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  • Do you know what you’re researching?...

    One of the newest research chemicals to become more readily available, in this case, a selective insulin receptor modulator (SIRM) called S597(1) caught my eye due to an incredible claim (in a thread title) that it had “all of the benefits” and “no negatives” of insulin. As such, it sounded to me like (and so far folks are still suggesting) that S597 must therefore be a highly engineered (or fortuitously stumbled upon) insulin analogue does some pretty impressive stuff.

    I’m thinking it would have to be something that carries no risk of hypoglycemia (as a glucose disposal agent), but still promotes glycogen storage, without any unwanted effect lipid storage (fat gain). These claims also suggested to me that this SIRM lacks the negative mitogenic (carcinogenic) or even the potentially adverse cardiovascular effects that elevating insulin levels might have on research subjects in a study of muscle hypertrophy.

    So, I figured – why not take a look at what a researcher might expect, e.g., in actually looking at the scientific literature available, when developing a hypothesis regarding S597’s effects on his / her research subjects. In other words, what’s the real deal on S597 and SIRMs?

    Well, SIRMs, have been discovered in fungi(2-4) and plants(5), and have been more recently been engineered in the lab as monoclonal antibodies(6) or simply as small peptides, like S597(7). SIRMs have actually been researched for over a decade, with the intention of developing drug treatments for diabetes – by *selectively* *modulating* the cellular actions mediated by the insulin receptor (in particular for glucose control). (In the case of S*A*RMs we generally want to activate the androgen receptor. As far as S*E*RMs go, we’re usually talking about antagonizing the estrogen receptor in some tissue. When it comes to SIRMs, the name of the game from a medical standpoint is generally to modulate insulin receptor activity to help with disease, in particular diabetes mellitus.) As an example, one fungal derivative, DMAQ1 (which has been tested in mice), seems promising because it lowers glucose (like insulin), but doesn’t turn on the genes of vascular cellular proliferation that have been implicated in insulin’s connection with cardiovascular disease(8).

    Before getting into the nitty gritty of S597, I think it makes sense to address another SIRM. On professionalmuscle.com, some misunderstanding about the effects of S597 versus XMetA have come about, I think simply because both were mentioned in a particular short review on SIRMs(1) that was posted. Let’s take a look at XMetA and compare it with S597 to see why all SIRMs were not created equally.

    XMetA is a human monoclonal antibody that binds to the insulin receptor at an allosteric binding site, meaning it doesn’t bind where insulin does. (It was created artificially under circumstances very carefully created to produce an antibody that does not bind at the orthosteric (normal) binding site for insulin(6).) When administered to mice with chemically induced diabetes, XMetA effectively controls blood sugar without causing weight gain(6, 9) – a good thing. In particular, it does this by selectively activating the Akt pathway(6), which is more strongly involved with glucoregulation (10). XMetA however, unlike insulin(7), does not bring about phosphorylation (activation) of ERK, a key enzymatic component of the mitogen activated protein kinase(MAPK) pathway, which mediates insulin’s effects on cellular proliferation and growth. Thus, XMetA could be considered a “safer” compound than insulin for use as a prospective SIRM, because it would be expected to have minimal growth / proliferative or carcinogenic effects(6).

    S597, on the other hand, is a synthetic protein, and created in an entirely different manner than a monoclonal antibody like XMetA(7). S597, unlike XMetA, has not, to my knowledge, been studied (meaning studies published in peer-reviewed scientific journals) in intact animals, be they mice, men or other mammals. The two studies I’m aware of looking *specifically* at S597 (using cell cultures)(7, 11), found that S597 competes with insulin for binding at the normal (orthosteric) binding site, but shows little affinity for the IGF-1 receptor. In terms of the maximal effects of S597 vs. insulin (i.e., those found at the highest concentrations tested), the maximal mitogenic activity (related to ERK1 phosphorylation and effects on cell growth) of S597 is actually <25% that of insulin. However, S597 seems to maximally turn on glycogen synthesis with only <75% of the action of insulin (see table 1 in Jensen et al, 2007(7).)

    On the other hand, and ***more importantly in terms of physiological effects in intact test subjects (living, breathing animals, be they mice or men)***, when specifically comparing concentrations needed to maximize glycogen synthesis (see Figure 5A and B in Jensen et al. 2007(7)), or key regulatory enzyme activity indicative of insulin’s metabolic actions like glucose disposal (Protein Kinase B phosphorylation; Figure 2E), S597 caused ***more than twice the rate of cell growth*** compared to insulin. In other words, because S597 has a different dose-response than insulin with regard to glucose handling versus stimulating cell division, these data (Figures 2 and 5) actually suggest that S597 would cause greater cell growth (carcinogenic potential) compared to insulin if both were applied at concentrations (in vitro) or administered (in vivo) in doses that maximally affect blood glucose and skeletal muscle glycogen storage. From a practical standpoint, in a whole animal where hypoglycemia were of concern, in my interpretation, these data point to insulin as a more potent metabolic agent for a given carcinogenic risk.

    An analysis of the genes turned on by insulin and S597 again found that insulin to be the more mitogenic compound, but only under circumstances of extreme concentrations (after cells were exposed to those levels of S597 eliciting maximal effects on glycogen synthesis, but at supraphysiologic concentrations of insulin – 100 fold greater than those needed for insulin’s maximal metabolic effects)(11). S597 activated some but not all of the genes that insulin does, but from a practical standpoint, there was not a single incidence of S597 turning a gene on or off in a direction opposite that of insulin(11). This is important because I have read claims of “repartitioning” effects of S597 which would be hypothetically be due to lipolytic effects of S597, i.e., opposite of those lipogenic effects insulin is known for. This kind of mechanism – S597 working in a manner opposite of insulin – is absolutely not supported by the analysis of the effects of S597 on every single rat gene thus far identified – the entire rat genome.

    ----

    So, what’s the bottom line here, as far as “researchers” who are interested in evaluating the effects of S597 on body composition, for instance, or otherwise?... Here’s a bit of a summary of my thoughts, where I’ll also address some comments I’ve read over the past couple weeks regarding S597:

    ---XMetA, an antibody, is not the same as S597, a small peptide, so applying / administering S597 in a whole animal, in the manner that XMetA, which very the firmly binds the insulin receptor at an allosteric site(6), is based on a faulty assumption.

    ---In vitro studies suggest that S597 exerts many, but not all of the same effects as insulin, in a complex way(11). There is no evidence of S597 acting in a manner opposite to that of insulin (e.g., lipolytically).

    ---S597 competes with insulin at the insulin receptor, which in in vitro and presumably in in vivo situations where insulin levels could vary, e.g., after eating where insulin levels have already increased vs. in the fasted state, might possibly cause some variation in the effects of S597 on blood glucose. As noted above, the data so far actually suggest a concern (at least to me), that at concentrations that maximize cellular metabolism (glycogen synthesis, etc.) for S597 may actually turn out to be more mitogenic compared to those for insulin.

    ---The effects, short or long term, of S597 on an intact animal have not been reported in the scientific literature (that I’m aware of). Useful information, in my opinion, would include: Any and all pharmacokinetic information about S597, including half life, routes of excretion and hepatic or other deactivation and effects on endogenous insulin release and glycemic control in general. Data on the time course of S597’s effects on signaling pathways of cells in culture seem similar to those of insulin (when followed for up to 60 minutes). However, unlike insulin, ***S597 appears to be very poorly internalized***, instead remaining bound on the receptor, potentially facilitating metabolic actions and/or thus interfering with the effects of insulin, as well(7). This could be another potentially unpredictable effect of S597 on glucoregulation. In lay terms, we don’t know shit from a scientific standpoint about how the body metabolizes S597 (pharmacokinetics) or how S597 really affects the body either (pharmacodynamics). Guinea pigs should know this, I think.

    ---Does S597 cause an immunological reaction of any sort, rendering it useless and/or causing immunological difficulties (related to immune responses to other, similar proteins) in research subjects who might be exposed to it (acutely or over time)?...

    That’s all I have for now on this one. I hope you’ve found this useful.

    Here’s a potentially helpful figure showing insulin receptor signaling: http://www.cellsignal.com/reference/...n_Receptor.pdf

    Also, here’s a two part article on evaluating a supplement that might come in handy when evaluating a research chemical as well:

    http://www.musclemag.com/nutrition-s.../#.UJMk54XbZDE

    http://www.musclemag.com/nutrition-s.../#.UJMlC4XbZDE

    -Scott

    References

    1. Vigneri, R., et al., Selective insulin receptor modulators (SIRM): a new class of antidiabetes drugs? Diabetes, 2012. 61(5): p. 984-5. http://www.ncbi.nlm.nih.gov/pubmed/22517652
    2. Zhang, B., et al., Discovery of a small molecule insulin mimetic with antidiabetic activity in mice. Science, 1999. 284(5416): p. 974-7. http://www.ncbi.nlm.nih.gov/pubmed/10320380
    3. Salituro, G.M., et al., Discovery of a small molecule insulin receptor activator. Recent progress in hormone research, 2001. 56: p. 107-26. http://www.ncbi.nlm.nih.gov/pubmed/11237209
    4. Qureshi, S.A., et al., Activation of insulin signal transduction pathway and anti-diabetic activity of small molecule insulin receptor activators. The Journal of biological chemistry, 2000. 275(47): p. 36590-5. http://www.ncbi.nlm.nih.gov/pubmed/10967116
    5. Jung, S.H., et al., Insulin-mimetic and insulin-sensitizing activities of a pentacyclic triterpenoid insulin receptor activator. The Biochemical journal, 2007. 403(2): p. 243-50. http://www.ncbi.nlm.nih.gov/pubmed/17201692
    6. Bhaskar, V., et al., A fully human, allosteric monoclonal antibody that activates the insulin receptor and improves glycemic control. Diabetes, 2012. 61(5): p. 1263-71. http://www.ncbi.nlm.nih.gov/pubmed/22403294
    7. Jensen, M., et al., Activation of the insulin receptor by insulin and a synthetic peptide leads to divergent metabolic and mitogenic signaling and responses. The Journal of biological chemistry, 2007. 282(48): p. 35179-86. http://www.ncbi.nlm.nih.gov/pubmed/17925406
    8. Webster, N.J., et al., Signaling effects of demethylasterriquinone B1, a selective insulin receptor modulator. Chembiochem : a European journal of chemical biology, 2003. 4(5): p. 379-85. http://www.ncbi.nlm.nih.gov/pubmed/12740809
    9. Bhaskar, V., et al., XMetA, an allosteric monoclonal antibody to the insulin receptor, improves glycemic control in mice with diet-induced obesity. Diabetes, obesity & metabolism, 2012. http://www.ncbi.nlm.nih.gov/pubmed/23039274
    10. Kido, Y., et al., Clinical review 125: The insulin receptor and its cellular targets. The Journal of clinical endocrinology and metabolism, 2001. 86(3): p. 972-9. http://www.ncbi.nlm.nih.gov/pubmed/11238471
    11. Jensen, M., et al., Activation of the insulin receptor (IR) by insulin and a synthetic peptide has different effects on gene expression in IR-transfected L6 myoblasts. The Biochemical journal, 2008. 412(3): p. 435-45. http://www.ncbi.nlm.nih.gov/pubmed/18318661
    The Book Has Arrived!
    The Book Has Arrived!

    Life's journey is not to arrive at the grave safely in a pristine, well-preserved body, but rather to skid in sideways, used up, worn out, and shouting, "Holy #$&^%$^... What a ride!!!"


    www.TrueNutrition.com

    2012 NPC Master's Nationals HW 5th. Mid-USA HW & Overall
    2010 NPC Jr. USA HW 4th, Pacific USA Heavy 2nd
    2009 NPC Mr. Arizona HW & Overall, Jr. Nationals HW 16th, Smoked at USA's

  • #2
    Scott,

    Thank you for taking the time for putting this together-I really enjoyed reading it. While there is a lot of research info over there, I often find it difficult to sift through it all and determine what is legitimate and what is not.

    Comment


    • #3
      Originally posted by dougisbig View Post
      Scott,

      Thank you for taking the time for putting this together-I really enjoyed reading it. While there is a lot of research info over there, I often find it difficult to sift through it all and determine what is legitimate and what is not.
      No problemo!

      Hoping this keeps everyone and everything safe n' sound.

      -S
      The Book Has Arrived!
      The Book Has Arrived!

      Life's journey is not to arrive at the grave safely in a pristine, well-preserved body, but rather to skid in sideways, used up, worn out, and shouting, "Holy #$&^%$^... What a ride!!!"


      www.TrueNutrition.com

      2012 NPC Master's Nationals HW 5th. Mid-USA HW & Overall
      2010 NPC Jr. USA HW 4th, Pacific USA Heavy 2nd
      2009 NPC Mr. Arizona HW & Overall, Jr. Nationals HW 16th, Smoked at USA's

      Comment


      • #4
        Your awesome Scott!
        :preach:

        Comment


        • #5
          You are a saint, Scott. I'm sure you have definitely helped sway some opinions in a much 'safer' direction than promuscle tends to do.



          Sent from my SCH-I535 using Tapatalk 2
          Owner of 316FIT and Team Skip Approved Trainer


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          Comment


          • #6
            Great post Scott.
            Anyone can become angry - that is easy, but to be angry with the right
            person, to the right degree, at the right time, for the right purpose,
            and in the right way, that is not easy.
            -- Aristotle (384-322 B.C.)

            Comment


            • #7
              I wouldn't touch ANY research based injectables...EVER!!

              The only one I have ever used is Melanotan 2 and trust me baby ...it was .2 um filtered before use with BAH20. It's really surprised that someone hasn't got fucked up by using this stuff since the stuff is made in China in vet grade conditions if that.

              I cringe at all the ridiculous claims made by these labeling/shipping/ handling/re-mailing companies selling them, especially since they are bought on the open market from Chinese companies and these "research companies" copy and paste articles that back no human use.

              Caveat emptor!

              Every one of these new magic peptides-is being promoted by people taking massive amounts of other drugs but yet each new "strain" people are supposed to gain 5-6 lbs of pure muscle .....


              Baloney!
              Massive G
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              • #8
                Wow Scott... just plain wow. I knew you had taken an interest in the claims of this compound but I had no idea how exensively you have dug through the details to sort out fact from fiction.

                As Massive G said, some of the claims made by "research companies" are outlandish and for the individual looking for the next big thing or who thinks they need to find the missing link to put their physique over the top and is willing to try the next hot fad, this is dangerous business.

                With this, due to the lack of scientific evidence supporting the effects on humans, it almost sound as if a researcher is just saying, "Let's stick this in my body and see what happens.."

                I really appreciate you taking the time to put together this article. Very well written.
                Be true to yourself and fuel your body with nothing less the highest quality supplements. Only available at TrueNutrition.com Use discount code: KSP945 to save 5% on your order!

                Stickies...just read the damn stickies...

                2014 Xcalibur Cup Bantam Open - 1st
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                Comment


                • #9
                  I like an unbiased literary review, something I need to do more often regarding things that interest.

                  Comment


                  • #10
                    You're welcome, Guys. My pleasure.

                    My main purpose really was simply to reduce health risks for the research subjects. This particular substance, S597, just seemed a bit over the top for me to simply let slide, when I'm in a position to grasp the research that's out there and provide what I think is truly useful info.

                    -S
                    The Book Has Arrived!
                    The Book Has Arrived!

                    Life's journey is not to arrive at the grave safely in a pristine, well-preserved body, but rather to skid in sideways, used up, worn out, and shouting, "Holy #$&^%$^... What a ride!!!"


                    www.TrueNutrition.com

                    2012 NPC Master's Nationals HW 5th. Mid-USA HW & Overall
                    2010 NPC Jr. USA HW 4th, Pacific USA Heavy 2nd
                    2009 NPC Mr. Arizona HW & Overall, Jr. Nationals HW 16th, Smoked at USA's

                    Comment


                    • #11
                      Scott
                      Can you express your feelings on GW-501516, or perhaps direct me to an informative source?

                      Comment


                      • #12
                        Originally posted by VanillaGorilla3 View Post
                        Scott
                        Can you express your feelings on GW-501516, or perhaps direct me to an informative source?
                        VG,

                        I'd just have to go to Medline and read the studies. Go right to the literature, my man.

                        (I had to just dig in with S597, get all the studies I could and spend time, just like everything. That analysis of the mitogenic vs. metabolic effects comes from looking at the data in the rawest form I could aside from getting the data sets from the researchers themselves. Digging in like that is what really gives you some true knowledge, IMO...)

                        -S
                        The Book Has Arrived!
                        The Book Has Arrived!

                        Life's journey is not to arrive at the grave safely in a pristine, well-preserved body, but rather to skid in sideways, used up, worn out, and shouting, "Holy #$&^%$^... What a ride!!!"


                        www.TrueNutrition.com

                        2012 NPC Master's Nationals HW 5th. Mid-USA HW & Overall
                        2010 NPC Jr. USA HW 4th, Pacific USA Heavy 2nd
                        2009 NPC Mr. Arizona HW & Overall, Jr. Nationals HW 16th, Smoked at USA's

                        Comment


                        • #13
                          OK thanks Scott. If you ever get an oppertunity to check on this one, please do. So far all I have seen is "copy & paste" articles on the sales pages from PubMed etc. Will continue to dig

                          Comment


                          • #14
                            Originally posted by VanillaGorilla3 View Post
                            OK thanks Scott. If you ever get an oppertunity to check on this one, please do. So far all I have seen is "copy & paste" articles on the sales pages from PubMed etc. Will continue to dig
                            You gotta start somewhere, my man. Why not download the free articles and glean from them what you can?...

                            -S
                            The Book Has Arrived!
                            The Book Has Arrived!

                            Life's journey is not to arrive at the grave safely in a pristine, well-preserved body, but rather to skid in sideways, used up, worn out, and shouting, "Holy #$&^%$^... What a ride!!!"


                            www.TrueNutrition.com

                            2012 NPC Master's Nationals HW 5th. Mid-USA HW & Overall
                            2010 NPC Jr. USA HW 4th, Pacific USA Heavy 2nd
                            2009 NPC Mr. Arizona HW & Overall, Jr. Nationals HW 16th, Smoked at USA's

                            Comment


                            • #15
                              LOL as we speak sir

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