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Insulin Resistance Is Caused By Elevated Fatty Acids (FFA)

Discussion in 'Scientific Studies' started by haidut, Mar 25, 2015.

  1. haidut

    haidut Member

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    This is probably one of the biggest debates currently, and I have seen many people over at Peatarian.com argue over it. According to the studies below, and confirmed by the usage of high dose aspirin to restore insulin sensitivity, it is the chronic elevation of free fatty acids (FFA) that cause insulin resistance and one proposed mechanism of action is the increase of inflammation mediated through NF-kappaB, and not so much the Randle cycle implications of elevated fatty acids.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC507380/

    "...To examine the mechanism by which lipids cause insulin resistance in humans, skeletal muscle glycogen and glucose-6-phosphate concentrations were measured every 15 min by simultaneous 13C and 31P nuclear magnetic resonance spectroscopy in nine healthy subjects in the presence of low (0.18 +/- 0.02 mM [mean +/- SEM]; control) or high (1.93 +/- 0.04 mM; lipid infusion) plasma free fatty acid levels under euglycemic (approximately 5.2 mM) hyperinsulinemic (approximately 400 pM) clamp conditions for 6 h. During the initial 3.5 h of the clamp the rate of whole-body glucose uptake was not affected by lipid infusion, but it then decreased continuously to be approximately 46% of control values after 6 h (P < 0.00001). Augmented lipid oxidation was accompanied by a approximately 40% reduction of oxidative glucose metabolism starting during the third hour of lipid infusion (P < 0.05). Rates of muscle glycogen synthesis were similar during the first 3 h of lipid and control infusion, but thereafter decreased to approximately 50% of control values (4.0 +/- 1.0 vs. 9.3 +/- 1.6 mumol/[kg.min], P < 0.05). Reduction of muscle glycogen synthesis by elevated plasma free fatty acids was preceded by a fall of muscle glucose-6-phosphate concentrations starting at approximately 1.5 h (195 +/- 25 vs. control: 237 +/- 26 mM; P < 0.01). Therefore in contrast to the originally postulated mechanism in which free fatty acids were thought to inhibit insulin-stimulated glucose uptake in muscle through initial inhibition of pyruvate dehydrogenase these results demonstrate that free fatty acids induce insulin resistance in humans by initial inhibition of glucose transport/phosphorylation which is then followed by an approximately 50% reduction in both the rate of muscle glycogen synthesis and glucose oxidation.

    http://omicsonline.org/mechanisms-of-fa ... hp?aid=715

    http://www.hhmi.org/research/cellular-m ... resistance
    "...Increased plasma free fatty acid concentrations are typically associated with many insulin-resistant states, including obesity and type 2 diabetes mellitus. In a cross-sectional study of young, normal-weight offspring of type 2 diabetic patients, we found an inverse relationship between fasting plasma fatty acid concentrations and insulin sensitivity, consistent with the hypothesis that altered fatty acid metabolism contributes to insulin resistance in patients with type 2 diabetes. Furthermore, recent studies measuring intramyocellular triglyceride content by 1H MRS have shown an even stronger relationship between accumulation of triglyceride and insulin resistance. Approximately 40 years ago, Philip Randle and his colleagues demonstrated that fatty acids compete with glucose for substrate oxidation in isolated rat heart and diaphragm muscle preparations. They speculated that increased fat oxidation was responsible for the insulin resistance associated with obesity. The mechanism they proposed to explain this resistance was that an increase in fatty acids caused an increase in the intramitochondrial acetyl-CoA/CoA and NADH/NAD+ ratios, with subsequent inactivation of pyruvate dehydrogenase. This in turn would cause intracellular citrate concentrations to increase, leading to inhibition of phosphofructokinase, a key rate-controlling enzyme in glycolysis. Subsequent accumulation of glucose-6-phosphate would inhibit hexokinase II activity, resulting in an increase in intracellular glucose concentrations and decreased glucose uptake. A recent series of studies by our group have challenged this hypothesis.
    We applied 13C and 31P MRS to measure skeletal muscle glycogen and glucose-6-phosphate concentrations in healthy subjects. The subjects were maintained at euglycemic, hyperinsulinemic conditions, with either low or high levels of plasma fatty acids. The increment of the plasma fatty acid concentration caused a 50 percent reduction in insulin-stimulated rates of muscle glycogen synthesis compared to the control studies. In contrast to Randle's model, which predicted that fat-induced insulin resistance would result in an increase in intramuscular glucose-6-phosphate concentrations, we found that the drop in muscle glycogen synthesis was preceded by a fall in intramuscular glucose-6-phosphate, suggesting that increases in plasma fatty acid concentrations initially induce insulin resistance by inhibiting glucose transport or phosphorylation activity, and that the reduction in muscle glycogen synthesis and glucose oxidation follows. The reduction in insulin-activated glucose transport/phosphorylation activity in normal subjects maintained at high plasma fatty acid levels is similar to that seen in obese individuals, patients with type 2 diabetes, and healthy, lean, normoglycemic insulin-resistant offspring of type 2 diabetic patients. Hence, accumulation of intramuscular fatty acid metabolites appears to play an important role in the pathogenesis of insulin resistance seen in obese individuals and patients with type 2 diabetes."

    http://diabetes.diabetesjournals.org/co ... /3458.full
    "...To study mechanisms by which free fatty acids (FFAs) cause hepatic insulin resistance, we have used euglycemic-hyperinsulinemic clamping with and without infusion of lipid/heparin (to raise or to lower plasma FFAs) in alert male rats. FFA-induced hepatic insulin resistance was associated with increased hepatic diacylglycerol content (+210%), increased activities of two serine/threonine kinases (protein kinase C-δ and inhibitor of κB [IκB] kinase-β), increased activation of the proinflammatory nuclear factor-κB (NF-κB) pathway (IκB kinase-β, +640%; IκB-α, −54%; and NF-κB, +73%), and increased expression of inflammatory cytokines (tumor necrosis factor-α, +1,700% and interleukin-1β, +440%) and plasma levels of monocyte chemoattractant protein-1 (+220%). We conclude that FFAs caused hepatic insulin resistance, which can produce overproduction of glucose and hyperglycemia, and initiated inflammatory processes in the liver that could potentially result in the development of steatohepatitis."

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1202744/
    http://www.sciencedirect.com/science/ar ... 3663915010 (human study)
     
  2. RPDiciple

    RPDiciple Member

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    Cool.
    I still cant figure out why aspirin is beneficial to use during a weight/fat loss phase?
     
  3. OP
    haidut

    haidut Member

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    One of the studies I posted in the thread "15 aspirins a day" showed that it actually increases fatty acid oxidation, but I think the mice that were used for the study were given the aspirin on empty stomach. Either way there is conflicting information on how aspirin actually works in such cases, but the human study using 7g/day showed greatly decreased plasma fatty acids and insulin, so I am guessing it does inhibit lipolysis at least.
     
  4. RPDiciple

    RPDiciple Member

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    Hmm 7g a day is a hefty amount.
    In terms of taking aspirin with food or on empty stomach. Has Peat talked about the pros and cons of that? i know he talks about with coffee, but what about aspirin?

    Im currently calorie restricting to loose some more fat and i am using aspirin but im not really sure how much to use for best effects
     
  5. burtlancast

    burtlancast Member

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    Seems to me the basic premises of Randle, ie the elevated fatty acids in the blood shutting off glucose oxidation is still valid.
    It is just the biochemical explanation that has been improved.
     
  6. OP
    haidut

    haidut Member

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    Yeah, I guess it still holds in principle but the studies said something along the lines "FFA damage the ability to synthesize glycogen so sugar floats around, and not so much inability of cells to burn glucose". It's the organism's inability to store extra glucose in the liver. Pointing us once again back to the liver as central in insulin resistance and diabetes type II.
     
  7. RPDiciple

    RPDiciple Member

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    In terms of aspirin dosages. I dont feel much from aspirin even with bigger dosages, what can this mean?

    I took 1.5gram aspirin together with a meal yesterday but did not feel anything from it. I have pure aspirin powder. I dont get bleeding, bruising or stuff like that either
     
  8. schultz

    schultz Member

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    So elevated FFA in the blood are throwing off the regulation of NF-kB, and it is the things associated with this, like inflammation, that are causing the blood sugar problems? I wonder if this phenomenon depends on PUFA to occur?
     
  9. OP
    haidut

    haidut Member

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    Yes, at least this is one of the proposed mechanisms. Aspirin, being a potent inhibitor of NF-KB restored insulin sensitivity in humans with diabetes type II and lowered NF-KB by more than 80%. As far as the type of FAT - I do believe that it is the PUFA that mostly cause this since saturated fat and especially short chain and medium chain acids are metabolized more like carbs.
     
  10. OP
    haidut

    haidut Member

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    The human dose used for insulin sensitivity was 90mg/kg so it likely is a lot more than 1.5g per day. If you don't get bleeding issues or stomach problems then you can try to get close to the dose used in the study and see how that affects you. I think there are reports of getting desensitized to aspirin so that may be the other reason.
     
  11. RPDiciple

    RPDiciple Member

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    The 1.5g i took was just one time with a meal, i took 1g 2x earlier that day so 3.5g total that day

    That was a daily dose or single dose done 3x a day?
     
  12. OP
    haidut

    haidut Member

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    That was the total daily dose split into 3-4 ingestions. So, I guess 2.3g x 3 a day would do.
     
  13. RPDiciple

    RPDiciple Member

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    Great, thank you.

    But is this good when loosing fat as well? to use those dosages? will it help or hinder it?
     
  14. OP
    haidut

    haidut Member

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    I don't know the answer to that, but the patients in the study did NOT lose weight during the study even though they got a profound improvement in insulin sensitivity.
     
  15. rei

    rei Member

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    They infused some of the highest concentration PUFA oils with emulsifiers, along with insulin with a goal of keeping hyperinsulinemia. Then they push heparin to force TG breakdown (which normally is inhibited powerfully by hyperinsulinemia). This study is in every conceivable way designed to make FFA look bad/prove their faulty hypothesis.

    Insulin resistance, like any other drug or hormone resistance is caused by overstimulation of the target and subsequent downregulation.
     
  16. Sourdoughbanana

    Sourdoughbanana Member

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    But isn’t overstimulation of the target caused by excess insulin which is itself caused by FFA?

    You always have to go back one step when you’re facing a faulty mechanism. That’s why they did those experiments, speeding up the IR.
     
  17. rei

    rei Member

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    Eating multiple high GI meals with processed proteins that absorb quickly is the way to get high insulin. Fats have almost zero insulin response (and they delay sugar/protein absorption), and are largely stored as triglycerides as long as insulin is high. FFA elevates when insulin goes down.

    My own theory is that high GI foods cause dramatic insulin response that overshoots, which leads to low blood glucose once the food is processed. This leads to compensatory actions (insulin sensitivity downregulation) to prevent it in the future. If you become hungry/crave sugar an hour after eating you can assume this is happening to you.
     
  18. Sourdoughbanana

    Sourdoughbanana Member

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    so, another blow against starch ;)
     
  19. Joeyd

    Joeyd Member

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    So best approach would be absolute minimal fat intake, high carb??
     
  20. Sourdoughbanana

    Sourdoughbanana Member

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    15-20% calories from fats and lots of low GI carbs (basically the plant based diets) have shown very solid overall health improvements, compared to 10% or less (think Kempner, Pritikin over the long run). Obviously much better than the "standard" 25-35% calories from fats in a mixed diet.

    Speaking of which, maybe Kempner's improvements came from the high fruit content, white rice being a neutral bystander, or potentially leading to the minority of poor reactions to the diet with all that glucose.
     
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