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  1. #31
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    @Greg B


    Insulin acts as a ligand for several different receptors, but the principal target is actually called Insulin Receptor. It's not that cool architecturally; like many proteins, it's basically a blob that sits embedded in the cell membrane exposed to both the extracellular space and the cytosol. Insulin finds the receptor site on the outside and binds, causing a change in protein shape which allows a portion on the other side of the membrane to stick a phosphate onto IRS-1 (Insulin Receptor Substrate 1). IRS-1 goes on to signal how many GLUT4 proteins are needed to transport glucose across the membrane. Too much insulin for too long, and receptor density is decreased, making each molecule of insulin that much less likely to successfully send a signal to that cell. The result is that glucose transport becomes very difficult. You are now insulin resistant!


    @ SerialSinner


    A) The brain is very much a blind spot of mine (I've been putting off too intense a study of it until we figure more of the damn thing out). That said, I'll do what I can.


    The brain needs fuel, and lots of it. If glucose is available, it transports it across the blood-brain barrier and burns it. If not, it signals for ketones to be produced so that it can keep going about the important business of keeping you alive.


    Ketones diffuse across the blood-brain barrier and are then used for fuel in a fairly similar fashion to glucose. The thing is, they seem to have a variety of beneficial effects as well (once you've adapted to them. You can be a bit fuzzy at first, which is why some people say "ketones make you stupid"). The mechanisms for this are pretty unclear still, but some of them have plausible explanations.


    Over time, particularly in the presence of chronic hyperinsulinemia, a number of issues begin to develop with the brain's capacity to efficiently metabolize glucose and to clear certain molecules from the brain. Ketones can help ameliorate some of these problems by providing an alternative energy substrate and encouraging the clearance of some of these molecules.


    Ketones also have a protective effect against brain damage, mechanism highly disputed.


    Definitely good for the brain to spend at least some of its time fueled by ketones.


    B) More or less, fasting appears to trigger improved insulin sensitivity (presumably so that you can get fat out of your adipocytes more easily), neuroprotection (possibly from the ketones), improved autophagy and protein turnover (when protein is low, clear out the junk proteins) and a host of benefits (such as reduced inflammation, lower susceptibility to cancer, increased mitochondrial function) associated with calorie restriction signalling. I think it's highly plausible that the calorie restriction targets like TOR and SIR2 only have to be tripped periodically like switches which reset after a period of time. The research for both IF and CR is promising in humans, but it remains to be seen whether maximum (rather than average) lifespan is extended by either intervention.


    Its likely a mix of signals which trigger the effect, both actual nutrient levels and various senses (particularly smell) which help discern nutrient availability in the environment. It has been established in drosophila that the benefits of CR are severely curtailed when the flies have access to even the scent of food. In humans, however, I expect the effect would be more modest.

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    Thank you for the answer regarding insulin resistance, but I'd like to know a bit more. What is the process by which the number of insulin receptors is reduced. Specifically how does elevated insulin lead to the cell having fewer receptors.


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    Fascinating, thanks.


    Greg B, this might interest you as well:
    [quote]

    A team including Robert Margolskee and Bedrich Mosinger, then at Mount Sinai School of Medicine in New York City, reported that taste receptors weren’t just active in the rodent gut, but also in human intestinal cells.</blockquote>


    http://goo.gl/rpyj


    Threads like this make me wonder why is a heavy background in biochemistry not mandatory for anyone eligible to become a nutritionist. It would seem like a no-brainer.

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    @ GregB


    A precise, molecule by molecule explanation escapes me, but here&#39;s the basic blueprint:


    Insulin binds IR.

    IR phosphorylates IRS-1

    Phosphorylation cascade occurs, activating IRS 2 through 4

    IRS-1 and 3 activate RAS, which is a central regulator of gene expression

    Expression of IR is reduced a bit downstream after a further phosphorylation cascade through selective methylation of certain regions of DNA

    Lower receptor density at cell surface leads to less signalling

    Less signalling results in fewer GLUT4 containing vesicles being called to the cell surface

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    MG -- thanks so much for your response. Very helpful!


    To quote you:

    And, as you suspect, this is pretty much a moot point in someone eating ~100g carbs a day. You&#39;re just not getting much of an insulin response to that, for a variety of reasons I&#39;ll enumerate if you care.


    Yes! If you&#39;re so inspired, I&#39;d love to hear more about the reasons a person eating fewer that 100g carbs/day won&#39;t experience much of an insulin response. Particularly, how much does the distribution of those carbs matter? Will a 60g carb meal cause a spike even in a person with low insulin resistence?

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    And, Molecular Grokologist, following up on Barbey&#39;s question, if a meal does give you an insulin spike, which then comes back down quickly, does that do you harm or good?


    It seems to me that during the peak of that spike you could move some nutrients into cells which otherwise might not get there if your insulin remains remorselessly low?


    Assuming, of course, that your insulin background levels aren&#39;t high already ...


    thanks


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    WOW... this thread is money... you&#39;re a genius! thank you for all this... i understand "some" of it haha. wont ask questions will just keep reading!


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    @Barbeygirl

    At a carbohydrate intake sub 100g/day, all or nearly all of it (depending on your age/gender/mass etc.) is going to be used by your greedy brain and a couple other particularly sugar-hungry tissues. Your brain can&#39;t use it all at once, however, so that 100g/day is going to be stored in branching chains as glycogen in the liver (and to a lesser extent, the muscles) and lopped off one molecule at a time from the ends to keep blood glucose nice and even. Very, very little insulin is necessary to encourage sugar uptake by the brain, and the liver doesn&#39;t need any insulin at all to make glycogen (in fact, it needs glucagon, which is in most respects antagonized by insulin), so insulin spikes will be very minimal.


    Even if your glycogen stores were full (from, say, a couple of high carbohydrate meals the previous day), 100g/day of carbohydrates, especially in the form of (mostly) low glycemic index fruits and vegetables and spread out over 2 or 3 meals just isn&#39;t going to provoke an impressive insulin response.


    @PDL


    Does an insulin spike do you good? There&#39;s some debate over that, but insulin sensitivity appears to be modestly improved by periodic spiking (say, once or twice a week). It&#39;s the same principle I keep repeating: "moderate, acute stressors tend to improve the baseline functionality of the system they stress". People eating a VLC diet interspersed with high-carb feed meals have better insulin sensitivity and lower fasting insulin levels than people eating a VLC diet alone, and it MAY be the insulin spike that&#39;s actually doing this.


    We&#39;re pretty good at delivering nutrients to cells as long as our insulin/glucagon signalling isn&#39;t broken. There might be some slightly improved uptake of amino acids, but unless you just squatted or something, the effect is going to be minimal (it&#39;s not even all that impressive post-workout).

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    Okay two more questions. I really appreciate this, by the way. Do you know of any public, reputable studies that objectively demonstrate the effects of different macronutrients on blood lipid profiles? The more detailed the better.


    Also: on antioxidants. There has been much evidence to support the efficacy of certain polyphenols on overall health and longevity and I want to know your opinion on herbs and spices like turmeric, oregano, ginger, cinnamon, cocoa, grapeseed/resveratrol etc in human health. Clearly they have merit in protecting meat while cooking, but do you think that it is a good idea to use them in a supplemental role in a paleolithic diet? I have been using this stuff ever since I was into the hippie-dippie diet and although I have reduced fruit greatly and vegetables somewhat for obvious reasons, the evidence points me to these polyphenols as being nothing but beneficial. Perhaps Grok didn&#39;t have these things but there is definite adaptation if not macroevolution and perhaps we still have a little of our more herbavorous ancestors in us? Also, I don&#39;t think Grok had the same kind of free-radical producing polution that we do now.


    Gee that was rambly. Anyway, your take on antioxidant herbs/spices.

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    Unfortunately, if you&#39;re looking for one-stop-shopping, I&#39;m not sure where to send you, as reviews and meta-analyses in this area are rarely without their flaws. You absolutely could not go wrong, however, in checking out WholeHealthSource or Hyperlipid for their excellent discussions of individual studies of how blood lipid profiles are affected by different macronutrients.


    Regarding phytochemicals like circumin, resveratrol, quercetin and the like: I think there is good evidence for many of them having a beneficial role in promotion of health (obviously some are better established than others). I&#39;m unconvinced by many of the ZC/veggie-skeptic evolutionary arguments for why herbs/spices/vegetables ought not to have a beneficial effect on us, but I won&#39;t inflict the details on you unless you&#39;re interested. I don&#39;t think that these compounds should be ingested every day, but with periodic breaks I think they are likely to be beneficial and very unlikely to do any harm to anything but your wallet.

    Give me liberty. Exploration of other options will be vigorously discouraged.

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