Insulin resistance cause of cardio-vascular disease

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The following paper, based on literature review (not an independent study!) explains the mechanisms behind cardiovascular diseases: cardiomyopathy, endothelial dysfunction, atherosclerotic plaque formation and coronary heart disease. The main cause = insulin resistance!

"Association between insulin resistance and the development of cardiovascular disease", by
Valeska Ormazabal, Soumyalekshmi Nair, Omar Elfeky, Claudio Aguayo, Carlos Salomon and Felipe A. Zuñiga
Cardiovascular Diabetology201817:122


Quotes:

...epidemiological and pathophysiological studies suggest that hyperglycemia may be largely responsible for CVD. Blood glucose has been reported as an independent predictor of atherosclerosis and blood glucose level greater than 90 mg/dl can lead to atherosclerosis in the carotid artery [125]. Long-term follow up data from patients with type 1 and type 2 diabetes suggest that hyperglycemia is a risk factor for diabetes related diseases and CVDMoreover, it has been suggested by Salvin et al. [126] that a 1 unit increase in the total glycosylated hemoglobin or HbA1C, can increase the risk of CVD by up to 18%. Even in the absence of overt diabetes, impairment in the glucose homeostasis can affect the cardiac autonomic function leading to high risk of cardiac diseases [127].

...
In this sense, recently it has been shown that cyclic ketone bodies preserve “young cardiac phenotype” in old mice [167]. On the other hand, it has been reported that isocaloric ketogenic diet (very low in carbohydrates and high in fats and/or proteins) increases lifespan [168].


Overall, insulin resistance contributes to generate CVD via two independent pathways: (1) atheroma plaque formation and (2) ventricular hypertrophy and diastolic abnormality.

How ketogenic diet protects against vascular aging

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It has been noticed that ketone bodies producing diets such as calorie-restricted diet and ketogenic diets exert some anti-aging effects (on test animals). This study, see the article linked below, pinpoints the mechanism of this effect to the specific ketone body molecule: β-Hydroxybutyrate.

Natural “Fasting” Molecule Exerts Anti-Aging Effects to Protect Vascular System
By NutritonReview.org - May 16, 2019


Quote:

In their study, the research team explores the link between calorie restriction (eating less or fasting) and delaying aging, which is unknown and has been poorly studied. The findings are published in the journal Molecular Cell.

The researchers identified an important, small molecule that is produced during fasting or calorie restriction conditions. The molecule, β-Hydroxybutyrate, is one type of a ketone body, or a water-soluble molecule that contains a ketone group and is produced by the liver from fatty acids during periods of low food intake, carbohydrate restrictive diets, starvation and prolonged intense exercise.

The researchers reported that β-Hydroxybutyrate delays vascular aging by providing a chemical link between calorie restriction and fasting and the anti-aging effect.

This compound can delay vascular aging of the endothelial cells, which line the interior surface of blood vessels and lymphatic vessels, preventing a type of cell aging called senescence, or cellular aging.

Senescent cells can no longer multiple and divide. The researchers found β-Hydroxybutyrate can promote cell division and prevent these cells from becoming old. Because this molecule is produced during calorie restriction or fasting, when people overeat or become obese this molecule is possibly suppressed, which would accelerate aging.

In addition, the researchers found when β-Hydroxybutyrate binds to a certain RNA-binding protein, this increases activity of a stem cell factor called Octamer-binding transcriptional factor (Oct4) in vascular smooth muscle and endothelial cells in mice.

Stem cell factor Oct4 increases a key factor against DNA damage-induced senescence, which can keep blood vessels young.

Reference:

1. "β-Hydroxybutyrate Prevents Vascular Senescence through hnRNP A1-Mediated Upregulation of Oct4",
Young-min Han et al., Molecular Cell, VOLUME 71, ISSUE 6, P1064-1078.E5, SEPTEMBER 20, 2018.

Example of a ketogenic (high fat low carb) dish.  Ketogenic diet has been described by some as BBB diet, meaning Butter, Bacon and Brie.  It is not limited to that!  

Ketogenic diet protects against chemotherapy

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"β-Hydroxybutyrate, a ketone body, reduces the cytotoxic effect of cisplatin via activation of HDAC5 in human renal cortical epithelial cells", Daisuke Mikami et al., Life Sciences
Volume 222, 1 April 2019, Pages 125-132

Quote:

Main methods

In this study, we used human renal cortical epithelial (HRCE) cells. The anti-apoptotic effect of βOHB was evaluated using flow cytometry analysis. The expression of apoptosis-related proteins and HDACs was evaluated by western immunoblot.

Key findings

The results showed that βOHB significantly reduced cisplatin-induced apoptosis in HRCE cells. Furthermore, βOHB significantly reduced cisplatin-induced cleavage of caspase-3, acetylation of histone H3, and phosphorylation of AMP-activated kinase. This anti-apoptotic effect of βOHB was markedly attenuated by an inhibitor of HDAC4/5, and βOHB-mediated suppression of cleavage of caspase3 was significantly blocked by siRNA-induced gene silencing of HDAC5.

Significance

βOHB attenuates cisplatin-induced apoptosis by activation of HDAC5 in HRCE cells, suggesting that βOHB may be a new therapeutic agent for cisplatin nephropathy.

Ketogenic diet used to cure infections

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From 1933 paper:

Quote:

SUMMARY.
The principal factor inhibiting the growth of bacteria in the urine from patients receiving the ketogenic diet is l-𝛃-hydroxybutyric acid. The activity of this substance increases in proportion to the acidity of the urine.

The link is this: "THE NATURE OF THE BACTERICIDAL
SUBSTANCE IN THE URINE OF PATIENTS RECEIVING A KETOGENIC DIET."
BY ALBERT THOMAS FULLER, 1933

(Thanks Anonymous)

Fasting - something is missing...

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Fasting for three days can regenerate entire immune system, study finds

Glucose and epileptic seizures

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Interesting paper, requires more discussion (to be added later):


Fructose-1,6-Bisphosphate Has Anticonvulsant Activity in Models of Acute Seizures in Adult Rats

A variety of observations suggest that decreasing glycolysis and increasing levels of reduced glutathione, generated by metabolism of glucose through the pentose phosphate pathway, would have an anticonvulsant effect. 

Glucose is the primary source of energy for the CNS. Imaging of children with Lennox–Gastaut and infantile spasms has shown decreased glucose utilization between seizures and excessive glycolysis immediately before, and during, seizures (Chugani and Chugani, 1999). 

Evidence suggests that the changes in glucose metabolism and decreased glutathione levels observed in the brains of patients with epilepsy favor the generation of each seizure. First, hyperglycemia has been associated with seizure activity (Schwechter et al., 2003; Lammouchi et al., 2004), whereas relative hypoglycemia has been shown to have an anticonvulsant effect (Greene et al., 2001). Second, the ketogenic diet (KD), which provides energy substrates for the brain that bypass glycolysis, has been shown to be an effective treatment for seizures (Freeman et al., 2007). Finally, animals with low levels of GSH have a low seizure threshold or spontaneous seizures (Wu et al., 2004).

[add discussion]

Ketogenic diet reverses kidney failure caused by sugar

... in diabetic mice!

Chinese braised pork belly

New study was just reported on the BBC Health: Diet 'can reverse kidney failure' in mice with diabetes

Quote:

A controlled diet high in fat and low in carbohydrate can repair kidney damage in diabetic mice, according to US scientists. The study, published in journal PLoS ONE, showed a "ketogenic diet" could reverse damage caused to tubes in the kidneys by too much sugar in the blood. ... After eight weeks the researchers noted that kidney damage was reversed. Professor Charles Mobbs, who led the research at Mount Sinai School of Medicine, said: "Our study is the first to show that a dietary intervention alone is enough to reverse this serious complication of diabetes.

The study:

Reversal of Diabetic Nephropathy by a Ketogenic Diet

Quote:

In mouse models for both Type 1 (Akita) and Type 2 (db/db) diabetes, diabetic nephropathy (as indicated by albuminuria) was allowed to develop, then half the mice were switched to a ketogenic diet. After 8 weeks on the diet, mice were sacrificed to assess gene expression and histology. Diabetic nephropathy, as indicated by albumin/creatinine ratios as well as expression of stress-induced genes, was completely reversed by 2 months maintenance on a ketogenic diet. However, histological evidence of nephropathy was only partly reversed. These studies demonstrate that diabetic nephropathy can be reversed by a relatively simple dietary intervention. Whether reduced glucose metabolism mediates the protective effects of the ketogenic diet remains to be determined.

Let's look at this detail, quote:

None of the conditions influenced blood pH, although there was a non-significant trend toward reduced blood pH (i.e., acidification) in diabetic mice, and the ketogenic diet reversed this trend.

In other words:

-- KETOGENIC DIET REVERSED DIABETIC ACIDIFICATION! --

Which totally undermines all the bullshit that the mainstream medical authorities together with vegetarian promoters used to hurl against Atkins! Furthermore:

-- KETONE PROTECTS AGAINST GLUCOSE TOXICITY AND AGAINST OXIDATIVE STRESS --

As the authors explain, quote:

The ketone 3-OHB is cytoprotective
To further assess potential mechanisms mediating the protective effects of the ketogenic diet, and since glucose toxicity in diabetes is thought to be mediated by glucose-induced oxidative stress, we assessed if the ketone 3-OHB would protect cells from oxidative stress enhanced by either high or low glucose. As shown in Figure 6, 3-OHB produced a dose-responsive cytoprotective effect at both elevated and reduced glucose.

The authors also concluded that:

-- REDUCTION OF GLUCOSE METABOLISM MAY BE GENERALLY BENEFICIAL --

Quote:

...we hypothesize that at least part of the restorative effect was mediated by reduction of glucose metabolism. This hypothesis is supported by several lines of evidence. First, the ketogenic diet appears to reduce the frequency of epileptic seizures by reducing glucose metabolism [11], [12]. Second, molecular responses to the ketogenic diet indicates a re-routing of cellular metabolism away from glucose utilization and toward the use of alternative fuels [13], [14]. Finally, we have shown that ketone 3-OHB blocks molecular effects of glucose [9]. We therefore hypothesize that the ketogenic diet reverses diabetic nephropathy by raising blood levels of 3-OHB which subsequently reduce glucose metabolism in at least some tissues including kidney. Since ketones and the ketogenic diet are neuroprotective in a wide range of conditions [31], a phenomenon we have corroborated in the present study (Figure 6), it seems highly likely that the ketogenic diet will be protective in diabetic neuropathy and possibly retinopathy as well.

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Fatty meal may reduce heart risk

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(Beefsteak Tartare, wiki)

The findings were presented April 14 2011 at the 2011 Experimental Biology meeting in Washington DC.

Quoting after "Fatty splurge may reduce heart risk" article publishd yesterday in the Irish "Indo".

The surprising findings show that a short saturated fat "splurge" can actually reduce damage to the heart. Scientists who conducted the research in mice are still trying to explain the effect. But they believe it could have important implications for human health, possibly leading to a way to "pre-treat" people at high risk of heart attacks. Previous studies have found that certain patients with high cholesterol levels are more likely survive heart attacks than those with lower levels. Yet the idea that fatty food can reduce injury from heart attacks is completely at odds with general thinking about diet and heart health.

"at odds", yeah right...

Heretic
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Ketone bodies protect neurons from stress hormone-induced damage

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[Part 1 of 2]

This is inspired by this video presentation:

Robert Sapolsky: Stress, Neurodegeneration and Individual Differences

Scrolling to minute 26 of the video, reveals a slide summarizing the results of an experiment, where neural tissue was exposed to an "insult" (damage cause) equivalent to hypoglycemia.

The degree of damage to the neurons was asessed in volume units (vertical) while the 4 cases are represented by color bars:

green - damage caused solely by the original "insult"
yellow - damage caused by the "insult" in the presence of glucocorticoid (stress hormone)
red - damage caused by the "insult" in the presence of glucocorticoids and mannose sugar
white - damage caused by the "insult" in the presence of glucocorticoids and ketone bodies (beta-hydroxy-butyrate)

What do I make out of that? Basically, it shows that not only ketone bodies work better as the energy source than mannose sugar, but also protect against the damage caused by both factors combined: hypoglycemia and glucocorticoid: - the white bar is smaller than the original green bar on the left!

[part 2 essay inspired by the same video will be titled "Lack of social skills made us human!" ]

Very-Low-Fat Diets: What Are the Benefits?

JC from the WebMD Diet Debate forum posted the following slide - see beside and the reference below (thanks!). The author's conclusions do not surprize me. MI ("heart attack") events depend on the quality (type) of plaque more than on the quantity of plaque. Excess polyunsaturated fats (e.g. popular vegetable oils) lead probably to abnormalities in the composition of cellular structures that use fats, such as cellular membranes. This probably affects mostly the newly grown tissue such as scar tissue and the plaque tissue (plaque is a scar tissue!). The bulk of the plaque on the other hand, according to Dr. Jan Kwasniewski ("Homo Optimus"), results from excessive pentose cycle that synthesizes fats (and NADP, RNA etc) in-situ inside the arterial walls. Pentose cycle is on the other hand driven by excessive carbohydrates (plus a few other conditions such as reduced availability of oxygen, lack of magnesium etc).

If that hypothesis is true then one could perhaps draw the following general guidelines:

- To reduce the overall plaque buildup - consume less carbohydrates!

- To reduce the risk of MI events (once the plaque exists) - reduce consumption of vegetable oils and artificial baking fats (polyunsaturated fats, transfats)

Please notice that low fat vegan diets also reduce vegetable fats by discouraging all fats. They also may reduce the total glycemic load. Interestingly, when you stop eating fat, liver will manufacture some of the necessary fats internally - mostly saturated fat! Did anyone notice that this theory is the only one that explain why both types of diets: low fat vegan (sometimes) and high animal fat low carb (always) may reduce the risk of MI?!

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Reference:

Very-Low-Fat Diets: What Are the Benefits?

Effects of Lifestyle and Dietary Modification on HDL-C Levels (Margo A. Denke, MD)

Snacking and glucose/ketogenic cycling

This is a theory, very speculative. I came to think about it, inspired after reading the latest articles by Peter (Hyperlipid blog, see also his Kitava articles). I am thinking about the effect of frequent snacking in between the meals on a high carb diet, may be more damaging than we thought. Under a healthy metabolism, even on a high carb diet, one's body goes back to ketogenic state some time after every meal, when most body tissues revert back to using lipids and ketone bodies as fuel. This should happen in between the meals providing that the body is given enough time to burn glucose off and to switch. On the other hand, any time one eats something sugary or starchy in between the meals, insulin inrush causes the body to switch back to glucose processing state, turning off production of ketone bodies and turns off the release of adipose fat into bloodstream. It takes about 1-2 hours to work out all that insulin peak. Probably longer for older people.

For some reason, our bodies probably require this alternating between glucose-burning/ketogenic cycles to be done throughout the day to work properly. This is based upon the assumption that ketogenic mode is essential for the body and must take place at least some of the time throughout the day, every day. I suspect that frequent snacking on a high carbohydrate diet derails that cycling and may be one of main triggering factors behind the development of the metabolic syndrome.

From my personal observation, one can notice that people who are used to snack frequently are often obese and often have metabolic syndrome. Perhaps there is a causual connection? Perhaps it is not just what and how much one eats but how often and when?

Diets based on natural whole food like our vegetarian friends recommend, usually discourage sugary or starchy snacks, or discourage consumption of the processed food that forms the typical fast food snacks. It makes snacking more difficult, especially that preparation of meals out of natural unprocessed whole food is time consuming and labor intensive. Perhaps that may be one of the reason why such whole food natural diets are often helpful?

Of course, the high fat low carb diets make that issue irrelevent since a high fat snack would not cause the glucose+insulin spike thus would not break the ketogenic mode. This could be another reason why the high fat low carb diets work so well!

Just some thought,
Stan (Heretic)

Carbohydrates and Diabetes

Response for TG (on McDougall forum)

http://www.drmcdougall.com/forums/viewtopic.php?t=8095&postdays=0&postorder=asc&start=0

I know you have studied this issue and you did notice that your glucose response is dependent on the carbohydrate load (primarily) while other factors such as the presence of fat may only modulate the insulin sensitivity somewhat but it is not the main factor. The main factor is the total glycemic load ( GL = GI * mass of carbs ).

Typically, our insulin response is equal to about 10 insulin units per every 100g of carbohydrate (GL). It is as simple as that and no amount of wiggling or waving by vegan followers with their refined versus natural theories; potatoes versus rice versus sweet potateoes etc., is going to change this.

Your blood glucose post-prandial peaks at 140mg/dl are on the higher limit of the normal (on a high carbohydrate diet) and probably indicate that your insulin secretion may be insufficient (as I wrote before check against dm t1) or that your tissue became insulin resistant (metabolic syndrome).

Insulin resistance depends on the amount of fat you consume with the carbohydrates but important is also that you allow a time of metabolic rest in between the meals. This is the period when the body wants to switch from burning glucose to burning lipids (from body fat) and ketone bodies.

Preventing the appearance of such a cycle of rest in-between the meals, through frequent snacking may be one of the culprit behind the metabolic syndrome.

There are two ways of preventing metabolic syndrome:

1) Eat low fat high carbohydrate natural low glycemic food (vegetarianism is not necessary and probably not even relevant) and make long breaks between the meals to allow for the ketogenic cycle in between the meals

2) Eat a low carbohydrate high ANIMAL fat meals. Avoid polyunsaturated oils and transfats! In this case snacking in between the meals is not harmful as long as it is with fat only, not with carbohydrates (the reason is that fatty snacks do not break the ketogenic "resting" cycle).

Both styles of eating 1 or 2 will result in low average insulin level in between the meals, and will protect you against the chronic diseases associated with the metabolic syndrome such as CHD, cancer and autoimmune. Such disease are associated with the elevated insulin level rather than with the glucose itself. Kidney failure however, is related to glucose peaks since every time it exceeds 160mg/dl, it forces kidneys to excrete glucose. Other risk factors have different causes. For example diabetic neuropathy (and retinal damage) is probably more associated with fructose leakage to the bloodstream than with glucose.

If you decide to follow (2) then do not try to avoid fat. The more fat (animal, saturated and monounsaturated) the better it works. There is absolutely no need to worry about the heart disease since it is the insulin, not fat, in particular not animal fat, that seems to be the main growth promoter for arterial plaque and arteriosclerosis. For example, see R.W. Stout http://www.ptbo.igs.net/~stanb/Lancet_Stout_pg_702.pdf and http://www.ptbo.igs.net/~stanb/Lancet_Stout_pg_467.pdf

Besides if what I am saying were wrong and McDougall's crowd were right, I wouldn't be typing it. I would be dead. Over in the last 9 years I have been consuming about 150g (to 200g) of butter, cream or pork lard every day. If you read this message it means it's true! :)

Stan (Heretic)