Insulin Resistance Is Caused By Elevated Fatty Acids (FFA)

[Sourdoughbanana]

Has the Randle cycle actually been proven incorrect? It seems to be very accurate more often than not.

Ray:

In 1963, P.J. Randle clearly described the inhibition of glucose oxidation by free fatty acids. Later, when lipid emulsions came into use for intravenous feeding in hospitals, it was found that they blocked glucose oxidation, lowered the metabolic rate, suppressed immunity, and increased lipid peroxidation and oxidative stress.

Could be PUFA-related, obviously.
Glucose and sucrose for diabetes.

 

[haidut]

Fats have almost zero insulin response

A number of studies have found that not to be true. In fact, FFA block the insulin receptor which leads to the organism perceiving that there is not enough insulin and this can lead to hyperinsulinemia. You can test this pretty easily. Fast for 6-8 hours and then get a blood test for insulin. In lean people the effects is less pronounced since they produce less estrogen. In obese people both baseline and induced lipolysis is enhanced due to the elevated estrogen. Speaking of estrogen, aromatase inhibitors are well known to improve insulin sensitivity without changing obesity profile and the mechanism of action is exactly that - lowering estrogen and increasing DHEA, T, DHT, etc.

PUFA have another nasty effect - increase in inflammation and cortisol release that also contribute to insulin resistance.
Free fatty acids, insulin resistance, and type 2 diabetes mellitus. - PubMed - NCBI
"...On the one hand, FFA increase gluconeogenesis, which enhances EGP; on the other hand, FFA increase insulin secretion, which decreases EGP."
Free fatty acids and insulin resistance. - PubMed - NCBI
Mechanisms of Fatty Acid-Induced Insulin Resistance in Muscle and Liver
Free Fatty Acids Produce Insulin Resistance and Activate the Proinflammatory Nuclear Factor-κB Pathway in Rat Liver

Two studies on FFA interfering directly with insulin binding and receptor activation.
Effect of free fatty acids on insulin receptor binding and tyrosine kinase activity in hepatocytes isolated from lean and obese rats. - PubMed - NCBI
Mechanism by Which Fatty Acids Inhibit Insulin Activation of Insulin Receptor Substrate-1 (IRS-1)-associated Phosphatidylinositol 3-Kinase Activity in Muscle

 

[haidut]

Has the Randle cycle actually been proven incorrect? It seems to be very accurate more often than not.

Ray:


Could be PUFA-related, obviously.
Glucose and sucrose for diabetes.

There are plenty of studies on the forum that show Randle cycle is legit and widespread. Read the below thread in its entirety. Comments further down discuss more recent evidence.
The Fatty Acid Syndrome (Randle Cycle)

 

[rei]

That is simply not true. If after skipping breakfast a smaller amount of insulin can take care of same amount of food that is by definition improved sensitivity, not resistance.

Even Intermittent Fasting Reduces Insulin Sensitivity (in The Obese)

Have you found any study where insulin is charted and you can see increased insulin as a result of increasing FFA through fasting? Or a study where giving only fat causes noticeable increase in insulin? The ones i have seen show linear insulin decrease after not eating, and fat having negligible effect on insulin.

 

[haidut]

That is simply not true. If after skipping breakfast a smaller amount of insulin can take care of same amount of food that is by definition improved sensitivity, not resistance.

Even Intermittent Fasting Reduces Insulin Sensitivity (in The Obese)

Have you found any study where insulin is charted and you can see increased insulin as a result of increasing FFA through fasting? Or a study where giving only fat causes noticeable increase in insulin? The ones i have seen show linear insulin decrease after not eating, and fat having negligible effect on insulin.

That very thread you linked to is about a study called "Fasting Until Noon Triggers Increased Postprandial Hyperglycemia and Impaired Insulin Response After Lunch and Dinner in Individuals With Type 2 Diabetes: A Randomized Clinical Trial."

What more than that do you need? Fasting increases FFA and due to the Randle cycle glucose is not oxidized. Hyperglycemia is hardly evidence for improved insulin sensitivity.

 

[rei]

i referred to my post there:

>I don't see what the title is claiming after reading the study. Insulin AUC is clearly lower when skipping breakfast and the excretion spike is not as extreme. Yet glucose AUC is clearly higher. So a smaller amount of insulin is able to take care of the same amount of food. This is clear increase in insulin sensitivity. Only thing that this study found is that when you start from a fasted state with low insulin/high FFA it takes a bit longer to react to the onslaught of food.

You are using junk science. The data in the study supports me, the interpretation of the scientists writing the headline supports the FFA hypothesis.

 

[haidut]

i referred to my post there:

>I don't see what the title is claiming after reading the study. Insulin AUC is clearly lower when skipping breakfast and the excretion spike is not as extreme. Yet glucose AUC is clearly higher. So a smaller amount of insulin is able to take care of the same amount of food. This is clear increase in insulin sensitivity. Only thing that this study found is that when you start from a fasted state with low insulin/high FFA it takes a bit longer to react to the onslaught of food.

You are using junk science. The data in the study supports me, the interpretation of the scientists writing the headline supports your view/FFA hypothesis.

The image below is Table 1 from the study.

Look at glucose and FFA and compare the values of YesB (breatfast) with NoB (no breakfast). Do you see what I see? FFA increases at breakfast, lunch and dinner and the increases at breakfast was the biggest since there was no food given to the NoB group, so lipolysis was the highest. FFA increase in the NoB group at lunch and dinner is less pronounced than at breakfast but still 20%-36% higher compared to the FFA increase in the YesB group. The glucose numbers tell the same story except at breakfast when the glucose levels in the NoB group was lower than in the YesB group probably because no food (carbs) was given. But then at lunch and dinner the fasting group NoB had 25%-40% higher glucose levels compared to the YesB group. How is this not consistent with the title that skipping breakfast causes hyperglycemia during subsequent meals?
Elevated FFA and blood glucose are the hallmarks of insulin resistance. The lower insulin could actually be a bad sign and an indication of FFA somehow inhibiting pancreatic function (there is plenty of evidence for that too). A normal response would have been for the insulin to increase in order to handle the 20%-36% higher glucose levels. Failure to mount an insulin response to hyperglycemia with is one of the signs of impending diabetes I.

And look at all the other studies I posted in this comment. Are they all wrong too?
Insulin Resistance Is Caused By Elevated Fatty Acids (FFA)

The insulin receptor antagonism by fatty acids is well proven at this point. So, fatty acids interfere with glucose oxidation not just by blocking PDH and increasing inflammation but also by directly interfering with insulin signalling.

 

[rei]

>A normal response would have been for the insulin to increase in order to handle the 20%-36% higher glucose levels. Failure to mount an insulin response to hyperglycemia with is one of the signs of impending diabetes I.

Or a sign of the body driving sugar to all tissues via transient high blood glucose, instead of freaking out and forcing insulin obeying pathways to take care of it? When you start at low(fasting) blood glucose the cells eagerly take in more when it becomes available. This represents the difference between systemically increased metabolic rate vs. gaining fat through insulin.

If you have fasted for 5 days and happen to find some food do you think the body will start to increase fat stores as soon as it senses sugar coming in? No, it will ensure all cells are full of energy before that. Then if the found food amount is large enough that the whole body has taken in all the excess it can, then it starts to drive the sugar into fat using insulin. This is the reason for a delayed and smaller insulin response. Increased insulin sensitivity: less is needed to take care of the same amount of food.

There are an unlimited number of valid theories based on the data. It is all an interpretation. What matters is which interpretation matches reality. And reality has found that fasting is almost universally curative for metabolic syndrome/t2d. The exception seems to be such severe cases that cannot take the stress of/until the metabolic switch.

>And look at all the other studies I posted in this comment. Are they all wrong too?

Like the 2 studies i already debunked also their conclusions are probably wrong. I could not however be bothered to look at the data/analyze them.

 

[Sourdoughbanana]

Fasting works because of reduced daily calories @rei

I’d listen to @haidut if i were you (by the way thanks for the link to the other thread. Fierce defender of the Randle cycle here. I don’t get what’s the motivation behind “debunking” it)

 

[rei]

no, it works because no insulin increase from baseline is experienced for some time. This rule is true for almost every process, excess stimulation causes downregulation. But maybe this is not the thread for this theory.

 

[Mito]

no, it works because no insulin increase from baseline is experienced for some time. This rule is true for almost every process, excess stimulation causes downregulation. But maybe this is not the thread for this theory.

 

[Sourdoughbanana]

no, it works because no insulin increase from baseline is experienced for some time. This rule is true for almost every process, excess stimulation causes downregulation. But maybe this is not the thread for this theory.

No, it works because you’re not overloading your liver anymore on a daily basis, and you’re furthering sleep-induced lipolysis. People eat high glucose high fat breakfasts like crazy. Skip that, burn visceral fat.

This is going to improve your liver glycogen, your cholesterol status, raise the SHBG + sex hormones + thyroid etc. Big picture is being overfed causing “detrimental” adaptations, it’s all quite established. Thus, when people finally eat less calories than they burn, everything normalizes starting with the liver. And they should have more fruit.

A couple of interesting studies:

https://www.hindawi.com/journals/jdr/2012/361863/

High lanosterol and desmosterol to cholesterol ratios were significantly associated with increased visceral and liver fat content

The lathosterol to cholesterol ratio was inversely related to insulin sensitivity

The lathosterol to cholesterol ratio significantly decreased in response to very-high-fructose diet but not in response to very-high-glucose diet with the difference between interventions reaching statistical significance (Table 5)

Correlation between lipid and glycogen contents in liver and insulin resistance in high-fat-fed rats treated with the lipoprotein lipase activator NO... - PubMed - NCBI

= reduce liver fat, improve glycogen, improve liver health, improve insulin and metabolism.

 

[rei]

caloric deficit has been the weight loss dogma forever and has proven not to work in vast majority of cases, because insulin stays elevated. The body adapts to the decreasing intake by ramping down metabolism until you are unable to continue and then you gain it back. Contrast this to fasting where your metabolic rate actually increases and the low insulin allows the refeeding energy to flow to actually beneficial processes, like building muscle through the several hundred % increased growth hormone and into maturing up fasting activated stem cells.

When your insulin reaches fasting level (and especially once glycogen is depleted) the visceral fat is the first to vanish. This as you say improves the insulin sensitivity and thus cures the t2d. Caloric restriction under elevated insulin is not specific to burning visceral fat.

 

[Sourdoughbanana]

caloric deficit has been the weight loss dogma forever and has proven not to work in vast majority of cases

I agree here, I’m saying fasting = caloric restriction. During the fasting period, that is. Sorry if that was unclear.

I’m absolutely against the strict mainstream “neurotic” 24/7 calorie counting BS. I don’t buy it, I find it impractical, and what’s happening when you’re recommending to eat a half burger and half potato? In real life, people go destroy that ice cream in the freezer. Mainstream medicine needs to move on from calorie counting, reconnect with basic liver biochemistry, and understand that it’s all a very dynamic way of having times of underfeeding and refeeding that will lead to stable blood sugar and health improvements beyond fat loss.

 

[Sourdoughbanana]

From one of RP’s articles

diabetes Metab. 21(2), 79-88, 1995. Role of free fatty acids in insulin resistance of subjects with non-insulin-dependent diabetes, Girard J.

"Studies performed in the rat suggest that impaired glucose-induced insulin secretion could also be related to chronic exposure of pancreatic beta cells to elevated plasma free fatty acid levels."

[This direct effect of free fatty acids on the beta cells is extremely important. Estrogen--probably via GH--increases free fatty acids, and adrenalin--which is elevated in hypothyroidism--increases the release of free fatty acids from storage. Free fatty acids impair mitochondrail energy production.]

I don’t doubt that losing bodyfat by all means is a necessary evil in the long run, but clearly there’s more to the story than low insulin levels. Free fatty acid levels matter more

 

[Mito]

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

“But today I want to focus on why would an individual cell “decide” to stop responding to insulin?.... each cell has to make executive decisions about how – whether and how it will respond to hormones.....So if you have insulin, for example, it’s made by the pancreas in response to various factors, especially carbohydrate intake. And then it’s circulating through the blood and then it’s telling cells in other tissues such as adipose tissue, such as the brain, such as skeletal muscle – it’s telling them to do certain things in response to the perceived needs of the body as a whole. But then those cells that are supposed to respond to that hormone, they have their own needs and they have their own priorities. And so the cell has to survey all of these different signals coming from outside itself, and then it needs to take that information and incorporate it into a model that includes information from inside the cell about the needs, the abilities and the priorities of that cell for its own survival, whether to respond and how to respond to those hormones. And it’s not so much that the cell is being selfish in this regard, as much as it is that the – it’s in the interests of the body for the cells to protect themselves, because if all of the cells are going to obey the commands of circulating hormones to their own detriment, then all of the cells can die, because they’re trying to unselfishly meet the needs of the body, and then the body’s going to be like, oh crap, kinda don’t have any cells anymore, what am I going to do? So in making this executive decision, I believe that one of the main drivers of insulin response is cellular energy overload, such that the cell says yes, I see these signals that are telling me that it’s in the body’s interest for me to take in more energy and to do something with that energy such as store it or metabolize it, so that it can produce useful fuel. But at this particular time, in this particular context I don’t have the capacity to take in any more energy in a healthy way, and therefore I am not going to take it in.”

https://chrismasterjohnphd.com/2016/08/24/insulin-resistance-isnt-all-about-carbs-and-insulin/

 

[rei]

Would the cell have arrived at said energy overload without insulin forcing it? No. Saturated fat overload causes remarkable increase in metabolic rate of animals, not fat accumulation. They handle the energy overload in a healthy way. Same is true for ketones, they cause fat to become brown, which causes it to increase metabolic rate, do housekeeping etc. Again very healthy. Only commanded by insulin does fat cells convert glucose into fat. This causes oxidative damage that slowly accumulates according to the size of the cell, and if no periods of fasting happen it damages the cell, causing insulin resistance.

You can always take one step back and ask "well what causes that?" And in my opinion "insulin causes insulin resistance" is the way we should be thinking about this disease and not "energy overload causes insulin resistance". I can give you a diet of 1000kcal per day and still cause you to become fat and have metabolic syndrome. I only need to make sure the energy overload is specific to your fat cells. I do this by adding insulin and cortisol to the food. You will be bed ridden, freezing under two blankets because energy is not available for anything else besides storing fat.

 

[Sourdoughbanana]

You need some publications to back up your train of thoughts, because nearly every part of this looks precisely like theories from the crackpipe. That, or you’re attending very advanced biochemistry lessons, and it would be nice to share what the cutting edge research is saying.

 

[rei]

I don't think i said anything that is controversial on it's own. What is new is linking the facts together into a coherent picture.

What was the most outrageous claim to you, so i know what piece if information/source to point you towards?

The ones hitting the crackpipe are the people in charge of the world's healthcare systems. Hard data shows things are regressing not advancing. So do you really want to listen to their interpretation of the data?

 

[Sourdoughbanana]

But no one is looking up to those people here. Those health authorities are actually the guys who are also very quick to blame things on insulin, and seem to let go the war against fats doubling down against sugar - that war was never a thing anyway, in real life, people consume more fats (and starch) by the decade

I’m on my phone and can’t seem to multi quote unfortunately. I’d be very interested in the claims that sat fat overloads don’t make you fat, only raise metabolism up, the part on brown fat from ketones when we all know how detrimental a ketogenic diet is on thyroid to begin with, also the part on oxidative damage, and lastly the 1000kcal diet making people fat (metabolic syndrome is different, as per its very definition)

2 criteria:
- Studies on rodents receiving crazy amounts of purified solutions with little nutritional values not accepted - that’s called reductionism and it isn’t acceptable
- Studies on humans with a poor design obviously not acceptable - it needs to be comparable to what people actually do in the real world (kinda similar to the 1st point)