Click the following link to see the full article. Formos J Endocrinol Metab 2017;8:49-54.
After years of waiting, another review article appears in peer reviewed journal reminding health care professionals not to be too obssessed with LDL-C.
Click the following link to see the full article. Formos J Endocrinol Metab 2017;8:49-54.
This is an excerpt from news media describing the research done by one of the mainstream cancer researchers, Dr Lewis Cantley.
Dr. Cantley was a professor at Tufts University School of Medicine in the '80s when he identified a previously unknown enzyme, phosphoinositide-3-kinase, or PI3K, that would turn out to be a sort of master switch for cancer. The protein's normal function is to alert cells to the presence of insulin, prompting them to pump in glucose, cells' metabolic fuel. This signaling pathway is crucial to cells' growth, proliferation and survival, so it makes sense that malfunctions can cause serious problems. If the pathway runs too slowly, the body becomes insulin-resistant and cells fail to take up enough glucose: this is Type II diabetes. In cancer, however, the pathway shifts into high gear, providing tumors with an overabundant supply of glucose, which drives their growth.
It turned out that the gene that encodes PI3K is the most frequently mutated cancer-promoting gene in humans—and in the years since Dr. Cantley's revolutionary discovery, it has been implicated in as many as 80 percent of cancers, including those of the breast, brain and bladder. The pathway has also served as a target for new drugs, including the breakthrough lymphoma and leukemia drug idelalisib, which in 2014 became the first PI3K inhibitor to be approved by the FDA. Dr. Cantley came to Weill Cornell Medicine in 2012, his scientific reputation well-established; he has won a host of prestigious international awards, and his name comes up frequently when colleagues speculate about future Nobel laureates. Since setting up his lab at Weill Cornell Medicine, he has continued to investigate the role of PI3K.
One of oncology's major frustrations is that some drugs that aim to inhibit PI3K have been less successful in clinical trials than originally hoped. Blocking the enzyme should impede the signals that allow cancer cells to take in the high levels of glucose they need to survive, but it doesn't always work that way. In many patients, PI3K inhibitors cause blood sugar to spike, suggesting that the drugs meant to starve tumors were telling the liver that the body itself was starving, too. In response, the liver—which stores extra glucose in the form of a compound called glycogen—was sending too much sugar into the blood, which triggered the pancreas to release excess insulin. Meanwhile, these patients' tumors continued to grow.
Dr. Cantley and his colleagues wondered whether the excess insulin might be countering the effect of the drugs by reactivating the PI3K pathway in the cancer cells. They theorized that a diet very low in carbohydrates—limiting both sugar and starch, which breaks down into simple sugars in the body—would prevent spikes in blood sugar and might help the drug do its work, starving the tumor while the patient's body fueled itself with fat and protein instead, a state called ketosis. So researchers in Dr. Cantley's lab, including instructor in medicine Dr. Benjamin Hopkins, worked with colleagues at Columbia University Irving Medical Center and NewYork-Presbyterian to test the hypothesis.
Using mice that had been genetically engineered to develop pancreatic, bladder, endometrial and breast cancers and treated with a new PI3K inhibitor (which is currently in clinical trials), they demonstrated that spikes of insulin did indeed reactivate the pathway in tumors, countering the anti-cancer effect of the drug. But when the researchers severely restricted the mice's carbohydrate intake, putting them on what's known as a ketogenic diet in addition to the medication, the tumors shrank. (Adding a diabetes drug meant to lower blood sugar levels also helped, but the effects of the diet in conjunction with the PI3K inhibitor were more dramatic.) The encouraging results were published in the journal Nature in July 2018 with Dr. Hopkins as lead author. "The mutations to the PI3K pathway that cause cancer also enhance the ability of insulin to activate the enzyme," Dr. Cantley explains. "Our preclinical research suggests that if somewhere in your body you have one of these PI3K mutations and you eat a lot of rapid-release carbohydrates, every time your insulin goes up, it will drive the growth of a tumor. The evidence really suggests that if you have cancer, the sugar you're eating may be making it grow faster."
Is Ketosis Key?
The Internet is full of diet advice, and among today's hottest fads is a low-carb regimen popularly known as "keto." It was the most Googled diet trend of 2018, a popular weight loss strategy among celebrities like reality TV star Kourtney Kardashian and basketball icon Lebron James, who sometimes refer to it as "paleo," for its supposed resemblance to the diets of our Paleolithic ancestors. But that's not what clinicians or researchers mean when they talk about a ketogenic diet, explains Dr. Katie Hootman, a registered dietician and director of the Metabolic Research Unit at Weill Cornell Medicine's Clinical and Translational Science Center (CTSC). "The diets on the internet tend to be way too high in protein," she says. "There is a pretty big difference between that and a clinical ketogenic diet, one that's actually intended to get the patient into ketosis."
Ketosis, Dr. Hootman explains, is a state in which the body relies on the metabolism of fat as the primary fuel to meet energy demands, rather than glucose, cells' preferred source of energy. From the breakdown of fat, the liver circulates molecules called ketone bodies, which cells use as fuel until carbohydrates become abundant again. This metabolic process evolved to help mammals survive food shortages, but in a clinical context it has been used since the early 20th century to reduce seizures in people with epilepsy. A few studies in the late 20th and early 21st centuries suggested a ketogenic diet might also be helpful against some forms of cancer, but it is only recently that researchers have studied its usefulness in conjunction with anti-cancer drugs. Among the clearest evidence is the Dr. Cantley Lab's mouse study, which Dr. Hootman is now helping to translate to human patients.
In the meantime, Dr. Cantley—ever the anti-sugar evangelist—adds that limiting sweets certainly couldn't hurt. Eating less sugar, he says, is clearly beneficial. "It'll help you in so many different ways, with so many different diseases," he says. "And once you don't have that addiction anymore, it's actually quite easy. After all, I've had no trouble doing it for 40 years."
Dr. Lewis Cantley has a very simple rule, he says. "I eat fruit, but I don't eat anything that has sugar added to it. And I guarantee everybody would be better off if they ate zero sugar."
WHO recommends that populations consume less than 2 g/day sodium as a preventive measure against cardiovascular disease, but this target has not been achieved in any country. In PURE study, less than 1% of general population follow this recommendation. That's ridiculous! 2g sodium / day is approximately 5g NaCl (or 1 teaspoon of salt) and the PURE study is an international prospective epidemiolgy study involving 18 countries with a median follow-up of 8 years. If it is undoable, what good is that suggestion? Furthermore, there is also harm in that suggestion. Please read on to find out.
According to a study published in Lancet, 80% of people from mainland China consume more than 12.5 gm of salt /day whereas 84% of people from other countries have salt intake of 7.5 ~12.5 gm/ day. When we look at cardiovascular [CV] events (eg. Stroke or heart attacks), positive association is seen only in mainland China, which means higher salt intake is associated with stroke. In other countries, those in the highest tertile (one third) of salt intake (more than 12.5g/ day) have non-significant association with CV events. There was no association between salt intake and CV events in the middle tertile (salt intake 10 ~12.5 g/ day). In the lowest tertile (ie. Salt intake less than 10 g/ day), there is inverse association meaning less salt intake is associated with more CV events. One important finding is CV events decreased with increasing potassium intake (K in chemistry) in all countries. Therefore, those in countries other than mainland China, following WHO recommendation of low sodium intake might lead to more CV events.
I will cite another study from Lancet which analyzed data from 4 studies and followed people for a mean period of 4 years. N = 133118 (63559 with hypertension & 69559 without hypertension), so a very large study with huge statistical power. Findings: in those people with hypertension, salt intake of more than 17.5 g/day AND less than 7.5 g/ day were both associated with increased risk of death or CV events (stroke or heart attack). Please note, this is the case in hypertensive patients. Those with normal blood pressure have another story: higher salt intake (NaCl more than 17.5 g/day) was NOT associated with risk of death or CV events. Read carefully please, in these people WITHOUT hypertension, salt intake < 7.5g/ day was associated with a significantly increased risk of death or CV events! What all these mean is: following WHO recommendation (salt intake < 5g/day) is likely to increase your risk of death or CV events whether or not you have hypertension. Luckily, only less than 1% of the world population complies to their darn suggestion.
This brings up the issue of “salt sensitivity” which is found only in a small % of the population. In these salt-sensitive people, higher salt intake might increase blood pressure, but not in those insensitive to salt. There is also evidence that this salt sensitivity is related to sugar intake, so if you quit sugar or reduce its intake, your sensitivity to salt might improve, so blood pressure may not go up with increased salt intake.
PURE study is an international prospective epidemiolgy study involving 18 countries with a median follow-up of 7·4 years. Just as in Women's Health Initiative which is another huge study showing low fat diet fails, PURE study shows once again that intake of total fat and each type of fat was associated with lower risk of total mortality (quintile 5 vs quintile 1, total fat: HR 0·77 [95% CI 0·67-0·87], ptrend<0·0001; saturated fat, HR 0·86 [0·76-0·99], ptrend=0·0088; monounsaturated fat: HR 0·81 [0·71-0·92], p trend<0·0001; and polyunsaturated fat: HR 0·80 [0·71-0·89], p trend<0·0001). Higher saturated fat intake was associated with lower risk of stroke (quintile 5 vs quintile 1, HR 0·79 [95% CI 0·64-0·98], p trend=0·0498). Total fat and saturated and unsaturated fats were not significantly associated with risk of myocardial infarction or cardiovascular disease mortality. This is totally in contrast to Ancel Key's Seven country study which started the low-fat mania 3 decades ago.
Despite all these giant high quality studies published in peer-reviewed medical journals, the expert organizations keep on singing the old song of low fat diet with saturated fat less than 10% of total calorie. Old dogmas die hard and we must keep on fighting outdated guidelines from organizations with huge conflicts of interest.
A relatively large study (N=773) done in Europe gives clues to answer the above question. This study is called DiOGenes(Diet, Obesity and Genes study), which is a Randominzed Controlled Trial involving volunteers from 8 European countries. There are 2 parts in this study: 1st part is weight loss phase during which volunteers ate low-calorie diets for 8 weeks and lost weight; 2nd part is weight maintenance phase during which subjects were randomized to 1 of 5 ad libitum diets for 26 weeks. These 5 were (1)Low protein, low glycemic index [GI];
(2) Low protein, high GI; (3)High protein, low GI; (4)High protein high GI; (5)Control diet [according to national dietary guidelines]. Their hsCRP levels were compared in the following figure which shows only low GI groups (whether low protein or high protein) have significant reduction in hsCPR levels (P<0.05). The 2 high GI groups (both low protein and high protein) and control group had changes that were statistically non-significant (P>0.05). This might be related to expected reductions of postprandial glucose levels with low-glycemic-index diets, with glucose known to stimulate the expression of inflammatory genes by epigenetic mechanisms. Furthermore, transient increases in glucose induce persistent changes in histone methylation patterns at promoters of inflammatory genes, which is related to glucose-induced mitochondrial generation of oxygen radicals. Long-term increases in basal glucose concentrations are associated with both high fasting insulin concentrations and insulin resistance, which is known to promote inflammatory processes and an increment of hsCRP.
According to Dr. Steven Gundry, all autoimmune diseases are caused by alterations in the good bugs and the bad bugs that live in our gut, our mouth and on our skin (known as microbiome), along with a change in the permeability of our gut wall (aka leaky gut).
What impacts that permeability? NSAIDs, antibiotics, acid-blocking drugs such as Nexium and pesticide Roundup all change our gut flora and the mucous layer of our gut. This compromises the barrier of our intestines on a daily basis, thereby allowing lectins in.
Copious research over the last half century reveals that gulping down NSAIDs is like swallowing a live grenade. These drugs blow gaping holes in the mucus-lined intestinal barrier. As a result, lectins, LPSs, & living bacteria are able to deluge the breaks in your gut, flooding your body with foreign invaders. And this confluence of forces prompts our immune system to unleash an attack on ourselves, in a classic case of mistaken identity caused by molecular mimicry.
In fact, much of what we assume as a normal part of the aging process is actually the cumulative effect of Lectin toxicity.
Ref: Plant Paradox by Steven Gundry
Growing number of studies from top milk-producing countries like Australia, New Zealand, and some European nations enumerate the benefits of A2 milk and the health risks associated with continuous consumption of A1 milk.
In his book called Plant Paradox, Dr Gundry from the US explained like this: about 2000 years ago, a spontaneous mutation in Northern European cows caused them to make the protein casein A–1 in their milk instead of the normal casein A-2. During digestion, casein A-1 is turned into a lectinlike protein called beta-casomorphine. This protein attaches to the pancreas's insulin-producing beta cells, which prompts an immune attack on the pancreas of people who consume milk from these cows or cheeses made from it. I could not believe what I saw, so searched pub med & sure enough I found the following:
Type I (insulin-dependent) diabetes mellitus and cow milk:
casein variant consumption.
An extract from this 1999 paper says: The A1 and B variants of beta-casein have a histidine at position 67 that determines the enzymatic cleavage of the molecules yielding beta-casomorphin 7. The A2 variant does not cleave at this position due to the presence of a different amino-acid (proline). Beta-casomorphin-7 has opioid properties, and has been shown to inhibit human intestinal lymphocyte proliferation in vitro. It is possible that such an immune suppressant influences the development of gut-associated immune tolerance, or suppresses defence mechanisms towards enteroviruses, both of which have been implicated in the aetiology of Type I diabetes. Other immunosuppressive effects which might contribute to diabetes include activation of endogenous retroviruses associated with the disease. Click the link below to see full abstract on medline:
Another paper included even IHD. Holy shit! Look below:
Ischaemic heart disease, Type 1 diabetes, and cow milk A1 beta-casein.
According to New Zealand research conducted by CN McLachlan, the regular intake of common milk containing A1 beta-casein inspires the development of coronary heart disease. Click the link below for full abstract:
Luckily this is still controversial. That said, Dr Gundry's case reports showed that in susceptible persons, different breeds provoke different responses.
The following is a website providing information about A1 & A2 difference:
The following was extracted from RD:
Low-carb diets have been around for years, but adding healthy fat is the new twist. Fats from dairy, nuts, fish and eggs (including the yolk) are healthy, whereas overconsumption of vegetable oils and trans fats can lead to chronic disease. A growing body of evidence shows our 30-year message to avoid fat has been misguided and fat instead is satiating, good for the heart and brain, and, compared to other food groups, has the least impact on insulin release. Swedish diabetes researcher and head of internal medicine at Linkoping University Dr. Fredrik Nystrom agrees. His dietary advice: “Carbohydrate restriction in combination with the high fat Mediterranean diet [fish, some meat, vegetables, cheese, nuts, olive oil]".
Click the link below to see the whole article
Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in folate & homocysteine metabolism. MTHFR is also acronym for the gene that encodes this enzyme. MTHFR enzyme deficiency can cause hyperhomocysteinemia. Currently, 34 rare but deleterious mutations in MTHFR gene, & 9 common variants (polymorphisms) have been reported. The 677C→T (A222V) variant is the most common genetic cause of hyperhomocysteinemia. The disruption of homocysteine metabolism by this polymorphism influences risk for several complex disorders. Mental health issues, such as depression, bipolar disorder, schizophrenia, ADHD, or autism are linked to having an MTHFR mutation. MTHFR mutations also increase the risk of CVD and stroke, recurrent early miscarriage, migraine with aura, osteoporosis, and some cancers.
Mudd et al 1st identified a patient with homocystinuria due to a severe deficiency of the MTHFR enzyme. This type of deficiency is relatively rare. In 1988, a thermolabile variant of MTHFR enzyme was identified in patients with cardiovascular disease. With the identification of a MTHFR polymorphism (i.e., a common mutation) that results in mild hyperhomocysteinemia, it became clear that some diseases of adulthood, such as CVD, reflect milder versions of the fulminant biochemical defect present in the newborn or child with severe MTHFR deficiency. This milder deficiency, which appeared to be more common, resulted in a mild to moderate elevation of plasma total homocysteine, an emerging risk factor for cardiovascular disease.
The 2 most common polymorphic variants that affect enzyme activity are the C677T & the A1298C variants. Because there are 2 copies of each gene, an individual can be homozygous for the C677T variant. This can cause hyperhomocysteinemia if the individual also has a low plasma folate. Individuals who are heterozygous for C677T have one copy of the C677T variant and one "wild type" or normal copy. These C677T heterozygous individuals do not demonstrate elevated homocysteine. C677T homozygous variant enzyme is thermolabile and demonstrates 70% reduced enzyme activity in vitro. The heterozygous C677T MTHFR enzyme has 35% reduced activity in vitro. It is estimated that 32% of Mexicans, 10-15% of North American Caucasians, and 6% of people of African descent are C677T homozygous.
An Italian study investigating forms of folate (dietary, 5-MTHF, and folic acid) & effect on total plasma homocysteine levels found that all 3 experimental groups had lowered plasma homocysteine levels compared to the controls. The study showed that a folic acid-enriched food diet (400 µg/day), supplemental folate in the form of 5-MTHF (200 µg/day), and folic acid (200 µg/day) are comparable in reducing total homocysteine levels irrespective of MTHFR genotype status.
For further details click the following links:
The advent of the agricultural revolution about 10,000 years ago meant that a totally new source of food – grain and beans – became the dietary staple relatively quickly. Until then, the human microbiome had never encountered lectins in grains or legumes, and therefore the human gut bacteria and immune system had zero experience handling them.
We can see that lectins in oats, grains & legumes have always been toxic. But given the choice between starvation & some serious health trade-offs, humans will always opt for survival. Without grains & beans, civilization would not have occurred.
Plants attack your defense system with their own three-pronged approach, making you feel sick on several fronts.
Strategy # 1:
The first mission of lectins is to pry apart tight junctions between enterocytes. Normally lectins should not be able to squeeze past the mucosal cells. But if your defense lines are breached, lectins can pry apart tight junctions by binding with receptors on certain cells to produce Zonulin. Zonulin opens up the spaces between enterocytes, which enables lectins to access the surrounding tissues, lymph nodes, or bloodstream. Once there, they act like any foreign protein, prompting your immune system to attack them.
Plants purposely make lectins that are virtually indistinguishable from other proteins in your body, a tactic called molecular mimicry. By mimicking human proteins, lectins fool the host’s immune system, causing it to attack the body’s own proteins. Multiple studies of arthritic patients have demonstrated elevated antibody levels for gliadin which is the principal component of wheat gluten. Gluten-free diets have been shown to be effective in reducing arthritic symptoms in celiac patients.
Lectins can bind to important receptors on the cell walls, either giving wrong information or blocking release of the correct information. For example, the lectin WGA bears a striking resemblance to insulin. It can attach to insulin receptor as if it were the actual insulin molecule, but unlike the real hormone, it never lets go – with devastating results, including reduced muscle mass, starved brain cells, and plenty of fat.
Gluten, the protein found in wheat, barley,rye, and often oats, is just one form of lectin.
All gluten foods contain lectins. Almost all grains & pseudo-grains contain glutenlike lectins. So-called gluten-free products are actually full of lectins in the form of flours made from corn, oats, buckwheat, quinoa,and other grains & pseudo-grains, as well as soybeans & other legumes.
Wheat germ agglutinin (WGA) is found in Bran. This means that white bread contains gluten but not WGA, while whole wheat bread contains both.
WGA is a small protein compared with most other lectins. So even if the gut mucosal barrier has not been compromised, WGA can pass through the walls of intestine more easily than other lectins can. WGA also: