liver can de-phosphorylate glucose (remove the phosphate group), and because of this de-phosphorylation, liver glycogen has the ability to release glucose into the blood stream for other processes in the body. This is significant, because it indicates that muscle glycogen is normally used in skeletal muscle only, and not to fuel other glucose reclamation projects in other tissues- so once muscle glycogen is deposited, it is generally only used for intra-muscular processes. Therefore, with intelligent nutrition, glycogen levels can be increased dramatically, with little interference from other processes in the body, and muscle glycogen super-compensation is a very crucial area of recovery, as well as building lean body mass (81,91-93).
• An average athlete maintains roughly 75-85 millimoles (a millimole is a measurement of the amounts of specialized compounds in the body) of glycogen per kg of skeletal muscle. Studies on glycogen deposition and super-compensation on humans have shown that trained athletes can achieve at least 175 millimoles. This is very significant, in that there is an enormous delta between what the amount of glycogen the average athlete (weight trainer) normally stores, and what the same athlete could potentially store. Seeing where I am going with this? More glycogen, more mass and density!! This is where several crucial ingredients in N.O. Uptake™, arginine alpha-ketoglutarate, leucine nitrate, and uridine, as well as SAM-e cycle activation, come into play (15,28-31,42,48-51,94-96).
• When glucose is ingested and is released into the blood, it must be regulated closely by insulin and glucagon Insulin can lower blood sugar significantly and allow for the process of glycogen storage to begin, while glucagon can raise blood sugar if necessary by triggering glycogenlysis in the liver. Insulin is more important to this topic- it binds to specific targets on the cell membrane and allows for the movement of glucose into the myofiber. Myofibers are not permeable to glucose, so a transport mechanism is needed to allow for the fast transport of glucose into muscle cells. Normally the cell membranes are impermeable to glucose, but when a cell receptor is activated the membrane allows for a rapid entry of glucose into the cells. This rapid entry of glucose is important, as is the manner that the glucose transport occurs. Because of the impermeablility of the myofibers to glucose, glucose transport proteins (GLUT) are required to shuttle blood glucose into skeletal muscle. Insulin can activate these proteins, but tends to be a “double-edged sword” in that it tends to allow for equal deposition of glucose in muscle and fat cells. This is where the first MOA behind N.O. Uptake™ comes in: specialized glucose transport. The formula uses a combination of nitric oxide (from Leucine Nitrate, AAKG, and L-Norvaline), hydrogen sulfide (H²S) from SAM-e cycle utilization (TMG, B6, and Folate), and uridine, which have been shown to have the ability to increase the activity of a specific type of glucose transport protein found in skeletal muscle- GLUT4, even independent of insulin (22-24,26,100-102,104-106).

Figure 6: GLUT 4 Activity and Glucose Uptake

• GLUT4 transfer proteins are found in high abundance in skeletal muscle and adipose tissue, and are responsible for the rapid movement of glucose into a target cell. This fast movement requires that the transporter be moved (translocated) from inside the cell (where it is bound to a specialized structure called the golgi apparatus) to the cell surface. GLUT4 translocation in N.O. Uptake ™ is stimulated by leucine, hydrogen sulfide (from the SAM-e cycle), and nitric oxide (which can be derived from the leucine nitrate, AAKG, and L-Norvaline in the product), and once this subsequent movement of the transporter occurs, rapid glucose uptake into the cell can begin.. When ingested, leucine nitrate (and NO in general) has the ability to act as a strong activator of GLUT4 in skeletal muscle- this is the first step to glycogen enhancement by N.O. Uptake™- the activation of GLUT4 instigates glucose uptake into skeletal muscle, independently of insulin (97,98,103-105,118,119).
• When glucose has entered the cell, it can be stored as glycogen- and this is where a specialized component of N.O. Uptake™, Uridine, can facilitate increased glycogen production by providing substrates for the glycogen formation, perform the added function of generating higher levels of ATP, and by providing substrates for mRNA. Glycogenesis (the production of glycogen) requires one of two things: the phosphorylation of glucose or the addition of a phosphate group. Glucose interacts with UTP (uridine tri-phosphate) to form UDP glucose. The red blood cells can then act as a storage pool for the newly formed UDP glucose, and allow for the delivery of glucose and uridine to skeletal muscle tissue. This is an irreversible reaction, and UDP- glucose monomers (think back to the description above) can be converted to glycogen by the enzyme glycogen synthase (or GS). This upregulation of GS is very important, as it is one of the more important steps in glycogen synthesis- we will discuss this in the next section (16,17,19).

Figure 7: Uridine: the Production of PRPP

• Uridine also allows for the generation of high-energy ATP- the above diagram shows how uridine-5-monophosphate fits into the pyrimidine pathway, and how uridine can go on to form ATP (adenosine tri-phosphate), which is an important energy source. Uridine has a significant effect on ATP levels for several reasons (18, 20,68-71,83,88):
• It elevates UDP glucose levels (as mentioned earlier), which means more fuel for glycogen production and ultimately ATP production, if needed
• Increased musclular ATP demand for can lower the total pyrimidine (TPN = cytosine, uridine and their phosphate bound metabolites) and total adenine nucleotide (TAN = ATP, ADP, and AMP) pools. Depletion of TPN and TAN can hamper recovery significantly.
• Uridine is a precursor to phosphoribosylpyrophosphate (PRPP)- a main substrate in ATP production. PRPP levels tend to be very low, especially in hard-training athletes, and this can be a limiting factor in ATP re-synthesis
• Uridine increases the pool of uridine in the body- this allows for an ATP-sparing effect, because less ATP is needed to synthesize new uridine.
• We now know that supplementing uridine can increase ATP stores- in some studies an increase in muscular nucleotides (the building blocks for ATP) over 100% was noted. PRPP, which can be increased by having higher uridine levels, is also a substrate that is extremely important in the formation of DNA and mRNA- both the salvage and de novo synthesis pathways of purine and pyrimidine biosynthesis result in a large pool of nucleotides, which can be used as building blocks for mRNA and DNA. This is important to the function of N.O. Uptake™, as these building blocks are required for increased protein synthesis via mTOR, which is crucial in the recovery process (21,74,75,108,109,111,125,126,130).

How N.O. Uptake™ Can Aid in the Growth and Repair of Lean Muscle Through the Stimulation of the Mammalian Target of Rapamycin (mTOR) Pathway

• To recap, we now have increased glucose flow into skeletal muscle via enhanced GLUT4 translocation from L-Leucine, AAKG, L-norvaline, and nitric oxide, and we have an increased pool of UDP glucose for glycogen formation from uridine, as well as a large reservior of ATP and material for mRNA (nucleodtides from de novo synthesis and salvage)- now to put the final step to glycogen super-compensation in place: the upregulation of glycogen synthase. This can be accomplished by the stimulation of an important pathway involved in protein synthesis and anabolism: the Mammalian Target of Rapamycin (mTOR) pathway, which is the ultimate target the enzymatic pathway stimulated by nitric oxide, insulin, and IGF-1. N.O. Uptake™ does a fairly efficient job at stimulating these pathways via the inclusion of leucine nitrate, L-Norvaline, and AAKG. The effect of leucine on the mTOR pathway is well documented- mTOR functions effectively as a sensor of cellular energy-related substrates, and certain amino acids (77,84).

• The main enzymatic target of mTOR is the phosphorylation of p70-S6 Kinase 1 (S6K1), which is an enzyme that is part of a signalling cascade. Once phosphorylated, S6K1 can initiate protein synthesis via the translation of mRNA, and can take part in an active positive feeback loop to further stimulate additional mTOR activity. So, in a nutshell, when mTOR is stimulated, it starts an enzymatic signalling cascade that results in increased protein synthesis and ultimately muscular hypertrophy (growth). But what type of things allow for the signalling of mTOR? (4,103)

mTOR is activated when it senses high levels of the following substrates:

• Adenosine Tri-Phosphate (ATP)- in this case, supplied by UMP
• Alpha Ketoglutarate (AKG)
• L-Leucine (but through a different pathway than ATP)
• Insulin
• IGF-1 (as mentioned earlier)

Conversely, mTOR is inhibited by the following substrates:

• Rapamycin- or Sirolimus, and immunosuppressant drug
• Reductive Stress
• Curcumin
• Low ATP levels (5,6,7,96)

• Obviously, ATP is very important to this process- as it is the main cellular fuel in the body. Protein synthesis is very taxing to ATP reserves- this is why mTOR (and ultimately S6K1) is upregulated by high ATP levels. When high ATP levels (think energy) are discerned, the human body has the ability to complete the task of synthesizing new proteins and undertaking the hypertrophic process. For this reason, the formation of PRPP from UMP is crucial- because PRPP is such a potent ATP generator. Now think back to the previous two sections- we have increased pyrimidine synthesis from uridine, and have increased AKG levels from arginine alpha ketoglutarate. This is important for three reasons- high PRPP levels can jack ATP levels through the roof, and high ATP levels increase mTOR-related protein synthesis markedly, which can dramatically speed recovery from heavy training (4,10,90,107).

Putting It All Together: Glycogen Synthase, mTOR, and Glycogen Supercompensation From N.O. Uptake™

• OK- got it so far? We have upped ATP levels and mTOR activity, and increased activity in the enzymatic pathways stimulated by nitric oxide, insulin, and IGF-1- how does this relate to greater levels of glycogen synthase? The process is actually pretty straightforward, going back to the pathways we have already talked about- look at the diagram below. The glycogen synthase enzyme is controlled to a large extent by the glycogen synthase kinase beta enzyme (GSKß)- and GSKß is downregulated by several different compounds in N.O. Uptake™. Nitric oxide (NO) from Leucine Nitrate has the ability to increase the level of an enzyme called phosphoinositide 3-kinase (PI3K) through an increase in levels of the cellular [SUP]2nd[/SUP] messenger cyclic guanosine monophosphate (cGMP) via protein kinase G (PKG). Because N.O. Uptake™ contains leucine, there will also be an increase PI3K activity as through this mode, because Leucine has been shown to increase PI3K activity independently of IGF-1 stimulation, essentially the PI3K enzyme is being increased from multiple different angles (94,95,108).
• Once PI3K has been stimulated, there will be a subsequent up-regulation of the enzyme 3-phosphoinositide-dependent protein kinase 1 (PDK-1), which is essentially a master switch for multiple enzyme systems in the pathway. Once PDK-1 has been activated, there will be a subsequent activation of the enzyme Akt (also known as protein kinase B). Akt is responsible for multiple actions in the mTOR/GS pathway- AKT does not directly phosphorylate mTOR, but it has control over many of the enzymes that inhibit the pathway, so it has the ability to upregulate mTOR action. AKT also has a strong positive effect on glycogen synthase via the inhibition of GSKß (mentioned earlier), and it is through this mechanism that that N.O. Uptake™ activates glycogen synthase (108,109).

Figure 8 : mTOR and Accompanying Pathways

• We now have all of the important players where they need to be for glycogen super-compensation through the formulation of N.O. Uptake™: increased glucose flow into skeletal muscle via enhanced GLUT4 translocation from leucine nitrate, AAKG, and L-Norvaline, an increased pool of UDP glucose for glycogen formation from uridine-5-monophosphate, and an upregulation of glycogen synthase from the PI3K/AKT pathway. This is the perfect recipe for increased glycogen enhancement in skeletal muscle- so now we need to look at some ways to accomplish this task, so we can get the most out of the product. This next section will also explain why N.O. Uptake™ is such an excellent product for recovery and hypertrophy. Glycogen levels tend to be depleted by as much as 30-40% after resistance training, and glycogen re-synthesis post-weight training in skeletal muscle tends to be quite a bit faster than after endurance exercise. Eccentric exercise (the negative portion of a lift) is associated with micro-trauma in muscle fibers, and this micro-trauma tends to be associated with delayed onset muscle soreness (DOMS), disruption of enzymes with the myofiber, and lower glycogen re-synthesis within the muscle. There also tends to be a shift toward glycogenlysis (breakdown of glycogen) directly after the micro-trauma has been inflicted, and it has been speculated that this is due to a down-regulation in GLUT4 translocation in skeletal muscle. There is also an increase in an anti-inflammatory response within skeletal muscle that occurs after eccentric trauma, and this response tends limit plasma glucose uptake into the myofiber. Naturally, the mechanisms of action associated with N.O. Uptake™ are going to help dramatically to alleviate the deficiencies associated with these markers of recovery.

 

[drooks10]

Just got the e-mail for the sale! Buy it now, guys. You will not be disappointed at all!

David
Team APPNUT

 

[rms80]

• We now have all of the important players where they need to be for glycogen super-compensation through the formulation of N.O. Uptake™: increased glucose flow into skeletal muscle via enhanced GLUT4 translocation from leucine nitrate, AAKG, and L-Norvaline, an increased pool of UDP glucose for glycogen formation from uridine-5-monophosphate, and an upregulation of glycogen synthase from the PI3K/AKT pathway. This is the perfect recipe for increased glycogen enhancement in skeletal muscle- so now we need to look at some ways to accomplish this task, so we can get the most out of the product. This next section will also explain why N.O. Uptake™ is such an excellent product for recovery and hypertrophy. Glycogen levels tend to be depleted by as much as 30-40% after resistance training, and glycogen re-synthesis post-weight training in skeletal muscle tends to be quite a bit faster than after endurance exercise. Eccentric exercise (the negative portion of a lift) is associated with micro-trauma in muscle fibers, and this micro-trauma tends to be associated with delayed onset muscle soreness (DOMS), disruption of enzymes with the myofiber, and lower glycogen re-synthesis within the muscle. There also tends to be a shift toward glycogenlysis (breakdown of glycogen) directly after the micro-trauma has been inflicted, and it has been speculated that this is due to a down-regulation in GLUT4 translocation in skeletal muscle. There is also an increase in an anti-inflammatory response within skeletal muscle that occurs after eccentric trauma, and this response tends limit plasma glucose uptake into the myofiber. Naturally, the mechanisms of action associated with N.O. Uptake™ are going to help dramatically to alleviate the deficiencies associated with these markers of recovery.

Figure 9: The Glycogen Synthase Pathway

• We have established that N.O. Uptake ™ can increase glycogen stores in skeletal muscle, but what are some other things the average athlete can do to maximize glycogen uptake, and muscular fullness? Weight training increases insulin sensitivity, and also the need to decrease the markers of damage associated with training. Therefore, timing carbohydrate intake immediately post-workout along with N.O. Uptake™ can significantly increase the synthesis of new glycogen- but not just any type of carbohydrate. High-glycemic (simple sugars/glucose monomers) carbohydrates during this timing scenario will elicit the greatest benefit from the product, at least from a post-workout recovery/glycogen re-synthesis standpoint. Protein taken along with this meal will also further enhance this process. For post work-out recovery purposes, users of N.O. Uptake™ should consume roughly 0.8 grams per pound of body weight of these glucose monomers to maximize this effect, and roughly 30-40 grams of high-quality, fast-digesting protein (whey is best). This will allow for a rapid replacement of the glycogen lost during training, allowing the user a very quick, effective recovery(76-79).
• Now we know how to recover from our workout with N.O. Uptake™ and some good carb and protein sources, but how do we use N.O. Uptake™ for glycogen super-compensation? Once again, timing is really important, in that N.O. Uptake™ can be used effectively in several different situations. Here are some ways to super-saturating the muscles with glycogen and nutrients (81,91,94,95,120-124,127-129,131,132):

1. Make your post-workout meal the biggest carbohydrate meal of the day, and take N.O. Uptake™ along with it. This too will dramatically enhance glucose uptake and glycogen formation.
2. To maximize N.O. Uptake™ as an intra-workout product, add in 10 grams of whey protein and 30 grams of carbohydrates to the drink mix for consumption during your workout. This will have a strong anti-catabolic and glycogen-sparing effect, and will boost glycogen re-synthesis even further.
3. Carbohydrate depletion and then reloading with the product will maximize the effects of N.O. Uptake™. Two low-carbohydrate days (consume 0.6-0.8 grams per lb. of bodyweight), followed by 5 days of carbohydrate loading (consume 3-5 grams per lb. of bodyweight) will allow for a strong glycogen super-saturation effect. Carbohydrate depletion will also help to prime glycogen synthase even further, and the effects on skeletal muscle fullness are dramatic, if not shocking- try it out!!
4. Use Neovar™ in conjunction with N.O. Uptake™ post-workout, along with an extremely high-carbohydrate meal- this will maximize glucose uptake into skeletal muscle and allow for enhance glycogen formation and super-saturation.
5. Take in plenty of complex carbohydrates during the loading phase such as oatmeal, vegetables, brown rice, pasta, and sweet potatoes.
6. Consume at least 100 oz. of water per day while taking N.O. Uptake™. Hydration is essential to glycogen super-saturation- if you don’t drink enough water, you won’t realize the full potential of the concept.

Decreasing Attenuation to Nitrates, and Increasing the Effectiveness of Nitrate-Containing Compounds in N.O. Uptake™- Better Formulations Through Recent Scientific Developments

• N.O. Uptake™ has an added feature that adds to product effectiveness- N.O. Uptake™ has the ability to prevent the body from desensitizing to nitrates through the inclusion of Vitamin C and Riboflavin (Vitamin B-2). Many commonly- available processed and natural foods contain nitrates- specific vegetables tend to carry high amounts of nitrates, as well as meats and meat products. Leucine Nitrate have been included in N.O. Uptake™ due to their powerful nitric oxide-enhancing characteristics. When ingested, leucine nitrate dissociate into two separate entities: a molecule of leucine, and a molecule of nitrate. Leucine is easily metabolized; however, many individuals tend to become quickly sensitized to the nitrate portion of the compound, which causes attenuation (tolerance) to nitrates in general, potentially making them ineffective (110,112-114,137,138).
• Similarly, another issue with nitrates arises: nitrates can become converted to nitrites by bacteria in the mouth. Nitrite potent vasodilator at near-physiological concentrations, and nitrite functions as an endocrine reservoir of nitric oxide, which allows it to be helpful in maintaining nitric oxide levels. Nitrites are normally reduced to nitric oxide via intravascular reactions with hemoglobin (a component found in red blood cells) and with certain reductive compounds. However, in absence of these reductive compounds, nitrites can be converted into nitrosating agents These nitrosating agents, when introduced to the acidic environment of the stomach, form a compound called nitrosamine. Nitrosamine can cause some negative issues, so the next logical step is to prevent/mitigate the formation of them. But how would we go about this?
• Recent studies have found that taking reductive compounds can allow for the reduction of nitrites to nitric oxide, rather than converting nitrites to nitrosamine. One of the aforementioned reductive compounds, ascorbic acid (Vitamin C), is present in N.O. Uptake™ for this very reason. Ascorbic Acid has been shown to significantly limit the formation of nitrosamines, and has also been shown to reverse nitrate tolerance. A 1982 study by Schmael et al. found that ascorbic acid actually blocks the formation of nitrosamines in the gastrointestinal tract. Similarly, a 1998 study published in the Journal of Clinical Investigation (1998; July 1) looked at the effects of ascorbic acid on nitrate drug therapy in human patients. Nitrate tolerance occurred in all patients assessed, but when ascorbic acid was given with the nitrate drugs, tolerance to nitrates was virtually eliminated. So, to recount what we have learned so far- nitrates are normally converted to nitric oxide, but can be converted to potentially deleterious substances called nitrosamines under certain conditions. Also, the body can become attenuated to the effects of nitrates after a period of usage; Ascorbic acid help to keep this attenuation from occurring, and ascorbic acid has also been shown to have additional benefits in preventing the conversion of nitrite to nitrosamine (8,9,12,82,89,112,113).

Stacks and Tips to Maximize the Product

1. Take 6-7 capsules of N.O. Uptake™ either pre-workout, or any other time during the day on non-workout days. Can be taken with or without food
2. Stack N.O. Uptake™ with RPM™ and Drive™ for an amazing pre-workout experience; the products were designed to work in concert, and will make one another even more effective- you will get a MASSIVE pump.
3. Stack N.O. Uptake™ with Neovar™ and carbs post-workout; the combo will allow for rapid increases in muscle glycogen content.
4. Stack N.O. Uptake™ with HGH-Up™ Free Test™; there is a strong synergism in this relationship in terms of testosterone and GH enhancement- the effects are very close to those of a mild pro-hormone.
5. In general, maintain a healthy diet and lifestyle:
   • Drink Plenty of water; at least 64 oz. per day
   • Ingest at least 1 gram of protein per lb. of body weight daily
   • Sleep at least 7 hours per night
   • Eat lots of fruits and vegetables
   • Eat lots of complex carbs.
   • Eat 5-6 smaller protein and carb-rich meals throughout the day
   • Increase calories to at least 500 Kcal/day over your normal intake
   • Avoid alcohol and tobacco
6. N.O. Uptake™ is a revolutionary new product from Applied Nutriceuticals® that uses cutting-edge science to bring forth an innovative formula that can help users get stronger, gain lean muscle mass, and recover faster. N.O. Uptake™ utilizes several different complex pathways in a pharma-strength formulation to deliver nutrients to hard-working skeletal muscle- providing an optimal environment for recovery and lean muscle enhancement. N.O. Uptake™ is a unique product, in that it can be used successfully in multiple situations- N.O. Uptake™ can be taken pre-workout (along with RPM™ and/or Drive™) to enhance Testosterone levels and supply an awesome pump, post-workout to enhance hormonal recovery and glycogen re-composition, intra-workout to stave off muscle catabolism, or even before bed with HGH-Up™ to provide a boost of GH and testosterone for overnight nutritional “dead time.”

References

1. Hawasli AH, Benavides DR, Nguyen C, Kansy JW, Hayashi K, Chambon P, Greengard P, Powell CM, Cooper DC, Bibb JA (July 2007). "Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation". Nat. Neurosci. 10 (7): 880–6.
2. Haff, G. Lecture Notes for Graduate Study: Hormonal Parameters Relevant to Training. Appalachian State University, 2000.
3. Khoo, B. and Grossman, A. Normal Physiology of the Hypothalamus and Anterior Pituitary. St. Bartholomew’s Hospital, West Smithfield, London. Neuroendocrinology, Hypothalamus, and Pituitary. 2007 Ch. 1 Lecture.
4. Monteleone P, Beinat L, Tanzillo C, Maj M, Kemali D. Neuroendocrinology. 1990 Sep;52(3):243-8. Effects of phosphatidylserine on the neuroendocrine response to physical stress in humans. 1990 Sep;52(3):243-8.
5. Enza Topo , Andrea Soricelli , Antimo D'Aniello , Salvatore Ronsini and Gemma D'Aniello The role and molecular mechanism of D-aspartic acid in the release and synthesis of LH and testosterone in humans and rats. Reproductive Biology and Endocrinology 2009, 7:120.
6. Pyridoxine (B6) suppresses the rise in prolactin and increases the rise in growth hormone induced by exercise. 1982 Aug 12;307(7):444-5.
7. National Academy of Sciences. Institute of Medicine. Food and Nutrition Board., ed (1998). "Chapter 9 - Vitamin B12". Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: National Academy Press. pp. 306–356.
8. van Jaarsveld H, Schulenburg DH. Dietary iron alters liver, erythrocyte and plasma antioxidant and nitrite levels, and also sensitizes the heart to ischemia/reperfusion. Res Commun Mol Pathol Pharmacol. 1997 Sep;97(3):347-60.
9. Hon YY, Sun H, Dejam A, Gladwin MT. Characterization of erythrocytic uptake and release and disposition pathways of nitrite, nitrate, methemoglobin, and iron-nitrosyl hemoglobin in the human circulation. Drug Metab Dispos. 2010 Oct;38(10):1707-13.
10. Brilla, L. R. and Conte, V. (1999) A novel zinc and magnesium formulation (ZMA) increases anabolic hormones and strength in athletes. Medicine and Science in sports and Exercise, 31, 483.
11. Marieb,E. man Anatomy and Physiology with Interactive Physiology 10-System Suite, 8th Edition (2009).
12. Barletta C, Sellini M, Bartoli A, Bigi C, Buzzetti R, Giovannini C Influence of administration of pyridoxine on circadian rhythm of plasma ACTH, cortisol prolactin and somatotropin in normal subjects. Boll Soc Ital Biol Sper. 1984 Feb 28;60(2):273-8.
13. Meister A (1983) Metabolism and transport of glutathione and other g-glutamyl compounds. In: Larsson A, Orrenius S, Holmgren A, Mannervik B (eds) Functions of glutathione: biochemical, physiological, toxicological and clinical aspects. RavenPress, New York, pp 1–21
14. Mudd SH, Poole JR (1975) Labile methyl balances for normal humans on various dietary regimens. Metabolism 24 : 721–735
15. Vianna-Jorge R, Oliveira CF, Mounier Y, Suarez-Kurtz G. (1998) Functional effects of uridine triphosphate on human skinned skeletal muscle fibers. Can. J. Physiol. Pharmacol. 76: 110-117.
16. Yamamoto T, Moriwaki Y, Takahashi S, Tsutsumi Z, Yamakita J, Higashino K. (1997) Effect of muscular exercise on the concentration of uridine and purine bases in plasma ATP consumption induced pyrimidine degradation. Metabolism. 46:1339-1342. 14.
17. Tullson, P and R. Terjung. "Adenine nucleotide synthesis in exercising and endurance-trainined skeletal muscle." Am. J. Physiol. 261 (1991): C342-C347.
18. Dawson DM. Enzymatic conversion of uridine nucleotide to cytidine nucleotide by rat brain. J Neurochem. 1968 Jan;15(1):31-4.
19. Fausto N. (1972) The conversion of orotic acid into uridine 5-monophosphate b y isolated perfused normal and regenerating rat livers. Biochem.J. 129: 811-820.
20. Wang, L, Pooler AM, Albrecht MA, Wurtman, RJ. Dietary uridine-5’-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats. J Mol Neurosci. 2005;27(1):137-45.
21. Wang L, Albrecht MA, Wurtman RJ. Dietary uridine-5’-monophosphate (UMP), a membrane phosphatide precursor, increases acetylcholine level and release in striatum of aged rat. Brain Res. 2007 Feb 16;1133(1):42-8.
22. Tsao TS, Burcelin R, Katz EB, et al. Enhanced insulin action due to targeted GLUT4 overexpression exclusively in muscle. Diabetes. 1996; 45: 28–36.
23. Steinberg HO, Brechtel G, Johnson A, et al. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest. 1994; 94: 1172–1179.
24. Andersson K, Gaudiot N, Ribiere C, Elizalde M, Giudicelli Y, and Arner P. A nitric oxide-mediated mechanism regulates lipolysis in human adipose tissue in vivo. Br J Pharmacol 126: 1639–1645, 1999.

 

[Bolanrox]

samples for those of us not vegas bound? lol j/k .. but only kinda

 

[rms80]

samples for those of us not vegas bound? lol j/k .. but only kinda

Not yet

 

[southsideguy]

Not yet

Can I take this multiple times a day? As in 6 pre-workout and 6 more post? Maybe 6 more with a carb meal?

 

[OrganicShadow]

samples for those of us not vegas bound? lol j/k .. but only kinda

There's a promo to win the bottle going.

 

[3clipseGT]

How would this work for those on low to no carb diets for either prep or in a cutting phase before off season mode?

Formula looks good and has me really interested.

 

[OrganicShadow]

How would this work for those on low to no carb diets for either prep or in a cutting phase before off season mode?

Formula looks good and has me really interested.

I'll be experimenting with this in my competition prep log. Not sure how to go about it just yet.

 

[3clipseGT]

I'll be experimenting with this in my competition prep log. Not sure how to go about it just yet.

Well i just pulled the trigger and ordered a bottle. So there will be two of us!! haha

 

[PrepNwa23]

Well i just pulled the trigger and ordered a bottle. So there will be two of us!! haha

Gonna have to tell us how it goes I'm very curious.

 

[3clipseGT]

Gonna have to tell us how it goes I'm very curious.

For sure.

 

[rms80]

Can I take this multiple times a day? As in 6 pre-workout and 6 more post? Maybe 6 more with a carb meal?

The pre-workout out dose should cover the post-workout carb-up

 

[drooks10]

Well i just pulled the trigger and ordered a bottle. So there will be two of us!! haha

You're going to love this product. I promise you.

David
Team APPNUT

 

[Cary K]

You're going to love this product. I promise you.

David
Team APPNUT

I hope to receive my package (Uptake and HGH-Up) tomorrow!!

 

[AZMIDLYF]

You're going to love this product. I promise you.

David
Team APPNUT

How have you put it to use?

 

[Celorza]

Liking everything but the AAKG !

 

[Cary K]

View attachment 67139

Liking everything but the AAKG !

Why not the AAKG? Curious...

 

[Celorza]

Why not the AAKG? Curious...

Not a single google or pubmed search was given. I'm a fan of something else to substitute Arginine ! Like I said, product looks wonderful and mighty intriguing nonetheless.

 

[Cary K]

Not a single google or pubmed search was given. I'm a fan of something else to substitute Arginine ! Like I said, product looks wonderful and mighty intriguing nonetheless.

I agree, it does. I'm am fortunate enough to be getting a bottle of it and HGH-Up to log!!

 

[bolt10]

Didn't read the whole write up but I have seen things about the use of Arginine to help with Nitrate tolerance. Haven't really researched it though so I could be wrong (just posting up random ish)

 

[Cary K]

Look at what came in the mail today...

 

[jdg76]

The pre-workout out dose should cover the post-workout carb-up

Funny you should say that, I like it so well pre-workout I have yet to try it post. haha

N.O.Uptake + Freetest + RPM = :Eyecrazy:




jdg76
Team APPNUT

 

[OrganicShadow]

Funny you should say that, I like it so well pre-workout I have yet to try it post. haha

N.O.Uptake + Freetest + RPM = :Eyecrazy:




jdg76
Team APPNUT

I tried splitting it up 4/3 pre/post and the effects saturate faster but dont expect a hard hit in the beginning. I'd still rather dose up all preworkout.

 

[Cary K]

http://anabolicminds.com/forum/supplement-reviews-logs/214952-cary-goes-nutts.html

 

[southsideguy]

When will NO Uptake be back in stock?

 

[OrganicShadow]

When will NO Uptake be back in stock?

Sometime this week is the word.

 

[southsideguy]

Sometime this week is the word.

Good to know. Hats off you guys , great product

 

[JudoJosh]

Good to know. Hats off you guys , great product

thank you

 

[rms80]

View attachment 67139

Liking everything but the AAKG !

Yeah- I have heard this from a couple different people- I do have my reasons for having it in there- L-Norvaline inhibits arginase, so very little arginine is going to be metabolized by the enzyme. Plus, arginine has the ability to act as a glucose metabolizing agent in skeletal muscle:


Eur Rev Med Pharmacol Sci. 2012 Jun;16(6):816-23.
Effect of 3-month L-arginine supplementation on insulin resistance and tumor necrosis factor activity in patients with visceral obesity.

Bogdanski P, Suliburska J, Grabanska K, Musialik K, Cieslewicz A, Skoluda A, Jablecka A.
Source

Department of Internal Medicine, Metabolic Disorders and Hypertension, Poznan University of Medical Sciences, Poznan, Poland. [email protected]

Abstract

BACKGROUND:

The role of tumor necrosis factor alpha (TNF-alpha), one of the adipose tissue products, in the pathogenesis of insulin resistance is well-documented. Many recent studies have shown beneficial influence of L-arginine supplementation on cardiovascular system. However, molecular mechanisms of its positive actions are not fully elucidated.
AIM:

The aim of the study was to evaluate the influence of L-arginine supplementation on tumor necrosis factor alpha, insulin resistance and selected anthropometric and biochemical parameters in patients with visceral obesity.
PATIENTS AND METHODS:

60 patients with visceral obesity were randomly assigned to either receive 9 g of L-arginine or placebo for 3 months. 20 healthy lean subjects were used as control. Selected anthropometrical measurements and blood biochemical analyses were performed at baseline and after 3-months. TNF-alpha and its soluble receptor 2 (sTNFR2) were assessed in both treated groups. Insulin resistance in the participants was evaluated according to the homeostasis model assessment-insulin resistance (HOMA-IR) protocol.
RESULTS:

The concentration of insulin, TNF-a and sTNFR2 and HOMA-IR level in both obese groups significantly exceeded these observed in the control. Basal TNF-alpha and sTNFR2 concentrations were positively correlated with basal body mass index (BMI), waist circumference, percent of body fat and HOMA-IR. We found that 3-month L-arginine supplementation resulted in significant decrease of HOMA-IR and insulin concentration. Only insignificant tendency to decrease of TNF-alpha and sTNFR2 was observed.
CONCLUSIONS:

Our results confirm TNF-alpha role in the complex pathogenesis of insulin resistance in patients with visceral obesity. 3-months L-arginine supplementation in a dose of 9 g improves insulin sensitivity in patients with visceral obesity with no impact on tumor necrosis factor alpha concentration.



J Endocrinol Invest. 2012 Jun 25. [Epub ahead of print]
Supplementation with L-arginine favourably influences plasminogen activator inhibitor type 1 concentration in obese patients - a randomized, double blind trial.

Bogdanski P, Szulinska M, Suliburska J, Pupek-Musialik D, Jablecka A, Witmanowski H.
Source

Department of Internal Medicine, Metabolic Disorders and Hypertension, Poznan University of Medical Sciences, Poznan, Poland.

Abstract

Background. Elevated plasminogen activator inhibitor type 1 (PAI 1) plays an important role in the pathogenesis of excess blood coagulability in obese patients. L-arginine supplementation has shown to be associated with enhanced cardiovascular and metabolic health. The aim of the study was to assess the effect of L-arginine supplementation on PAI 1 concentration and to evaluate the relation to changes in nitric oxide (NO) plasma level, insulin sensitivity (M value) and total antioxidant status (TAS) in obese patients. Material/subjects and methods. A randomized, double-blind, placebo-controlled study was conducted from March 2010 to June 2011. 88 obese patients were randomly assigned to receive either 9 g of L-arginine or placebo daily for 6 months. At baseline and after 6 months selected anthropometrical measurements and blood biochemical analyses were performed, and PAI 1, NO, TAS levels were assessed. Insulin sensitivity was evaluated using the hyperinsulinemic euglycemic clamp technique. Results. We found that 6-month L-arginine supplementation resulted in significant decrease of PAI 1. Significant increase of NO, TAS and insulin sensitivity level were noticed. In a group of patients treated with L-arginine negative correlation between a change of insulin sensitivity value and a change of PAI 1 concentration was found. Conclusions. The present findings demonstrate favourable influence of L-arginine supplementation on PAI 1 concentartion in obese patients. Beneficial influence is related to insulin sensitivity improvement. The potential therapeutic role of L-arginine administration in patients with obesity needs further investigation.



Diabetes Obes Metab. 2012 Oct;14(10):893-900. doi: 10.1111/j.1463-1326.2012.01615.x. Epub 2012 May 21.
Effect of a long-term oral l-arginine supplementation on glucose metabolism: a randomized, double-blind, placebo-controlled trial.

Monti LD, Setola E, Lucotti PC, Marrocco-Trischitta MM, Comola M, Galluccio E, Poggi A, Mammì S, Catapano AL, Comi G, Chiesa R, Bosi E, Piatti PM.
Source

Cardio-Diabetes and Core Lab Unit, Metabolic and Cardiovascular Science Division, Department of Internal Medicine, San Raffaele Scientific Institute, Milan, ItalyCardio-Metabolism and Clinical Trials Unit, Metabolic and Cardiovascular Science Division, Department of Internal Medicine, San Raffaele Scientific Institute, Milan, ItalyVascular Surgery, Metabolic and Cardiovascular Science Division, Cardio-Thoraco-Vascular Department,San Raffaele Scientific Institute, Milan, ItalyNeurology Department, San Raffaele Scientific Institute, Milan, ItalyCentre for the Study of Atherosclerosis, Department of Pharmacological Sciences, University of Milan, Milan, Italy.

Abstract

Aim: This study assessed the efficacy of long-term l-arginine (l-arg) therapy in preventing or delaying type 2 diabetes mellitus. Methods: A mono-centre, randomized, double-blind, parallel-group, placebo-controlled, phase III trial (l-arg trial) was conducted on 144 individuals affected by impaired glucose tolerance (IGT) and metabolic syndrome (MS). l-Arg/placebo was administered (6.4 g/day) on a background structured lifestyle intervention for 18 months plus a 12-month extended follow-up period after study drug termination. Fasting glucose levels and glucose tolerance after oral glucose tolerance test were evaluated throughout the study. Results: After 18 months, l-arg as compared with placebo did not reduce the cumulative incidence of diabetes [21.4 and 20.8%, respectively, hazard ratio (HR), 1.04; 95% confidence interval (CI), 0.58-1.86] while the cumulative probability to become normal glucose tolerant (NGT) increased (42.4 and 22.1%, respectively, HR, 2.60; 95% CI, 1.51-4.46, p < 0.001). The higher cumulative probability to become of NGT was maintained during the extended period in subjects previously treated with l-arg (HR, 3.21; 95% CI, 1.87-5.51; p < 0.001). At the end of the extended period, the cumulative incidence of diabetes in subjects previously treated with l-arg was reduced as compared with placebo (27.2 and 47.1%, respectively, HR, 0.42; 95% CI, 0.24-0.75, p < 0.05). During both periods, l-arg significantly improved insulin sensitivity and β-cell function. Conclusion: Among persons with IGT and MS, the supplementation of l-arg for 18 months does not significantly reduce the incidence of diabetes but does significantly increase regression to NGT.


Metabolism. 2012 Aug 10. [Epub ahead of print]
L-Arginine enhances glucose and lipid metabolism in rat L6 myotubes via the NO/ c-GMP pathway.

de Castro Barbosa T, Jiang LQ, Zierath JR, Nunes MT.
Source

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil; Section of Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.

Abstract

OBJECTIVE:

The amino acid Arginine (Arg) is the main biological precursor of nitric oxide (NO) and has been described to improve insulin sensitivity in diabetes and obesity. We investigated the molecular mechanisms involved in the long-term effects of Arg on glucose and lipid metabolism.
MATERIALS AND METHODS:

L6 myotubes were treated with Arg (7mmol/L) for 6days. D-Mannitol (7mmol/L) was used as control; spermine NONOate (10μmol/L) and L-NAME (100μmol/L) were used to evaluate the NO/c-GMP pathway role. Basal and insulin-induced (120 nmol/L) glycogen synthesis, glucose uptake and lipid oxidation, c-GMP and nitrite levels, and the intracellular signaling pathways were evaluated.
RESULTS:

Arg-treatment increased: 1) basal and insulin-stimulated glycogen synthesis; 2) glucose uptake; 3) palmitate oxidation; 4) p-Akt (Ser(473)), total and plasma membrane GLUT4 content, total and p-AMPK-α and p-ACC (Ser(79)), p-GSK-3α/β (Ser(21/9)) and 5) nitrite and c-GMP levels. L-NAME treatment suppressed Arg effects on: 1) nitrite and c-GMP content; 2) glycogen synthesis and glucose uptake; 3) basal and insulin-stimulated p-Akt (Ser(473)), total and p-AMPK-α and ACC, and nNOS expression.
CONCLUSION:

We provide evidence that Arg improves glucose and lipid metabolism in skeletal muscle, in parallel with increased phosphorylation of Akt and AMPK-α. These effects were mediated by the NO/c-GMP pathway. Thus, arginine treatment enhances signal transduction and has a beneficial effect of metabolism in skeletal muscle through direct activation of Akt and AMPK pathways.





AKG is in the product for another reason entirely- read the tech write-up and focus on the section regarding mTOR- it will make more sense

 

[OrganicShadow]

^What a guy. Check that out.

 

[Cary K]

^What a guy. Check that out.

Yep, talk about science and research

 

[Celorza]

Yeah- I have heard this from a couple different people- I do have my reasons for having it in there- L-Norvaline inhibits arginase, so very little arginine is going to be metabolized by the enzyme. Plus, arginine has the ability to act as a glucose metabolizing agent in skeletal muscle:


Eur Rev Med Pharmacol Sci. 2012 Jun;16(6):816-23.
Effect of 3-month L-arginine supplementation on insulin resistance and tumor necrosis factor activity in patients with visceral obesity.

Bogdanski P, Suliburska J, Grabanska K, Musialik K, Cieslewicz A, Skoluda A, Jablecka A.
Source

Department of Internal Medicine, Metabolic Disorders and Hypertension, Poznan University of Medical Sciences, Poznan, Poland. [email protected]

Abstract

BACKGROUND:

The role of tumor necrosis factor alpha (TNF-alpha), one of the adipose tissue products, in the pathogenesis of insulin resistance is well-documented. Many recent studies have shown beneficial influence of L-arginine supplementation on cardiovascular system. However, molecular mechanisms of its positive actions are not fully elucidated.
AIM:

The aim of the study was to evaluate the influence of L-arginine supplementation on tumor necrosis factor alpha, insulin resistance and selected anthropometric and biochemical parameters in patients with visceral obesity.
PATIENTS AND METHODS:

60 patients with visceral obesity were randomly assigned to either receive 9 g of L-arginine or placebo for 3 months. 20 healthy lean subjects were used as control. Selected anthropometrical measurements and blood biochemical analyses were performed at baseline and after 3-months. TNF-alpha and its soluble receptor 2 (sTNFR2) were assessed in both treated groups. Insulin resistance in the participants was evaluated according to the homeostasis model assessment-insulin resistance (HOMA-IR) protocol.
RESULTS:

The concentration of insulin, TNF-a and sTNFR2 and HOMA-IR level in both obese groups significantly exceeded these observed in the control. Basal TNF-alpha and sTNFR2 concentrations were positively correlated with basal body mass index (BMI), waist circumference, percent of body fat and HOMA-IR. We found that 3-month L-arginine supplementation resulted in significant decrease of HOMA-IR and insulin concentration. Only insignificant tendency to decrease of TNF-alpha and sTNFR2 was observed.
CONCLUSIONS:

Our results confirm TNF-alpha role in the complex pathogenesis of insulin resistance in patients with visceral obesity. 3-months L-arginine supplementation in a dose of 9 g improves insulin sensitivity in patients with visceral obesity with no impact on tumor necrosis factor alpha concentration.



J Endocrinol Invest. 2012 Jun 25. [Epub ahead of print]
Supplementation with L-arginine favourably influences plasminogen activator inhibitor type 1 concentration in obese patients - a randomized, double blind trial.

Bogdanski P, Szulinska M, Suliburska J, Pupek-Musialik D, Jablecka A, Witmanowski H.
Source

Department of Internal Medicine, Metabolic Disorders and Hypertension, Poznan University of Medical Sciences, Poznan, Poland.

Abstract

Background. Elevated plasminogen activator inhibitor type 1 (PAI 1) plays an important role in the pathogenesis of excess blood coagulability in obese patients. L-arginine supplementation has shown to be associated with enhanced cardiovascular and metabolic health. The aim of the study was to assess the effect of L-arginine supplementation on PAI 1 concentration and to evaluate the relation to changes in nitric oxide (NO) plasma level, insulin sensitivity (M value) and total antioxidant status (TAS) in obese patients. Material/subjects and methods. A randomized, double-blind, placebo-controlled study was conducted from March 2010 to June 2011. 88 obese patients were randomly assigned to receive either 9 g of L-arginine or placebo daily for 6 months. At baseline and after 6 months selected anthropometrical measurements and blood biochemical analyses were performed, and PAI 1, NO, TAS levels were assessed. Insulin sensitivity was evaluated using the hyperinsulinemic euglycemic clamp technique. Results. We found that 6-month L-arginine supplementation resulted in significant decrease of PAI 1. Significant increase of NO, TAS and insulin sensitivity level were noticed. In a group of patients treated with L-arginine negative correlation between a change of insulin sensitivity value and a change of PAI 1 concentration was found. Conclusions. The present findings demonstrate favourable influence of L-arginine supplementation on PAI 1 concentartion in obese patients. Beneficial influence is related to insulin sensitivity improvement. The potential therapeutic role of L-arginine administration in patients with obesity needs further investigation.



Diabetes Obes Metab. 2012 Oct;14(10):893-900. doi: 10.1111/j.1463-1326.2012.01615.x. Epub 2012 May 21.
Effect of a long-term oral l-arginine supplementation on glucose metabolism: a randomized, double-blind, placebo-controlled trial.

Monti LD, Setola E, Lucotti PC, Marrocco-Trischitta MM, Comola M, Galluccio E, Poggi A, Mammì S, Catapano AL, Comi G, Chiesa R, Bosi E, Piatti PM.
Source

Cardio-Diabetes and Core Lab Unit, Metabolic and Cardiovascular Science Division, Department of Internal Medicine, San Raffaele Scientific Institute, Milan, ItalyCardio-Metabolism and Clinical Trials Unit, Metabolic and Cardiovascular Science Division, Department of Internal Medicine, San Raffaele Scientific Institute, Milan, ItalyVascular Surgery, Metabolic and Cardiovascular Science Division, Cardio-Thoraco-Vascular Department,San Raffaele Scientific Institute, Milan, ItalyNeurology Department, San Raffaele Scientific Institute, Milan, ItalyCentre for the Study of Atherosclerosis, Department of Pharmacological Sciences, University of Milan, Milan, Italy.

Abstract

Aim: This study assessed the efficacy of long-term l-arginine (l-arg) therapy in preventing or delaying type 2 diabetes mellitus. Methods: A mono-centre, randomized, double-blind, parallel-group, placebo-controlled, phase III trial (l-arg trial) was conducted on 144 individuals affected by impaired glucose tolerance (IGT) and metabolic syndrome (MS). l-Arg/placebo was administered (6.4 g/day) on a background structured lifestyle intervention for 18 months plus a 12-month extended follow-up period after study drug termination. Fasting glucose levels and glucose tolerance after oral glucose tolerance test were evaluated throughout the study. Results: After 18 months, l-arg as compared with placebo did not reduce the cumulative incidence of diabetes [21.4 and 20.8%, respectively, hazard ratio (HR), 1.04; 95% confidence interval (CI), 0.58-1.86] while the cumulative probability to become normal glucose tolerant (NGT) increased (42.4 and 22.1%, respectively, HR, 2.60; 95% CI, 1.51-4.46, p < 0.001). The higher cumulative probability to become of NGT was maintained during the extended period in subjects previously treated with l-arg (HR, 3.21; 95% CI, 1.87-5.51; p < 0.001). At the end of the extended period, the cumulative incidence of diabetes in subjects previously treated with l-arg was reduced as compared with placebo (27.2 and 47.1%, respectively, HR, 0.42; 95% CI, 0.24-0.75, p < 0.05). During both periods, l-arg significantly improved insulin sensitivity and β-cell function. Conclusion: Among persons with IGT and MS, the supplementation of l-arg for 18 months does not significantly reduce the incidence of diabetes but does significantly increase regression to NGT.


Metabolism. 2012 Aug 10. [Epub ahead of print]
L-Arginine enhances glucose and lipid metabolism in rat L6 myotubes via the NO/ c-GMP pathway.

de Castro Barbosa T, Jiang LQ, Zierath JR, Nunes MT.
Source

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil; Section of Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.

Abstract

OBJECTIVE:

The amino acid Arginine (Arg) is the main biological precursor of nitric oxide (NO) and has been described to improve insulin sensitivity in diabetes and obesity. We investigated the molecular mechanisms involved in the long-term effects of Arg on glucose and lipid metabolism.
MATERIALS AND METHODS:

L6 myotubes were treated with Arg (7mmol/L) for 6days. D-Mannitol (7mmol/L) was used as control; spermine NONOate (10μmol/L) and L-NAME (100μmol/L) were used to evaluate the NO/c-GMP pathway role. Basal and insulin-induced (120 nmol/L) glycogen synthesis, glucose uptake and lipid oxidation, c-GMP and nitrite levels, and the intracellular signaling pathways were evaluated.
RESULTS:

Arg-treatment increased: 1) basal and insulin-stimulated glycogen synthesis; 2) glucose uptake; 3) palmitate oxidation; 4) p-Akt (Ser(473)), total and plasma membrane GLUT4 content, total and p-AMPK-α and p-ACC (Ser(79)), p-GSK-3α/β (Ser(21/9)) and 5) nitrite and c-GMP levels. L-NAME treatment suppressed Arg effects on: 1) nitrite and c-GMP content; 2) glycogen synthesis and glucose uptake; 3) basal and insulin-stimulated p-Akt (Ser(473)), total and p-AMPK-α and ACC, and nNOS expression.
CONCLUSION:

We provide evidence that Arg improves glucose and lipid metabolism in skeletal muscle, in parallel with increased phosphorylation of Akt and AMPK-α. These effects were mediated by the NO/c-GMP pathway. Thus, arginine treatment enhances signal transduction and has a beneficial effect of metabolism in skeletal muscle through direct activation of Akt and AMPK pathways.





AKG is in the product for another reason entirely- read the tech write-up and focus on the section regarding mTOR- it will make more sense

Interesting indeed, this really beats my old thought that AAKG is bunk. Hadn't thought of it that way , I wanna try Uptake even more !

 

[Dewey99]

Interesting indeed, this really beats my old thought that AAKG is bunk. Hadn't thought of it that way , I wanna try Uptake even more !

Get in line Celorza!

 

[Celorza]

You are next in line Celorza!

Gee thanks Dewey I appreciate it! You have my Shipping address anyhow brother! I'll be stalking my mail woman from now on then!

 

[JudoJosh]

Yeah- I have heard this from a couple different people- I do have my reasons for having it in there- L-Norvaline inhibits arginase, so very little arginine is going to be metabolized by the enzyme. Plus, arginine has the ability to act as a glucose metabolizing agent in skeletal muscle:

Personally I am a fan of arginine and I feel it gets a bad rap in the supplement world. People tend to focus soley on the NO claims that are made about it and forget arginine may have other ergogenic properties .

Here they investigated the effect of oral arginine on vasolidation and VO2Max in soccer players.

http://www.libsport.ru/doc/8416b4f6-f738-4bd7-8c5b-42f9704976b1/

Oral supplementation of L-arginine significantly (p<0.01) decreased blood pressure indicesand increased VO[SUB]2[/SUB]max (p<0.01), blood flow (p<0.05), femoral artery diameter (p<0.05) and urea levels (p<0.05). There was no change in blood lipid levels (p<0.05). No significant changes were noted in the placebo and control groups.

 

[dtrain13]

Strong bump but how do you guys recommend cycling this?

 

[dtrain13]

One more thing any issues with using this and another product that has NMDA in it like Paragon or Intimidate?

 

[Nugget5]

Strong bump but how do you guys recommend cycling this?

Usually 6-8 weeks on with a 4-6 week cool down.

One more thing any issues with using this and another product that has NMDA in it like Paragon or Intimidate?

AFAIK it shouldn't matter but I will check and get back to this ASAP

 

[JudoJosh]

Strong bump but how do you guys recommend cycling this?

I would go 12-16 weeks on/6-8 weeks off

One more thing any issues with using this and another product that has NMDA in it like Paragon or Intimidate?

NO Uptake has plenty of NMA, no need to take another product with NMDA along with it


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