Free fatty acids (FFA) as the cause of insulin resistance

Discussion in 'Scientific Studies' started by haidut, Sep 16, 2015.

  1. haidut

    haidut Member

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    Peat has said this many times, but I think it is nice to see some independent "verification" of that statement, especially given how often it is questioned here on the forum by some. These two studies by the same scientist seem to imply that chronic suppression of free fatty acid elevation restores insulin sensitivity. Unfortunately, he does not say for how long the suppression should be done.
    The second study talks about NF-kB and its central role in the pathology of diabetes. The successful human trials with high dose aspirin were partly due to the dramatic reduction of NF-kB by aspirin (-70%).

    http://www.ncbi.nlm.nih.gov/pubmed/10354364
    "...Evidence is presented that shows that free fatty acids (FFA) are one important link between obesity, insulin resistance, and type 2 diabetes. Plasma FFA levels are elevated in most obese subjects, and physiological elevations of plasma FFA inhibit insulin-stimulated glucose uptake into muscle. This peripheral insulin resistance is caused by an FFA-induced defect, which develops 3-4 hr after raising plasma FFA, in insulin-stimulated glucose transport or phosphorylation, or both. This resistance is also caused by a second defect, which develops after 4-6 hr, consisting of inhibition of glycogen synthase activity. Whether elevated plasma FFA levels inhibit insulin action on endogenous glucose production (EGP), that is, cause central insulin resistance, is more difficult to demonstrate. On the one hand, FFA increase gluconeogenesis, which enhances EGP; on the other hand, FFA increase insulin secretion, which decreases EGP. Basal plasma FFA support approximately one third of basal insulin secretion in diabetic and nondiabetic subjects and, hence, are responsible for some of the hyperinsulinemia in obese, normoglycemic patients. In addition, elevated plasma FFA levels potentiate glucose-stimulated insulin secretion acutely and during prolonged exposure (48 hr). It is hypothesized that obese subjects who are genetically predisposed to develop type 2 diabetes will become partially "lipid blind," that is, unable to compensate for their FFA-induced insulin resistance with FFA-induced insulin oversecretion. The resulting insulin resistance/secretion deficit will then have to be compensated for with glucose-induced insulin secretion, which, because of their partial "glucose blindness," will result in hyperglycemia and eventually in type 2 diabetes."

    http://www.ncbi.nlm.nih.gov/pubmed/12784183
    "...Most obese individuals have elevated plasma levels of free fatty acids (FFA) which are known to cause peripheral (muscle) insulin resistance. They do this by inhibiting insulin-stimulated glucose uptake and glycogen synthesis. The mechanism involves intramyocellular accumulation of diacylglycerol and activation of protein kinase C. FFAs also cause hepatic insulin resistance. They do this by inhibiting insulin-mediated suppression of glycogenolysis. On the other hand, FFAs support between 30 and 50 % of basal insulin secretion and potentiate glucose-stimulated insulin secretion. The insulin stimulatory action of FFAs is responsible for the fact that the vast majority ( approximately 80 %) of obese insulin resistant people do not develop type 2 diabetes. They are able to compensate for their FFA mediated insulin resistance with increased FFA mediated insulin secretion. Individuals who are unable to do this (probably for genetic reasons) eventually develop type 2 diabetes. FFAs have recently been shown to activate the IkappaB/NFkappaB pathway which is involved in many inflammatory processes. Thus, elevated plasma levels of FFAs are not only a major cause of insulin resistance in skeletal muscle and liver but may, in addition, play a role in the pathogenesis of coronary artery disease."
     
  2. jaa

    jaa Member

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    haidut,

    Do you think this is applicable for T2 Diabetes resulting from factors other than obesity (specifically psoriasis?)

    I've created a thread on a recent study suggesting psoriatic cells are insulin resistant as a result of inflammatory cytokines. Feel free to reply there if you think my question is a bit of a derail.

    viewtopic.php?f=36&t=7825
     
  3. OP
    haidut

    haidut Member

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    Yes, and the above studies hint at that - i.e. FFA raise inflammatory mediators, and it is the inflammatory mediators that probably trigger an actual "disease". So, elevated FFA cause elevated NF-kB and TNF-alpha, which will eventually cause some type of named disease (i.e. diabetes, CVD, etc) even in a lean person. You don't have to be obese to be insulin resistant, most long distance runners have some sort of insulin resistance (due to adaptation to burn fat) and they are all very "lean". They also look untypically old for their age. I posted a study a week ago showing that the only difference between aged and young cells is that aged cells cannot switch to burning glucose when challenged with a glucose load. The aged cells "insist" on burning fat even in the presence of elevated insulin. So, aging is a type of whole-body diabetes energetically speaking. Just like Alzheimer's is diabetes of the brain. Inflammation plays a key causative role in diabetes and in aging, as Peat has said many times. Without PUFA there can be no inflammation as PUFA is the only precursor to the inflammatory cytokines. If you cannot deplete PUFA then vitamin E, aspirin and caffeine are your friends as they block pretty much the entire inflammatory cascade.
     
  4. jaa

    jaa Member

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    Thanks haidut. :hattip

    I currently eat low PUFA and take aspirin (~300mg) and vitamin E (~400UI) every other day. I find the vitamin E applied topically to psoriatic plaques very helpful. I am a bit wary about upping my vit E supplementation, but may increase my aspirin intake pending results from recent iron labs. Do you know what amounts of aspirin were used in those high dose aspirin trials? I've also been toying with the idea of eliminating my egg for breakfast a day (highest PUFA food I eat) and this gives me good reason to follow through with that experiment.
     
  5. OP
    haidut

    haidut Member

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    The study used 6g of aspirin for 2 weeks. All people got normalized sugar metabolism and insulin.
     
  6. jaa

    jaa Member

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    Thanks again.
     
  7. Ledo

    Ledo Member

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    "Without PUFA there can be no inflammation as PUFA is the only precursor to the inflammatory cytokines. If you cannot deplete PUFA then vitamin E, aspirin and caffeine are your friends as they block pretty much the entire inflammatory cascade."

    Hi Haidut,

    If one was PUFA deficient or on vit E, aspirin and caffeine, how would "appropriate" inflammation then develop? I.e. bacterial infection calling macrophages to action or a twisted ankle?
     
  8. OP
    haidut

    haidut Member

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    According to Peat there is no amount of "appropriate" inflammation. The lower it is the healthier the organism. Damaged tissue will release certain signals/field in the blood (creatine kinase, LDH, some mitochondrial proteins, etc) and this will signal that repair is needed. Then stem cells will migrate into that region. Peat says that in a chronically inflamed state the stem cells have a high probability of turning into cancer or fibrotic tissue (which is a pre-cancerous state btw). In an organism with high thyroid and CO2, the stem cells will diferentiate into whatever is needed to repair the damage and repair it without causing scars/lesions/fibrosis.
    As long as you have white blood cells, you should be able to respond to bacterial infection. ATP is also needed in order to mobilize iron out of the cells and thus prevent the bacteria from proliferating. Acute inflammatory reactions, including bacterial infections, can be diagnosed by testing ferritin and ceruloplasmin. In acute inflammation/infection ferritin may be low and ceruloplasmin high. In chronic infections/inflammation this could be reversed - i.e. high ferritin, low serum iron, low ceruloplasmin. It is a complex subject but it has been shown that animals depleted of PUFA and thus not producing ANY prostaglandins are remarkably resilient to lethal conditions like sepsis and nervous system infections.
     
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