Is Insulin Resistance A Result Of Impaired Beta Oxidation Or Excessive Beta Oxidation?

[Peater Piper]

Peat's obviously a big believer that healthy glucose metabolism should be favored over beta oxidation, and that many factors, including PUFA, excessive lypolysis, serotonin, estrogen, cortisol, lactate, and inflammation all steer the body away from oxidative metabolism, leading to even more derangements of metabolism. His focus often seems to be on how oxidative metabolism breaks down, but I haven't seen him pay much attention to how beta oxidation can become impaired.

This first study is about how glutathione depletion in elderly mice results in lower fasted mitochondrial NEFA oxidation, resulting in insulin resistance. Restoring glutathione levels increases NEFA oxidation and improves insulin sensitivity.
Impaired mitochondrial fatty acid oxidation and insulin resistance in aging: novel protective role of glutathione. - PubMed - NCBI

This study tested subjects with no family history of type 2 diabetes, along with subjects with a family history of type 2 diabetes. They were either given a high fat or high carbohydrate meal. Both groups were age and fatness matched. With the high fat meal, the subjects with a family history of type 2 diabetes showed an inability to increase fatty acid oxidation in response to the lipid overload. This suggests a genetic component in some type 2 diabetics that limits their metabolic flexibility, which precedes insulin resistance.
Impaired Fat Oxidation After a Single High-Fat Meal in Insulin-Sensitive Nondiabetic Individuals With a Family History of Type 2 Diabetes | Diabetes

I looked up some Peat friendly substances and their effects on beta oxidation. Everyone here knows the benefits of glycine. It lowers cortisol, balances methionine, decreases inflammation, improves insulin sensitivity, etc. In this study, rats were fed sucrose heavy diets to increase NEFA, fat cell size, intra-abdominal fat accumulation, and blood pressure. Supplementing their water with 1% glycine caused a reduction in all values. "Mitochondrial respiration, as an indicator of the rate of fat oxidation, showed an increase in the state IV oxidation rate of the beta-oxidation substrates octanoic acid and palmitoyl carnitine. This suggests an enhancement of hepatic fatty acid metabolism, i.e., in their transport, activation, or beta-oxidation. These findings imply that the protection by glycine against elevated BP might be attributed to its effect in increasing fatty acid oxidation, reducing intra-abdominal fat accumulation and circulating NEFA, which have been proposed as links between obesity and hypertension."
Glycine intake decreases plasma free fatty acids, adipose cell size, and blood pressure in sucrose-fed rats. - PubMed - NCBI

Next, taurine's potential role in beta oxidation. This paper hypothesizes that taurine forms a buffer in the mitochondrial matrix, allowing enzymes to function optimally. "Three acyl-CoA dehydrogenase enzymes, which are pivotal for beta-oxidation of fatty acids, are demonstrated to have optimal activity in a taurine buffer. By application of the model presented, taurine depletion caused by hyperglycemia could provide a link between mitochondrial dysfunction and diabetes."
A role for taurine in mitochondrial function

Caffeine and coffee (including decaf) are known to increase lipid metabolism in vivo. Peat's talked about coffee's ability to increase and support glucose oxidation. I haven't found any direct mechanisms for that, but it does increase hepatic beta oxidation through autophagy, which could be one of the (many) reasons habitual coffee drinkers seem to have improved glucose sensitivity compared to coffee abstainers.
Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice - Sinha - 2014 - Hepatology - Wiley Online Library
Coffee induces autophagy in vivo. - PubMed - NCBI

Just to potentially contradict all of the above, especially the one showing an inability for diabetic relatives to switch to oxidative metabolism after a meal, this study falls a bit more in line with Peat's thinking. Excessive beta oxidation and an inability to switch to oxidative metabolism in a fasted-to-fed state leads to insulin resistance. Take beta oxidation out of the equation and insulin resistance doesn't occur. "In mice lacking malonyl-CoA decarboxylase (MCD), an enzyme that promotes mitochondrial β-oxidation by relieving malonyl-CoA-mediated inhibition of carnitine palmitoyltransferase 1. Thus, mcd−/−mice exhibit reduced rates of fat catabolism and resist diet-induced glucose intolerance despite high intramuscular levels of long-chain acyl-CoAs. These findings reveal a strong connection between skeletal muscle insulin resistance and lipid-induced mitochondrial stress."
http://www.sciencedirect.com/science/article/pii/S1550413107003063

So we have some evidence that impaired beta oxidation can result in insulin resistance, but in the obese, excessive lypolysis and beta oxidation can also impair glucose metabolism. In both cases, hyperglycemia occurs, but for different reasons. Substances like glycine and taurine, which work through a number of mechanisms, may actually work in both scenarios by reducing lypolysis through lowering cortisol and inflammation, while supporting complete beta oxidation.

Does this look right, or am I making a wrong turn somewhere?

 

[ecstatichamster]

Fantastic post.

 

[DaveFoster]

I agree; great post.

What does @haidut think about your conclusion?

 

[haidut]

I agree; great post.

What does @haidut think about your conclusion?

There is nothing wrong with having beta oxidation. At rest, your muscles and especially the heart prefer to burn fat. The diabetic condition is caused by excessive lipolysis and temporary adaptation of cells to burn fat. Once excessive lipolysis is lowered and kept lowered for a while the cells begin to oxidize glucose normally. Estrogen, cortisol and FFA are the main factors in diabetes. Inhibitors of 11b-HSD1 can reverse diabetes II in a manner of days and lower cortisol improves glucose oxidation, not fat oxidation. Some synthetic progestins can cause diabetes due to acting as agonists of the GR receptor, so antagonists on that receptor can reverse the condition pretty reliably. Aspirin, which also reverses diabetes II, is also a (peripheral) inhibitor of 11b-HSD1. Emodin, which is probably the most powerful 11b-HSD1 inhibitor available, also reverses diabetes II. Excess lipolysis does a number of things that cumulatively lead to what we call "diabetes". If the fat is PUFA, it directly antagonizes the insulin "receptor", increases cortisol synthesis, and estrogen synthesis while at the same time lowering androgen synthesis and inhibiting both thyroid hormone release and transport into the cell. You can cure diabetes II with liposuction or bariatric surgery and these do not affect fatty acid oxidation but reduce the lipolysis and overall PUFA load on the organism. Bariatric surgery also raises the conversion of T4 into T3 as I posted in another thread.
Megestrol acetate - Wikipedia
"...MGA is an agonist of the glucocorticoid receptor (GR), with similar but less affinity in comparison to the PR and the AR (about 37% and 50% of the affinity, respectively, according to one assay).[12][23] One study found that, in the dose range tested, it possesses about 50% of the eosinopenic and hyperglycemic activity (markers of glucocorticoid activity) of an equal amount of medroxyprogesterone acetate, and about 25% that of cortisol.[27] Accordingly, manifestations of its glucocorticoid properties, including symptoms of Cushing's syndrome, steroid diabetes, and adrenal insufficiency, have been reported with the use of MGA in the medical literature, albeit sporadically.[28]"

Emodin - Wikipedia
"...Emodin is being studied as a potential agent that could reduce the impact of type 2 diabetes. It is a potent selective inhibitor of the enzyme 11β-HSD1.[5] In studies in obese mice, emodin limits the effect of glucocorticoidsand may therefore ameliorate diabetes and insulin resistance.[6] Pharmacological studies have demonstrated that emodin when isolated from rhubarb exhibits anti-cancer effects on several human cancers, including human pancreatic cancer.[7][8][9] Emodin in rhubarb extracts may also have neuroprotective properties against glutamate toxicity."
How Taurine May Treat Diabetes

Finally, if increasign beta oxidation was the way to go then why does mildronate ameliorate diabetes II?
Protective effects of mildronate in an experimental model of type 2 diabetes in Goto-Kakizaki rats
Maria Sharapova and Diabetes
"...Maria Sharapova announced today that she tested positive for a banned substance. In her announcement, she stated that her family physician prescribed the drug "mildronate" for several health conditions one of which is a "family history of diabetes."

 

[Koveras]

Fatty Acid Oxidation and Its Relation with Insulin Resistance and Associated Disorders. - PubMed - NCBI

"Alterations in muscle fatty acid metabolism have been implicated in mediating the severity of insulin resistance. In the insulin resistant heart fatty acids are favored as an energy source over glucose, which is thus associated with increased fatty acid oxidation, and an overall decrease in glycolysis and glucose oxidation. In addition, excessive uptake and beta-oxidation of fatty acids in obesity and diabetes can compromise cardiac function. In animal studies, mice fed a high fat diet (HFD) show cardiac insulin resistance in which the accumulation of intra-myocardial diacylglycerol has been implicated, likely involving parallel signaling pathways. A HFD also results in accumulation of fatty acid oxidation byproducts in muscle, further contributing to insulin resistance. Carnitine acetyltransferase (CrAT) has an essential role in the cardiomyocyte because of its need for large amounts of carnitine. In the cardiomyocyte, carnitine switches energy substrate preference in the heart from fatty acid oxidation to glucose oxidation. This carnitine-induced switch in fatty acid oxidation to glucose oxidation is due to the presence of cytosolic CrAT and reverse CrAT activity. Accordingly, inhibition of fatty acid oxidation, or stimulation of CrAT, may be a novel approach to treatment of insulin resistance."

 

[mujuro]

If glutathione is implicated then I guess that bodes well for coffee consumers. There was a thread not long ago about coffee higher in methylpyridinium (dark roast) increases RBC glutathione. I haven't the slightest idea whether that affects total body or liver glutathione levels.

Interesting article Koveras. I remember in my bodybuilding days injectable carnitine was something that some people in the more niche, enlightened circles used. The poor oral bioavailability reputedly cannot be circumvented. It was recommended as a cardioprotective agent as well as something to accelerate subcutaneous fat loss. I used it myself.

 

[paymanz]

So you guys think carnitin is a good thing?

 

[mujuro]

So you guys think carnitin is a good thing?

I would have said yes all those years ago but not anymore. Injectable is the surest way to saturate carnitine stores, and I did so for several months. At that point all I cared about was shaving a few % BF off.

However I am interested in it's cardiac mechanism. FAOIs like trimetazidine possess the same effect of shifting cardiomyocyte fuel from FA to glucose which apparently serves to protect from ischemia, improve coronary capillary flow, etc.

 

[paymanz]

I would have said yes all those years ago but not anymore. Injectable is the surest way to saturate carnitine stores, and I did so for several months. At that point all I cared about was shaving a few % BF off.

However I am interested in it's cardiac mechanism. FAOIs like trimetazidine possess the same effect of shifting cardiomyocyte fuel from FA to glucose which apparently serves to protect from ischemia, improve coronary capillary flow, etc.

Yes same with mildronate,a beta oxidation blocker with good effect on heart,an organ that's famous as a good beta oxidizer,that's interesting.

Carnitin gets fermented and become toxic ,as you may know.but with all good effects from those beta oxidation blockers I think injectable carnitin is not good either.

 

[paymanz]

My question is , if these drugs inhibit FFA oxidation, then I except that FFA levels rise in blood.that is bad...

Which cause insulin resistant, but all I read is that this drugs improve glucose oxidation!

What happens to the FFA in blood when the beta oxidation blocked?

One guess is that by improved glucose oxidation stress hormones come down and so FFA go down also!?

But again in presence of FFA how cells can oxidise sugar efficiently?

 

[Westside PUFAs]

I think IR is caused by intramyocellular lipids aka fat inside the muscle cell, which comes from the spillover effect from too much adipose tissue aka being obese:

Intramyocellular lipid kinetics and insulin resistance

Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion. - PubMed - NCBI

Intramyocellular lipid storage and insulin resistance - Type 2 diabetes mellitus - Diapedia, The Living Textbook of Diabetes

Effects of an overnight intravenous lipid infusion on intramyocellular lipid content and insulin sensitivity in African-American versus Caucasian a... - PubMed - NCBI

Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. - PubMed - NCBI

.

 

[Peater Piper]

The diabetic condition is caused by excessive lipolysis and temporary adaptation of cells to burn fat. Once excessive lipolysis is lowered and kept lowered for a while the cells begin to oxidize glucose normally.

What's your opinion of the study that tested healthy relatives of type 2 diabetics? They were less capable of shifting to beta oxidation after a high fat meal than the healthy controls. Obviously excessive lipolysis is common in obesity, but they have to get obese in the first place. Prior to that I guess there's cortisol and estrogen, but there seems to be a genetic component as well.

Carnitine acetyltransferase (CrAT) has an essential role in the cardiomyocyte because of its need for large amounts of carnitine. In the cardiomyocyte, carnitine switches energy substrate preference in the heart from fatty acid oxidation to glucose oxidation. This carnitine-induced switch in fatty acid oxidation to glucose oxidation is due to the presence of cytosolic CrAT and reverse CrAT activity. Accordingly, inhibition of fatty acid oxidation, or stimulation of CrAT, may be a novel approach to treatment of insulin resistance."

It's interesting because carnitine plays a role in transporting long chain fatty acids into the mitochondria and is needed for oxidation of quarried fatty acids.
L-carnitine is essential to beta-oxidation of quarried fatty acid from mitochondrial membrane by PLA(2). - PubMed - NCBI

It also plays a role in evacuation of fatty acids from the mitochondria that are unable to be oxidized?Medium-chain acyl-coenzyme A dehydrogenase deficiency - carnitine

 

[mujuro]

I think IR is caused by intramyocellular lipids aka fat inside the muscle cell, which comes from the spillover effect from too much adipose tissue aka being obese:

Intramyocellular lipid kinetics and insulin resistance

Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion. - PubMed - NCBI

Intramyocellular lipid storage and insulin resistance - Type 2 diabetes mellitus - Diapedia, The Living Textbook of Diabetes

Effects of an overnight intravenous lipid infusion on intramyocellular lipid content and insulin sensitivity in African-American versus Caucasian a... - PubMed - NCBI

Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. - PubMed - NCBI

.

I know that the inverse is true. IR causes intramuscular fatty deposits. Such is the result when bodybuilders combine ultra-high doses of insulin with growth hormone. There is a mystique that surrounds insulin and GH use, with phrases like "next level" and "next step" because of the increase in cross-sectional area of "muscle" bellies that can just never be achieved on AAS alone. In actuality what is happening is the muscle is marbling with adipose tissue similar to fatty cuts of beef in the supermarket.

 

[jyb]

I know that the inverse is true. IR causes intramuscular fatty deposits. Such is the result when bodybuilders combine ultra-high doses of insulin with growth hormone. There is a mystique that surrounds insulin and GH use, with phrases like "next level" and "next step" because of the increase in cross-sectional area of "muscle" bellies that can just never be achieved on AAS alone. In actuality what is happening is the muscle is marbling with adipose tissue similar to fatty cuts of beef in the supermarket.

It goes both ways. Insulin stops fatty acid oxidation, so you'd expect more fat to stay in the adipocytes until the insulin goes back to equilibrium (can take a few hours after a meal). Conventional diets kill fatty acid oxidation during a lot of the day. Several versions of the "Peat diet" would efficiently kill fatty acid oxidation during daytime too (niacinamide, very frequent low fat high sugar meals). When adipocytes are damaged or get too full, something else happens as they fail to store more or release normal, controlled levels of FFA seen in healthy fatty acid oxidation (there are dozens of articles on this blog like this one: Hyperlipid: Dunnigan-type Familial Partial Lipodystrophy. It also has some about the difference between terminal insulin resistance and physiological resistance post meal, which are not the same kind).

 

[Stryker]

So we have some evidence that impaired beta oxidation can result in insulin resistance, but in the obese, excessive lypolysis and beta oxidation can also impair glucose metabolism. In both cases, hyperglycemia occurs, but for different reasons. Substances like glycine and taurine, which work through a number of mechanisms, may actually work in both scenarios by reducing lypolysis through lowering cortisol and inflammation, while supporting complete beta oxidation.

Does this look right, or am I making a wrong turn somewhere?

impaired beta oxidation is caused by an elevated level of fatty acids inside the mitochondria

oxygen is needed to complete the process of beta oxidation and in times of intense stress or (chronic stress caused by ongoing elevated FFA levels) the oxygen demand by the mitochondria isnt met and the fatty acids pile up inside the cell and in doing so inhibit the oxidation of glucose and the oxidation of themselves .

so if i was to take a stab in the dark taurine and caffeine are lifting the gate on that stress to allow the demand for oxygen to be met more efficiently , temporarily restoring beta oxidation reducing the level of fatty acids inside the cell and allowing glucose and fatty acid metabolism to continue until oxygen supply becomes short and impairs oxidation again

and this is why mildronate is so effective.. it stops the entry of long chain fatty acids entering the mitochondria by inhibiting gamma-butyrobetaine dioxygenase(no carnitine to transport the LCFA).

so the take home note is basically what haidut said , nothing wrong with beta oxidation... the problem would be chronic lipolysis

 

[Peater Piper]

impaired beta oxidation is caused by an elevated level of fatty acids inside the mitochondria

oxygen is needed to complete the process of beta oxidation and in times of intense stress or (chronic stress caused by ongoing elevated FFA levels) the oxygen demand by the mitochondria isnt met and the fatty acids pile up inside the cell and in doing so inhibit the oxidation of glucose and the oxidation of themselves .

so if i was to take a stab in the dark taurine and caffeine are lifting the gate on that stress to allow the demand for oxygen to be met more efficiently , temporarily restoring beta oxidation reducing the level of fatty acids inside the cell and allowing glucose and fatty acid metabolism to continue until oxygen supply becomes short and impairs oxidation again

and this is why mildronate is so effective.. it stops the entry of long chain fatty acids entering the mitochondria by inhibiting gamma-butyrobetaine dioxygenase(no carnitine to transport the LCFA).

so the take home note is basically what haidut said , nothing wrong with beta oxidation... the problem would be chronic lipolysis

In the elderly though, where beta oxidation is often poor, lipolysis is often at a normal, not excessive level. Boosting glutathione still seemed to help, at least in mice. Insulin resistance and diabetes deplete glutathione. It seems like a vicious cycle since healthy insulin signaling is required for glutathione synthesis, and adequate glutathione seems necessary for appropriate substrate oxidation.

I'm still confused about carnitine, because it actually improves insulin sensitivity in many situations, and may even play a role in the removal of byproducts left by incomplete beta oxidation. What's the advantage of inhibiting beta oxidation itself over limiting beta oxidation indirectly through reducing lipolysis with the likes of niacinamide and aspirin?

 

[Kyle M]

I think it's a problem of either A) beta oxidation suppressing glucose oxidation to a higher than optimal degree, B) the molecular "switches" between the two becoming more rigid (malonyl CoA not suppressing beta oxidation, glucose abundance not suppressing lipolysis) or a combination of the two.

 

[Peater Piper]

I think it's a problem of either A) beta oxidation suppressing glucose oxidation to a higher than optimal degree, B) the molecular "switches" between the two becoming more rigid (malonyl CoA not suppressing beta oxidation, glucose abundance not suppressing lipolysis) or a combination of the two.

There reason I found the study with healthy relatives of diabetic relatives so interesting is that it was an inability to shift to beta oxidation that was the problem, and is the reverse of what we typically hear, especially from Peat. Their insulin, c-peptide, and glucose response to a high carbohydrate meal was nearly identical to the controls without a family history of diabetes. However, in response to the high fat meal, the healthy relatives of the diabetics had substantially higher levels of insulin and c-peptide, and their respiratory quotient didn't fall very much, meaning they continued to burn a lot of glucose in spite of the high fat meal, whereas the healthy controls had double the drop in RQ. They also had a decreased energy expenditure in response to the high fat meal (and in fact it was a bit low at baseline as well, but increased more substantially in response to carbohydrates). All of it points to the potential that they're going to gain weight, which probably will deteriorate the condition even more. Once insulin signaling is sufficiently impaired they'll be forced to use fatty acids, which is when we'll see excessive lipolysis and beta oxidation, but it was quite the opposite early on.

 

[Kyle M]

There reason I found the study with healthy relatives of diabetic relatives so interesting is that it was an inability to shift to beta oxidation that was the problem, and is the reverse of what we typically hear, especially from Peat. Their insulin, c-peptide, and glucose response to a high carbohydrate meal was nearly identical to the controls without a family history of diabetes. However, in response to the high fat meal, the healthy relatives of the diabetics had substantially higher levels of insulin and c-peptide, and their respiratory quotient didn't fall very much, meaning they continued to burn a lot of glucose in spite of the high fat meal, whereas the healthy controls had double the drop in RQ. They also had a decreased energy expenditure in response to the high fat meal (and in fact it was a bit low at baseline as well, but increased more substantially in response to carbohydrates). All of it points to the potential that they're going to gain weight, which probably will deteriorate the condition even more. Once insulin signaling is sufficiently impaired they'll be forced to use fatty acids, which is when we'll see excessive lipolysis and beta oxidation, but it was quite the opposite early on.

I think one of the problems with this contradiction you are seeing is that people often report the actions in the whole body, in a specific tissue (like liver), or in a cellular preparation, as the same. As we all know, muscle burns more fatty acids at rest than liver or the brain, and how they are affected by substrate availability and the hormonal signals is different as well. So at the whole body level, what you describe could be the effect and that is confusing. It's still possible, however, that the livers of those prediabetic people are having trouble using glucose, and that could be balanced out by muscle burning more glucose than fat compared to the healthy individuals. I think what the liver does (or doesn't do) is probably the most important for diabetic symptoms.

 

[haidut]

What's your opinion of the study that tested healthy relatives of type 2 diabetics? They were less capable of shifting to beta oxidation after a high fat meal than the healthy controls. Obviously excessive lipolysis is common in obesity, but they have to get obese in the first place. Prior to that I guess there's cortisol and estrogen, but there seems to be a genetic component as well.


It's interesting because carnitine plays a role in transporting long chain fatty acids into the mitochondria and is needed for oxidation of quarried fatty acids.
L-carnitine is essential to beta-oxidation of quarried fatty acid from mitochondrial membrane by PLA(2). - PubMed - NCBI

It also plays a role in evacuation of fatty acids from the mitochondria that are unable to be oxidized?Medium-chain acyl-coenzyme A dehydrogenase deficiency - carnitine

I think there is an epigenetic factor and it is probably related to suppress thyroid. As far as the lipolysis goes - you don't have to be fat to get stuck in excessive lipolysis. People with HIV and cancer have excessive lipolysis and most of them are not fat. I posted an article somewhere on the forum that lipolysis is increased during perceived energetic deficiency, which makes sense. In fact, the lower the ATP synthesis the higher the rate of lipolysis. That perceived energetic deficiency can be caused by many things, but ultimately has to come down to T3 being deficient or not doing its job properly due to PUFA or estrogen.