The Fatty Acid Syndrome (Randle Cycle)

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

  1. haidut

    haidut Member

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    This is the original study that postulated the existence of the Randle Cycle. I strongly recommend that everyone reads it as it will likely dispell whatever doubts you may have had about Peat and his ideas. I have posted many other studies that directly support the role of the Randle Cycle in many human pathologies, but it is nice to see that someone else decades before me summarized things so nicely and accessibly. The role of cortisol, adrenaline and growth hormone in human pathologies cquickly becomes evident after reading the study. I have extracted the relevant portions from the study below.
    Perhaps the main therapeutic takeaway fromt he study, aside from keeping fat intake and lipolysis low, is that a combination of thiamine, niacinamide, biotin and aspirin should be curative of this "fatty acid syndrome" and maybe even the pathologies that are associated with it. Thiamine is a stimlator of pyruvate dehydrogenase (PDH) and inhibitor of pyruvate dehydrogenase kinase (PDK), niacinamide is an inhibitor of lipolysis, biotin is an activator of pyruvate decarboxylase and is vital for Acetyl-Co-A carboxylase, and aspirin makes cells sensitive to insulin again. The extracts from the study below will show you why exactly these substances are so important.
    Finally, the study mentions sodium salicylate (aspirin, AlkaSeltzer) as an agent that reverses insulin insensitivity. Given that Alzheimer disease has been designated as "diabetes type III" now you know why aspirin cured it in an animal model as was recently reported in the news and here.


    https://www.ncbi.nlm.nih.gov/pubmed/13990765

    "...SEVERAL abnormalities of carbohydrate metabolism, common to many endocrine and nutritional disorders, are associated with a high plasma concentration of non- esterified fatty acids (N.E.F.A.). These abnormalities include impaired sensitivity to insulin; impaired pyruvate oxidation; emphasis in muscle on conversion of glucose to glycogen rather than to pyruvate; and, frequently, impaired glucose tolerance. The endocrine and nutritional disorders include diabetes, starvation, carbohydrate deprivation, excess of growth hormone and corticosteroids in acromegaly or Cushings syndrome or follow- ing administration of the hormones, and perhaps obesity. We now wish to summarise evidence which appears to show that the high plasma concentration of N.E.F.A. (or the underlying breakdown of glycerides of which it is a symptom) stands in a causal relationship to these abnormalities of carbohydrate metabolism, and we suggest that this is a distinct biochemical syndrome which could appropriately be called the fatty-acid syndrome. We wish to propose further that there are interactions between glucose and fatty-acid metabolism in muscle and adipose tissue which take the form of a cycle (the glucose fatty-acid cycle), and which are fundamental to the control of glucose and fatty- acid concentrations in the blood, and of insulin sensitivity."

    "...Control by the cycle is modified by insulin, which enhances glucose uptake in muscle and adipose tissue, inhibits release of fatty acids in adipose tissue, and increases esterification of fatty acids in adipose tissue and muscle. It may be noted that the effects of the hormone on glyceride metabolism may potentiate its effects on glucose uptake. Growth hormone, corticosteroids, and adrenaline, on the other hand, modify control by the cycle by accelerating release of fatty acids from adipose- tissue and muscle glycerides, and may through this action inhibit uptake of glucose by muscle at a particular insulin concentration-i.e., induce insulin insensitivity."

    "...These studies have shown that release of fatty acids is diminished by glucose, insulin, and panhypopituitarism, and enhanced by diabetes (clinical and experimental), starvation, carbohydrate deprivation, and actions of growth hormone, corticosteroids, and adrenaline (White and Engel 1958, Gordon and Cherkes 1958, Jeanrenaud and Renold 1960, Dole 1956, Gordon and Cherkes 1956, Bierman et al. 1957, Raben and Hollenberg 1960, Hales and Randle 1963)."

    "...With this method evidence has been obtained that glyceride breakdown in rat diaphragm and rat heart muscle in vitro is enhanced by alloxan diabetes, starvation, treatment of the rat with growth hormone and cortisol, and by treatment of the isolated muscle with growth hormone and adrenaline. Glyceride breakdown is diminished in hypophysectomised or alloxan-diabetic hypophysectomised rats. Insulin in vitro diminished output of glycerol by adipose tissue, but not by diaphragm or heart muscle (table I) (cf. Jungas and Ball 1962), Further evidence has been obtained, in preliminary experiments, that the intracellular concentration of fatty acids in diaphragm is increased 50% by starvation and 100% by alloxan diabetes."

    "...In the presence of insulin at a high concentration (0-1 unit per ml.) fatty acids and ketone bodies reduced glucose uptake in hearts from normal rats to levels comparable to those seen in tissues from diabetic or starved animals (see also Williamson and Krebs 1961)."

    "...Fatty acids and ketone bodies, like diabetes and starvation, led to substantial intracellular accumulation of glucose, showing that phosphorylation of glucose was impaired. When hearts from fed normal rats (plasma-insulin concentration more than 130 microunits per ml.) were perfused with medium lacking insulin, glucose uptake was similar to that seen in experiments in which the medium contained insulin at a high concentration. It seems reasonable, therefore, to suggest that these hearts were subject to the influence of a physiological amount of insulin carried over in the tissue when it was removed from the animal. Under these conditions addition of fatty acids or ketone bodies led to a very marked inhibition of glucose uptake which was associated with only slight intracellular accumulation of glucose (see also Shipp et al. 1961). The tentative conclusion is drawn that fatty acids and ketone bodies had almost totally suppressed the influence on glucose transport of insulin in the heart. Some further evidence for this view has been provided by the observation that fatty acids and ketone bodies can impair the transfer of the glucose analogue L-arabinose in rat heart. In diaphragm muscle from normal rats, palmitate (carried by plasma albumin) and butyrate depressed uptake of glucose in the presence of insulin, and the degree of impairment was similar to that seen in diabetes."

    "...That the concentration of glycogen in the heart is increased in diabetes and starvation has long been known (Cruickshank 1913, McLeod and Prendergast 1921). Moreover, treatment of fasting hypophysectomised or normal rats with growth hormone increases cardiac glycogen, and feeding hypophysectomised rats with long- or short-chain fatty acids or high-fat diets can increase glycogen in heart and skeletal muscle (Russell and Wilhelmi 1950, Lackey et al. 1946, Bowman 1959, Samuels et al. 1942). In hearts from normal rats perfused in vitro, ketone bodies (and to a lesser extent fatty acids) added to the perfused medium increased cardiac glycogen even though uptake of glucose was diminished (table 11). In rat diaphragm muscle the rate of glycogen synthesis was maintained even though glucose uptake was diminished by in-vitro addition of fatty acids or the development of alloxan diabetes (table 11)."

    "...The rate of glycolysis is markedly reduced in perfused isolated rat heart by diabetes and starvation, and in normal hearts by addition of fatty acids and ketone bodies to the perfused medium. Inhibition of glycolysis is associated in each instance with intracellular accumulation of glucose 6-phosphate (table 11). Newsholme and Randle (1962) suggest that this inhibition of glycolysis and the enhanced deposition of glycogen in these conditions results from inhibition of the phosphofructokinase reaction in rat heart. In rat diaphragm muscle glycolysis was impaired equally by diabetes and by in-vitro addition of fatty acids (table II)."

    "...In normal people pyruvate tolerance is known to be impaired by treatment with prednisone (Fajans 1961), and in dogs growth hormone exerts a similar effect (Weil et al. 1961). In patients with Cushings syndrome, or people treated with corticosteroids, plasma concentrations of pyruvate and lactate are raised, which suggests that pyruvate oxidation is impaired (Henneman and Bunker 1957). There is no comparable evidence for impairment of pyruvate oxidation in human diabetes, though the plasma concentration of pyruvate is increased during insulin-glucose tolerance tests in human diabetic patients (Fry and Butterfield 1962). Since Klein (1942) had previously shown that the ratio of lactate to pyruvate in blood plasma is not changed in man by diabetes or by glucose or insulin, the findings of Fry and Butterfield could be accepted as evidence for impaired pyruvate oxidation. In rat heart or rat diaphragm muscle the oxidation of pyruvate (added to the perfusion or incubation medium, or formed in the tissue from glucose) was impaired about equally by diabetes, starvation, and (in experiments with tissues from normal animals) by the in-vitro addition of fatty acids and ketone bodies (Garland, Newsholme, and Randle 1962). Similar effects of fatty acids on pyruvate oxidation in vitro have also been noted in liver and kidney slices."

    "...Further evidence that release of more fatty acids or ketone bodies for oxidation is responsible for diminished phosphorylation of glucose and impaired glycolysis in muscle has accrued from studies of the effects of anoxia and sodium salicylate. These agents completely abolish the inhibitory effects of diabetes, and of fatty acids and ketone bodies, on these steps in carbohydrate metabolism. This effect of salicylate could be an important factor in its known hypoglycasmic action in human diabetics. The observation that another hypoglycaemic compound, hypoglycin, is an inhibitor of fatty-acid oxidation might also support the view that this process is intimately concerned with the control of glucose metabolism in muscle (McKerns et al. 1960)."

    "...The experimental evidence which has been summarised appears to establish that abnormalities of glucose phosphorylation, glycogen metabolism, glycolysis, and pyruvate oxidation in muscles of diabetic or starved animals, or of animals treated with growth hormone and corticosteroids, are secondary to the release of more fatty acids or ketone bodies for oxidation. It suggests, moreover, that impaired oxidation of pyruvate in human diabetes, in Cushings syndrome, and in people treated with corticosteroids is due to this excess of fatty acids; that impaired oxidation of pyruvate should be found in acromegalic patients with a high plasma concentration of NEFA; and that the other abnormalities of carbohydrate metabolism in muscles of laboratory animals which have been attributed to a higher rate of release of fatty acids may also occur in human muscle in these disorders. Greater availability of fatty acids is likely to be an important factor in the insensitivity to insulin seen in muscles from diabetic animals, or from animals treated with growth hormone and corticosteroids. The insulin antagonism induced by adrenaline in vivo or in muscle in vitro may well be secondary to the release of fatty acid induced by the hormone, and not, as has been suggested, to breakdown of glycogen."

    "...The experimental evidence discussed above has been restricted to a consideration of effects of fatty acids derived from glycerides of muscle or transported from adipose tissue as plasma N.E.F.A. on glucose metabolism in muscle. There is also the possibility that other serum lipid fractions (e.g., glycerides or lipoproteins) might influence glucose metabolism in muscle through the provision of fatty acids. In this connection Stewart (1941) has observed that the intravenous injection of a fat emulsion into a normal rabbit could produce almost complete insensitivity to the hypoglycxmic action of a test dose of insulin."

    "...Our suggestion that release of more fatty acids for oxidation in muscle may be an important cause of insulin insensitivity, can provide a reasonable explanation for many hitherto unexplained features of human diabetes. Early diabetics are frequently obese, and the development of hypoglycaemia some hours after food is well documented. Moreover, insulin-glucose tolerance tests have shown that insensitivity to insulin action in diabetes (or carbohydrate deprivation) takes the form of a delayed response to the hormone (Himsworth 1939). At first sight obesity (the retention of glyceride) might appear to be incompatible with the view that an enhanced rate of glyceride breakdown is responsible for insensitivity to insulin, particularly since fatty-acid synthesis in adipose tissue is generally impaired when glyceride breakdown is accelerated. The paradox may be explained if in humans as in the rat, insulin inhibits glyceride breakdown in adipose tissue but not in muscle (cf. table I). The sequence of events in early diabetes might then be as follows. In the fasting state, in spite of a normal or raised plasma concentration of insulin, the rate of glyceride breakdown in muscle and adispose tissue is increased. After intake of food or glucose the plasma concentration of insulin rises higher, lipolysis is inhibited in adipose tissue but not in muscle, and the plasma concentration of N.E.F.A. falls (Hales and Randle 1963). Uptake of glucose by adipose tissue, and synthesis of fatty acids and deposi- tion of glycerides in the tissue then take place at an abnormally high rate because of the continuing high concentrations of insulin and glucose. Muscle glycerides, on the other hand, continue to be broken down at a rate which exceeds esterification of fatty acid, and insensitivity to insulin and diminished glucose uptake persist in this tissue. Eventually, when the plasma concentration of N.E.F.A. falls to a normal level, muscle may be able to re-esterify fatty acid quickly enough for its intracellular concentration to fall towards normal, and for glucose uptake to increase. At this stage, and with the persistence of a high concentration of insulin, the plasma-glucose concentration might fall precipitously and hypoglycaemia develop."

    "...These results and those of earlier studies in this laboratory have shown that agents which interfere with the formation of adenosine triphosphate (ATP) by respiration accelerate three of the reactions involved in glucose metabolism in muscle, and that release of more fatty acids and ketone bodies for respiration slows them. The reactions involved are membrane transport and phosphorylation of glucose, and the phosphofructokinase reaction (Randle and Smith 1958, Morgan, Randle et al. 1959, Newsholme and Randle 1961, 1962)."

    "...One possibility which might also explain the inhibitory influence of fatty acids and ketone bodies on pyruvate oxidation is inhibition of the enzymes concerned by acyl-coenzyme -A compounds (formed initially in the metabolism of fatty acids and ketone bodies). This, however, is a matter for future investigation."

    "...The degree of impairment among the four steps affected seems to be most severe at the level of the pyruvate dehydrogenase reaction. This could perhaps allow glycolysis to continue its function as an important pathway for the synthesis of cell constituents during periods of carbohydrate deprivation while ensuring that the end products of glycolysis, pyruvate and lactate, are not oxidised but reconverted to glucose in the liver."

    "...Evidence is presented that a higher rate of release of fatty acids and ketone bodies for oxidation is responsible for abnormalities of carbohydrate metabolism in muscle in diabetes, starvation, and carbohydrate deprivation, and in animals treated with, or exhibiting hypersecretion of, growth hormone or corticosteroids. We suggest that there is a distinct biochemical syndrome, common to these disorders, and due to breakdown of glycerides in adipose tissue and muscle, the symptoms of which are a high concentration of plasma non-esterified fatty acids, impaired sensitivity to insulin, impaired pyruvate tolerance, emphasis in muscle on metabolism of glucose to glycogen rather than to pyruvate, and, frequently, impaired glucose tolerance. We propose that the interactions between glucose and fatty-acid metabolism in muscle and adipose tissue take the form of a cycle, the glucose fatty-acid cycle, which is fundamental to the control of blood- glucose and fatty-acid concentrations and insulin sensitivity."
     

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  2. brandonk

    brandonk Member

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    I"m no expert, but compared to studies like this that seem (to me) very badly written, I think Ray Peat's writing is a work of art:

    http://members.westnet.com.au/pkolb/peat2.htm
     
  3. Wilfrid

    Wilfrid Member

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    When searching for the randle cycle mechanism a few months ago, I came across this in-vivo human study ( this study was made possible thanks to the NMR technology, technology that was not available during Randle's time ) which do not support the mechanism involved in fatty acids oxidation as originally described by Randle.

    http://www.ncbi.nlm.nih.gov/pmc/article ... 972859.pdf

    What do you, guys, think about it?
    Is there any flaws in it?
    Seems pretty legit to me.
     
  4. lexis

    lexis Member

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    Rays says hydrogenated peanut oil is safer than other PUFA laden oils.
     
  5. Agent207

    Agent207 Member

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    Haidut what is your take on aspirin protocol to keep/improve insulin sensitivity?
     
  6. OP
    haidut

    haidut Member

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    I've talked about this multiple times and posted studies. If you search the forum you will find it. Two weeks of 6g daily reverses insulin resistance.
     
  7. OP
    haidut

    haidut Member

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    I don't think the study disproves Randle's claims that free fatty acids induce insulin resistance. If the study is valid, it just proposes a new mechanism, but still due to elevated free fatty acids.
    "...In conclusion, contrary to the classical mechanism of free fatty acid–induced insulin resistance as proposed by Randle et al. (2, 27, 28) in which free fatty acids exert their effect through initial inhibition of pyruvate dehydrogenase, we found that elevation in plasma free fatty acid concentration causes insulin resistance by inhibition of glucose transport and/or phosphorylation with a subsequent reduction in rates of glucose oxidation and muscle glycogen synthesis. This reduction in insulin-inducible glucose transport/phosphorylation is similar to what is observed in patients with NIDDM (20) and their normoglycemic-insulin–resistant offspring (24) and suggests that alterations in intramuscular FFA metabolism may play an important role in the pathogenesis of the insulin resistance observed in patients with NIDDM."

    Also, during Randle's time it was not well known that elevated fatty acids in the form of PUFA increase several inflammation markers such as TNF-a and NF-kB and these are also causative in insulin resistance and diabetes.
    Bottom line is - free fatty acids make you insulin resistant and maybe even diabetic in the long run. Finally, the original Randle study above DID find inhibition in glycolysis as well, so not sure why this study claims otherwise. Below is a re-quote from the original study:
    "...The rate of glycolysis is markedly reduced in perfused isolated rat heart by diabetes and starvation, and in normal hearts by addition of fatty acids and ketone bodies to the perfused medium. Inhibition of glycolysis is associated in each instance with intracellular accumulation of glucose 6-phosphate (table 11). Newsholme and Randle (1962) suggest that this inhibition of glycolysis and the enhanced deposition of glycogen in these conditions results from inhibition of the phosphofructokinase reaction in rat heart. In rat diaphragm muscle glycolysis was impaired equally by diabetes and by in-vitro addition of fatty acids (table II)."
     
  8. brandonk

    brandonk Member

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    Yes, thanks Mittir. This study you posted is quite legit, as far as I can see. I think the study agrees with Ray Peat's description of how the Randle effect "works," while at the same time throwing into disrepute much of the molecular pathway "cycle" that Ray Peat does not write about, that I can see. I think one of the dangers of reading studies is that you can become brainwashed into thinking that molecular pathways are somehow well understood, when in fact they may be fabrications of big pharma trying to file patents.
     
  9. Wilfrid

    Wilfrid Member

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    Thank you both for your replies and clarifications.
     
  10. NathanK

    NathanK Member

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    what happened to Haidut's PDF? Look like it was deleted or lost in the database
     
  11. charlie

    charlie The Law & Order Admin

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    I checked and its not there. The 16th was the night that the forum was down for most the night.

    haidut will need to upload it again.
     
  12. Giraffe

    Giraffe Member

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    Haidut's PDF:
     

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  13. charlie

    charlie The Law & Order Admin

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    [ref]Giraffe[/ref], :hattip

    I have fixed haidut's post.
     
  14. NathanK

    NathanK Member

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  15. NathanK

    NathanK Member

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    It appears that the same author of Wilfred's paper wrote a follow up about 8 years after that one.
    How Free Fatty Acids Inhibit Glucose Utilization in Human Skeletal Muscle
    Full text: http://physiologyonline.physiology.org/ ... 2.full.pdf
     
  16. OP
    haidut

    haidut Member

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    Nice find, reading right now.
     
  17. OP
    haidut

    haidut Member

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    Key findings of the study you posted:
    "...On the other hand, chronic dietary-induced increases in circulating FFA and membrane fatty acids, in particular in sarcolemma, depend on
    the amount and quality of the ingested fat. Insulin resistance of glucose uptake seems to relate directly to elongation and desaturation of fatty acids in the outer layers of the sarcolemma in human skeletal muscle(4)."

    So, in addition to the elevated FFA in serum PUFA stored inside the cell directly cause insulin resistance. Even though the current study did not look specifically at role of PUFA in insulin resistance, the fat infusion used for the study contained 60% PUFA. In the author's own words:
    "...Studies in humans clearly demonstrated that FFA directly inhibit glucose transport and phosphorylation in skeletal muscle, which is mainly responsible for glucose disposal under insulin-stimulated conditions and for impaired glucose uptake in insulin-resistant states such as obesity and type 2 diabetes mellitus. These findings also indicate an important role of nutrition, particularly increased consumption of lipids and FFA, for the pathogenesis of insulin resistance."

    Now off to get me some niacinamide:):
     
  18. OldMan

    OldMan Member

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    Haidut

    .... if we were to maximize the theoretical benefit of the Randle Cycle in the long term......should we not avoid HaagenDaz Vanilla ice cream and why would Ray recommend it if its high fat hi sugar mixture is dangerous to the Randle? And if one were to drink milk everyday shouldnt it be skim milk or no fat milk and not whole fat?
     
  19. OP
    haidut

    haidut Member

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    Saturated fat has many benefits despite its tendency to also induce the Randle cycle. Increasing the ratio of saturated fat to PUFA is protective against stress and its related diseases like CVD and cancer. Saturated fat can reduce endotoxin load and effects. See the thread on coconut oil and endotoxin reaction. Saturated fatty acids like palmitic acid upregulate the enzyme PDH which is greatly reduced in diabetes and cancer. Finally, saturated fat has positive effects on cholesterol, steroid metabolism and liver health, all of which are things that tend to go down with age. So, while low fat is preferable, the saturated fat has its benefits.
     
  20. OldMan

    OldMan Member

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    Haidut.... but shouldnt saturated fat be eaten without sugar.?

    Haidut....

    But what if someone suffers from severe PTSD...where theres alot of cortisol and adrenaline flowin daily due to racked nerves... wouldnt it be best to stay away from fats and up the sugars? In other words wouldnt we want the randle cycle to prefer sugars and not have it be "distracted" by fats?
     
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