Dr. Oz on Sweeteners: Sugar, Fructose, Insulin/Resistance, AGE, FattyLiver

….All 190 posts here….

I was shocked when Dr. Oz recommended a snack made with agave syrup. I had seen a previous program by America's representative of the medical industry in which he revealed the hazards of agave syrup as a new source of fructose. Now he just skipped over the use of this fructose syrup as a "natural" sweetener, even though it is even less healthy than high fructose corn syrup, HFCS. There seems to be a lot of deliberate confusion about sweeteners and since I am trained as a carbohydrate chemist, I will try to tell it as I see it.

General Information 

• Carbohydrates are not needed in your diet, since your liver can make all the blood sugar that you need from protein. Most diabetics can benefit from a low carbohydrate diet. 
•  Glucose, the blood sugar, is primarily responsible for turning on insulin production, so sweeteners (glucose, sucrose, HFCS, corn syrup) or dietary carbohydrates (starch, e.g. cereal, rice, pasta, potatoes, bananas) that are readily converted to glucose, cause blood insulin levels to rise. 
•  Fructose in any form (HFCS, sucrose, agave syrup) contributes to liver damage. Fructose is the most chemically reactive sugar. 
•  Artificial sweeteners, especially in soft drinks, do not contribute dietary calories, but they apparently increase insulin production and contribute to hunger, eating and obesity. 
•  Insulin production removes glucose from the blood, i.e. lowers blood sugar, by increasing glucose transport into fat cells. If glucose is in your blood, but insulin is not present, e.g. type I diabetes, then you get thin. If glucose is in your blood and insulin is present, then you get fat. If you are fat and glucose is still high in the blood and insulin is present, then the fat cells will die unless they shut off the insulin response, i.e. insulin resistance. Lowering the amount of carbohydrates, sweeteners/starch, in your diet makes it easier to control blood sugar levels and avoid hunger. 
•  Decreasing dietary carbohydrates means that calories have to be present in some other form and the answer is saturated fat. Most polyunsaturated fats, e.g. vegetable oils, except olive oil, are not healthy. The fats in meat, butter, eggs and coconut oil are the healthy choices supported by the biomedical literature, and along with vegetables, form the foundation of a healthy, anti-inflammatory diet. 

Central Metabolism Started with Fructose not Glucose 
All organisms convert sugars through a common series of enzymatic steps, called central metabolism, to a simple, three-carbon compound called pyruvate. Pyruvate can be used as a source of energy in mitochondria in the presence of oxygen or converted into alcohol or acids in various forms of fermentation. No matter what sugars are used, e.g. glucose, galactose, mannose, they are all converted in cells into derivatives of fructose. Thus, fructose is common to all organisms and can be considered to be the most primitive. So why is glucose usually considered to be the the start of central metabolism and why is dietary fructose dangerous?

Fructose is too Reactive to Transport 
The first cells used fructose as the starting material to make the building block molecules of cells, e.g. carbs, proteins, fats, nucleic acids, and energy in the form of ATP. Multicellular organisms, such as animals and plants had to move sugars from cell to cell. It would be obvious to transport fructose, since all other molecules could be converted into fructose, but the problem is that fructose is too chemically reactive, i.e. it reacts with proteins to form AGE. It is for that reason that fructose is converted by cells into glucose, which is less than one tenth as chemically reactive. In plants, the reactive groups of glucose and fructose are bonded together to produce sucrose, table sugar, which is much less reactive and can be transported in plant vessels at very high concentrations.

High Blood Sugar is Bad, High Fructose is Worse (AGE-ing) 
High levels of blood sugar, glucose, react with proteins to produce advanced glycation end products, AGE. Fructose in the blood produces these inflammatory compounds more than ten times faster. That is why fructose is a bad sweetener for diabetics. Eating fructose, e.g. agave syrup or sucrose, doesn't directly raise blood sugar/glucose levels, since it raises blood fructose levels, which is worse.

Fructose Fattens Livers 
Fructose is rapidly absorbed in the intestines and transported to the liver. The blood vessels of the liver remove fructose from the blood and it is rapidly converted into fat. Fructose in sweeteners has now surpassed alcohol as the major source of liver disease.

Sweeteners
Fructose is ten times sweeter than glucose, and that is why cheap forms of glucose, such as corn syrup, are treated with enzymes to convert some of their glucose into fructose to produce high fructose corn syrup. Corn syrup is not as sweet as pure glucose, because the syrup contains a mixture of short chains of glucose of different lengths, and the chains decrease in sweetness with length. By changing some of the glucose into fructose, the HFCS can be made as sweet as table sugar, sucrose. Corn subsidies keep corn syrup cheap and make HFCS very profitable. Unfortunately, the HFCS contains fructose and therefore it has the liver toxicity and AGE-forming inflammation of fructose.  Agave syrup is like HFCS on steroids.

Agave Syrup is Fructose 
Agave syrup contains fructose produced by industrial processing of the fructose polysaccharides, inulin, in agave extracts. I cannot understand why anyone would use this commercially processed fructose as a sweetener. It doesn't raise blood sugar as much as sucrose, because there is much more fructose than sugar (like very high fructose corn syrup) it raises blood fructose levels instead, which is much, much worse.

Sugar Makes You Hungry 
The human body can only use simple sugars, e.g. glucose, fructose, sucrose, or starch. Body enzymes convert sucrose into fructose + glucose, and starch into glucose. Other carbs, such as soluble fiber, are only digested by gut bacteria in the colon. The conversion of starches to glucose begins with enzymes in saliva in the mouth and is completed in the upper part of the digestive tract. Starch should be considered as a simple sugar, because it causes a rapid rise in blood sugar, just like glucose. It may actually be faster than table sugar. The rapid rise of blood sugar causes a rapid increase in blood insulin, which in turn rapidly removes sugar into fat cells. The rapid rise and fall of blood sugar provides the experience of hunger. That is why cereal, e.g. oat meal, in the morning produces intense hunger just a few hours later. Actually, oat meal is not quite as unhealthy as most cereals, because it also has some soluble fiber to feed gut flora. A protein and fat breakfast, e.g. bacon and eggs, does not produce rapid hunger, because it does not produce a large insulin rise and glucose fall.

Insulin Resistance is Better than Death by Glucose 
As fat cells accumulate glucose as a result of blood sugar transported into the cells in response to insulin, more and more of the glucose is converted into fructose and on to pyruvate. The pyruvate accumulates in mitochondria and ATP production is saturated. This is potentially lethal for the cells, because the conversion of pyruvate into ATP is accomplished by removing high energy electrons as the pyruvate is converted to carbon dioxide. The high energy electrons accumulate in the inner membranes of the mitochondria and if they are not systematically converted to low energy electrons and dumped onto oxygen to produce water, reactive oxygen species, ROS are produced and the result is inflammatory oxidative stress. Antioxidants would be needed to protect from major cellular and organ damage. The cells protect themselves by responding to the accumulation of high energy electrons on the mitochondria by shutting down the response to insulin and blocking further intracellular glucose accumulation. This is insulin resistance.

Carbs: Never too Low 
Dietary carbs, such as sugars and starches are not needed, because the liver can convert protein into glucose. Thus, diabetics, who have a hard time balancing their dietary intake of carbs with the insulin that they inject, can simplify the process by routinely eating less carbs spread through many meals and triggering some glucose production by the liver. Craving for carbohydrates/sweets can be dramatically reduced simply by eating fewer carbs and avoiding insulin production that can lead to more dramatic swings of blood sugars and hunger. Using this strategy, I am hungry less than once a week.

Healthfulness of Sweeteners 
 --from Most Healthy....

• Stevia - is a diterpene glycoside (I previously made the silly error of listing it as a protein) (erythritol, another simple sugar alcohol is added to make the stevia granular) that is sweet, doesn't raise blood sugar, no insulin spike and no AGE 
• Glucose - raises blood sugar, spikes insulin and produces AGE 
• Xylitol - is a sugar alcohol that inhibits dental bacteria, doesn't raise blood sugar, no insulin spike or AGE 
• Corn Syrup - raises blood sugar, spikes insulin, produces AGE, low sweetness  
• Sucrose - raises blood sugar, spikes insulin and produces AGE, and liver damage 
• Honey - is half fructose and half glucose, raises blood sugar, spikes insulin, produces high AGE and may damage liver  

• Artificial Sweeteners, aspartame, sucralose, saccharin, etc. - don't raise blood sugar or produce AGE, but may have other risks, including hunger 

• HFCS - is high fructose corn syrup, raises blood sugar and spikes insulin, produces very high AGE and causes liver damage 
• Fructose - doesn't raise blood sugar or spike insulin, produces very high AGE and causes liver damage,  does not produce satiety and may encourage consumption of other sugars 
• Agave Nectar - is mostly fructose, doesn't raise blood sugar or spike insulin, produces very high AGE and causes liver damage 

 ...to Least Healthy or Health Risk--

Phytochemicals, Natural Antibiotics and Antioxidants

Plants are mean and sneaky.  They are natural organic chemists and make the nastiest toxins on earth.  Never trust a plant.  Eat them at your peril… or because they taste good.

Phytoalexins

Plants are Fast and Lethal

I was shocked when people started to laud the virtues of phytochemicals.  I thought that they must have alkaloid poisoning.  My PhD training involved separating and measuring the antifungal chemicals produced by soybean cotyledons exposed to the wall polysaccharides of a pathogenic fungus.  The plants would go crazy and produce a witch’s brew of toxins to provide protection from the fungus.  I eventually wrote a chapter on these toxic natural antibiotics, phytoalexins, for the Encyclopedia of Science and Engineering.  All plants produce these chemicals and as one might expect, seeds/nuts are provided with special protection to avoid being digested.

Lignin

Plants are Natural Chemical Killers

I developed a profound respect for the ability of plants to protect themselves.  Fungal spores germinate on the surface of leaves and their slender, threadlike hyphae attach and glue themselves to the waxy outer surface and then forcefully and enzymatically penetrate to the spongy cells below.  When the tip of the hypha touches the wall of the underlying cell, the plant nucleus lurches as its cytoskeleton reorients.  The surrounding plant cells respond in sympathy and all of these neighbors mobilize their biochemical processes to kill everything in their vicinity.  In a few hours, the plant chemicals kill the cells producing them along with the pathogen, and would continue to kill more and more of the leaf, but plant cell walls also contain enzymes that convert the phytoalexins to more wall material, lignin, and protect cells outside of the influence of the fungus.  As lignin in wood and plant litter is slowly degraded by microorganisms, it forms humus, the natural organic material in compost and soil, and also releases a potpourri of potent plant phenolics like BPA.  Compost is also a rich source of cell wall polysaccharides, a.k.a. soluble fiber, that feeds soil bacteria.

Phytochemicals are Natural Antibiotics

Most phytochemicals have evolved in plants as pathogen or herbivore defenses.  Since the nervous system is adapted to detect other organisms, it is not surprising that plants target the sensory system, brain and nerves of herbivores, and we detect the flavor and smell of plants/herbs/spices by their defensive molecules.  All of the flavor and taste components of herbs and spices are phytochemicals that kill bacteria, fungi and other pathogens.  Nicotine and caffeine are insecticides.  A detailed, worldwide study showed that spices are used in specific global areas, because of the local availability of the spices and their effectiveness against local food storage pathogens.  People develop a taste for the plant defensive chemicals that they must be exposed to for sustenance.  Cuisine represents a knife edge that separates attractive stimulation from death.  Natural or organic does not mean safe or healthy.  Plants are as dangerous to eat as pufferfish.

Phytoalexins are Useful, but Be Very Careful

Perfume Ingredients

If a grape notices a nearby fungal pathogen, it produces its phytoalexins, including resveritrol, which is a notable “antioxidant” that has been recognized as contributing to longevity.  People are encouraged to drink red wine for the health benefits of its phytoalexins.  Most of the pharmaceuticals derived from plants are phytoalexins in disguise.  Of course, the evolutionary origins of phytoalexins as natural broad spectrum antibiotics, makes it no surprise that phytoalexins are commonly toxic, carcinogenic and very dangerous to fetuses.  Morning sickness has been explained as nature’s way of telling a mother carrying a vulnerable fetus to not eat plants and potentially phytoalexins.  It is wise for women to avoid plants, perfumes and essential oils during their first trimester.  Essential oils are phytoalexin extracts from plants and many of these components are the essence of perfumes.  These same chemicals, e.g. limonene, serve dual purposes as fragrances and paint strippers, recreational drugs and insecticides.  We can smell these natural plant chemicals, because they are attacking our nervous system.  Multipurpose mixtures of essential oils, such as Vick’s Vaporub, contain menthol, camphor, eucalyptus oil and terpentine that kill bacteria and fungi (toe nail fungus) and also stimulate cold/hot sensing nerves in the skin, which triggers endorphin production and reduces underlying joint inflammation.

Fruits are Fake Seduction

Fructose is fruit sugar.  That is very appropriate.  Fructose derivatives are the most central intermediates of central metabolism, glycolysis; glucose is immediately converted to fructose after it enters a cell as the fundamental source of energy and carbon building blocks.  Fructose is not normally transported in plants or animals, because it is too chemically reactive and toxic.  It rapidly bonds and crosslinks proteins and is ten times worse than glucose in forming AGE (advanced glycation end products) such as hemoglobin A1C.  If you feed fructose to cattle, it makes their meat tough by cross linking protein fibers and it does the same thing to human skin.  Fructose in fruit is a fake, because it is cheap and sweet.  Animals eat fruit hoping to find starch, which is the only polysaccharide that animals can convert to glucose with their own (not bacterial gut flora) enzymes.  Starch quickly becomes sweet, because amylase in saliva digests the long chains of glucose molecules of starch into shorter dextrins that trigger sweet sensors in the tongue.  Fructose masquerades as starch by binding to sweet sensors a hundred times more strongly than dextrins.  The evolutionary advantage to using fructose to make plants sweet is that it takes much less energy and carbon, and it also poisons insects and microorganisms.  That is why honey is made of equal amounts of fructose and glucose, rather than sucrose, for example.  Fructose in high concentrations is toxic to microorganisms and honey can be used to dress wounds.  I can’t understand why fruits, especially juices, are recommended as part of a nutritional diet.  At best, fruit should be converted into juice.  The juice should be discarded and the pulp eaten as a source of soluble fiber, pectin, to feed gut flora. 

Phytochemicals Must be Detoxified to be Edible

Bacterial and fungal pathogens must avoid detection by plants to avoid death by phytoalexins.  Insects, similarly must avoid preformed phytochemicals that would kill or poison them with their first bite.  Pathogens and pests that are effective on one species of plant cannot eat others with different chemical defenses; plants and their pests/pathogens are mutually adapted.  Primates browse on new shoots of many different types of plants, to avoid building up lethal doses of particular phytochemicals.  The same is true of humans, who also have intestines and livers that chemically treat and neutralize plant toxins.  These same human defenses determine the rate at which other related chemicals, i.e. pharmaceuticals, most of which are derived from phytoalexins, are transformed and excreted.  Turmeric contains curcumin, which is the most potent inhibitor of inflammation yet identified.  Unfortunately, curcumin is “detoxified” in the intestine and large amounts must be eaten to suppress inflammation.  Fortunately, pepper contains another phytoalexin, piperine, which inhibits the detox system, so that most cuisines that use turmeric combine it with black pepper.

Trade Your Liver for Vegetables

The liver is the only organ that can be continually regenerated and that is because humans have evolved to eat plants, and phytoalexins take their toll on the liver.  As plants are digested and absorbed in the small intestines and transported to the liver, phytoalexins accompany the nutrients.  Most of the phytochemicals are chemically detoxified by liver enzymes, but the phytoalexins kill some liver cells with each meal and some of the phytoalexins circulate in the blood and reach other tissues.  The phytoalexins are evolutionarily adapted to bind to proteins to disrupt essential enzymes of microorganisms and herbivores, and like pharmaceuticals to which they are chemically and functionally related, they have numerous side effects.  The chemical reactivity is what is detected as the “antioxidant” property of phytoalexins.  Antioxidant is nutritionally meaningless and basically reflects the chemical toxicity of phytochemicals.  After all, you can’t easily sell chemicals that are inherently toxic.  Meat and humans are made of the same easily digestible stuff, i.e. protein, fat, plus indigestible polysaccharides in connective tissue, i.e. chondroitin sulfate and heparan sulfate.  Plants are essentially anti-human and are made of protein, vegetable oils (omega-6), digestible starch, undigestible cell wall polysaccharides, undigestible lignin and toxic phytoalexins.  Humans have adapted to eating plants with liver enzymes, liver regeneration, gut flora (to eat otherwise indigestible polysaccharides, soluble fiber to produce short chain fatty acids) and elaborate cultural habits.  We avoid most plants as too toxic and have domesticated some to produce reduced and tolerable levels of phytochemicals.  Of course this also means that the domesticated, defanged crop plants have a hard time defending themselves and we have to continually worry about blights and pestilences, and end up applying our own witch’s brew of fungicides, pesticides, and herbicides.

Polyphenols and Hormesis
I am going to add a few comments on the benefits of phytochemical "antioxidants", a.k.a. polyphenols, to clarify what I think is a misuse of the term "hormesis", which I thought meant the dilution of a toxin until it reached a magic lower concentration which was beneficial.  The trade offs of phytochemicals are nicely discussed by the Whole Health Source blogger, Dr. Stephan Guyenet.  I just don't think that the benefit of toxic chemicals stimulating the body's own antioxidant arsenal is an example of hormesis.  The point is that phytochemicals always act as toxins and stimulate toxin defenses.  Phytochemicals don't act as anti-oxidants in the body, even though they stimulate antioxidant defenses at all concentrations.  They provide a dubious benefit of unnecessarily heightening defenses with concomitant energy expenditure at low amounts and net damage at higher amounts.

Hakuna Matata and Sip the Tea

Tea Fanatic

I seem to have painted a compromising picture of plants as less than the perfect food.  They are tough and potentially toxic.  Plants clearly don’t like to be eaten and the best that can come of eaten plants is a full belly and a damaged liver.  But if you cook or ferment the plants first and bacteria start to digest and dull the chemical arsenal, plants can be safely and perhaps even enjoyably eaten.  We need not eat just safe meat.  We can also kick back and sip the tea.

Diabetic Hypertension, Browning of the Arteries

...View all 190 posts...

I decorated a flan with a drizzle of honey, and my torch produced a toasted spiral.  That was just fructose plus proteins, with a little heat, to produce advanced glycation end products (AGE) that are brown.  If you prefer, you can do the same reaction with egg whites and sugar in meringues, or by grilling brined pork chops basted with honey and anchovy paste.  Fructose is 10X better than other sugars at producing glycation, AGE and browning.

AGE and Arteries

Why do we care about the Maillard reaction and advanced glycation end products (AGEs)?  Of course, understanding the biochemistry of cooking is inherently satisfying and it helps to explain why Dr. House used vinegar to stop meatballs from browning too fast in his cooking class, but it also explains what’s cooking in atherosclerosis, cardiovascular disease.  It turns out that AGEs are highly inflammatory and inflammation of arteries leads to plaque formation.  [LDL is less important, because it only aggravates the primary event, inflammation, and that is why fish oil is more helpful for cardiovascular disease than statins.]  So increasing blood sugar is a problem, because it increases the rate of the Maillard reaction in binding blood sugar to the amino acids of proteins, such as hemoglobin to produce HgA1C, and causing vessel inflammation.  AGE in small capillaries also kills the capillaries and causes a rise in blood pressure by making harder for the heart to force blood from arteries to veins.  AGE causes hypertension and that is why salt consumption is not as important.   High blood sugar also increases the level of another powerful glycation agent, methylglyoxal, the active antibacterial agent in Manuka honey.  Honey is effective as a wound dressing, because it AGEs microbes to death!

The Trouble with AGE-ing is Inflammation

Cells detect the presence of AGEs with a surface Receptor for AGE (RAGE).  Binding of AGE to RAGE turns on the inflammation transcription factor, NFkB, with the release of inflammatory cytokines and the symptoms of inflammation.  One of my students did some computational protein modeling of the RAGE, because I was interested to see if RAGE would also bind Metformin.  Sure enough, our hunch was confirmed, indicating that Metformin might also reduce some forms of inflammation and be a treatment for diabetic high blood pressure.

Fructose vs. Inulin; AGE vs. Soluble Fiber

Fructose and the storage polymer of fructose, inulin, are similar to glucose and the storage polymer of glucose, starch.  The polysaccharides, inulin and starch can be converted to the sugars, fructose or glucose by industrial heating or enzymes.  Thus, agave inulin is converted into nectar, and corn starch is converted into syrup.  The polysaccharides are not sweet, but the sugars are.  The polysaccharides don't form AGEs with amino acids (unless they are broken up by high heat into sugars first) and fructose is 10X more chemically aggressive in forming AGEs than glucose.  Agave nectar (fructose) is a better browner than honey or high fructose corn syrup (corn syrup treated with a commercial enzyme to convert some of the glucose into sweeter fructose.)  Both inulin and some forms of starch (resistant starch), reach the colon and are digested by gut flora, i.e. they are soluble (fermentable) fiber.  The gut flora convert the resistant starch into short chain fatty acids that are anti-inflammatory.  Typical starch, e.g. corn starch or wheat flour, is digested by gut enzymes and goes directly into the blood as glucose, it is high glycemic and never reaches the gut flora.

AGE in Food

Should we fear browned foods as inflammatory.  I don't think that AGE in foods is any more of a hazard than all of the toxic phytochemicals that are touted as plant antioxidants.  I think that the gut and liver provide protection.  I brown the sugar on my flans and sear my steaks, even as I relish eating my veggies.  The body can detox these natural products in the gut better than it can handle the AGE made by high blood sugars.

Take Home Messages:

• Sugars in baked goods or blood, react with amino acids or proteins to make inflammatory AGEs.
• Blood sugar tests only measure glucose and ignore fructose, which is even more unhealthy.  So, foods laced with fructose can be low glycemic, but very unhealthy.
• The major AGE in blood is HgA1C.
• Diabetics have more stable, lower blood sugar on low carb diets, e.g. my Anti-Inflammatory Diet.  The liver produces needed blood sugar from protein.
• Diabetic use of fructose or agave nectar or honey encourages AGE, inflammation and diseases of diabetes.
• Starch (not RS) is the only polysaccharide digested by gut enzymes and is high glycemic.
• AGE is inflammatory leading to artery plaque and hypertension.
• AGE as browned foods are probably tolerated by the body.

HELLP, Preeclampsia, Antiphospholipid Antibodies and Basic Triplets

—-the other 200 posts —-

Clotted RBCs in Capillary

Some of my research involves the unique properties of milk and the development of the immune system, so I talk to medical people, lactation researchers and occasionally discuss the control of inflammation involved in ovulation, fertilization, implantation, gestation, labor and lactation.  It is clear to me that there are a few trends in disruption of these pregnancy processes resulting from the modern increase in inflammation and gut-related problems linked with immune tolerance.  Infertility is increasing, because women are becoming more chronically inflamed.  Miscarriages and premature births/low birth weight are increasing, because chronic inflammation enhances labor.  Pre-eclampsia (high blood pressure and protein leaking into the urine) results from chronic inflammation and omega-3 fatty acid depletion.  Now an even scarier form of pre-eclampsia, HELLP (Hemolysis, Elevated Liver enzymes, Low Platelets) is on the rise.  I want to discuss HELLP to put all of these pregnancy-related problems into perspective.

HELLP, Cause and Cure Unknown?

HELLP is an autoimmune disease and I have repeatedly discussed the cause of autoimmune diseases:  1) inflammation, 2) deficiency of Tregs (immune tolerance) and 3) antigen basic triplets (antigen presentation).  When HELLP was recently brought to my attention with a sudden rise in local hospitals, I decided to see if it could be easily explained and cured, just by examining the available medical literature.  Wikipedia indicated that the cause and cure was not known and that was confirmed by local doctors, who just treat the symptoms by early deliveries and long stays for the babies in neonatal intensive care units.  My work was cut out for me.

Autoimmune Disease with Unknown Autoantigen 

An examination of the symptoms, rupture of blood cells (fibrin production), liver damage, clotting (low serum heparin), high blood pressure (capillary apoptosis), proteinuria (low heparan sulfate (HS) to prevent protein loss), pointed to some obvious treatments and the causes.  Infertility is often treated by in vitro fertilization/insemination, supported with aspirin and heparin injections to maintain gestation.  These treatments are consistent with high levels of chronic inflammation that block implantation and stimulate labor.  Infertility is also associated with antiphospholipid antibodies.  A closer look at the antiphospholipid antibodies showed that they were directed against β₂-glycoprotein-I.  So, I expected the β₂-glycoprotein-I protein to be the original target for the antibodies, the initiating antigen, but when I looked up the sequence of that protein, it lacked the expected basic triplet I have found in all  other autoantigens and allergens.  This meant to me that there was a different protein with a related sequence that started the HELLP autoimmune disease.

Attack on P-Selectin Starts Immune Autoimmunity

I checked for other proteins with related sequences and basic triplets (RKR in the carboxy terminal sequence below), and found P-selectin that is produced most abundantly in liver and on the surface of blood cells.  A quick search of the literature showed that P-selectin reacts with anti-phospholipid antibodies and has a pair of basic triplets that enhance immune presentation and make this protein a strong candidate for becoming an autoantigen.  Antibodies against P-selectin will cause clotting as seen in HELLP.

ref|NP_002996.2| P-selectin precursor [Homo sapiens]:

......carboxy terminalGTLLALLRKRFRQKDDGKCPLNPHSHLGTYGVFTNAAFDPSP

Antibiotics and Liver Damage

I suspect that HELLP is caused by a combination of liver damage and prior exposure to antibiotics (or common drugs that have antibiotic activity) that cause gut dysbiosis, i.e. loss of gut bacteria that stimulate development of the suppressive part of the immune system, e.g. deficiency in regulatory T cells, Tregs.  Examples of the type of liver damage that may lead to HELLP are excessive consumption of alcohol (alcoholic fatty liver) or high fructose corn syrup (non-alcoholic fatty liver).

HELLP from Cause to Cure

• Diet and/or infection causes liver inflammation.
• Antibiotics/drugs and/or processed foods lacking prebiotic fiber produce gut dysbiosis.
• Lack of gut bacteria needed for development of the immune system in the gut produces a deficiency of Tregs and dysfunction of immune tolerance.
• Liver inflammation, deficiency of Tregs and availability of antigens with basic triplets leads to antibodies against liver proteins.
• Chronic inflammation leads to decrease in HS production and leaky kidneys/proteinuria.
• Chronic inflammation/liver damage produces fibrin production.
• Fibrin production and low HS enhances clotting and leads to apoptosis/cell death in capillaries.
• Loss of capillaries leads to high blood pressure.
• Cure of HELLP, anti-phospholipid antibodies and pre-ecampsia, involves lowering chronic inflammation (aspirin and heparin treatment) with an Anti-Inflammatory Diet, fixing vitamin D deficiency, increasing omega 3/6 ratio,  and repairing gut dysbiosis to fix immune tolerance.
• Without these interventions, HELLP symptoms will become more severe, especially in subsequent pregnancies and additional autoimmune diseases will develop.

Diet, Nutrition and Health

These are my generalizations (some would say prejudices) from 40 years of experience in plant biochemistry and molecular biology:

Plant Secondary Compounds Are Defensive and Toxic

The development of plant secondary compounds (all of the compounds that are not part of metabolism or structures) is in response to pathogens, herbivores and pollinator/disseminator attractants -- development of these compounds has nothing to do with humans. Examples: Nicotine and caffeine are very toxic to herbivores and are present in plants for protection. Humans learn to play with toxic plant chemicals, just as they have learned to play with fire and explosives.

Plants Are Not There For Us

People have learned to exploit local plants for protection against local human pathogens, but there is no selective advantage to plants (except for domesticated plants) for useful plants to grow near humans. This logic would suggest that rats and mosquitoes, that flourish near human habitations, are there because of their human utility. Human live near places were useful plants grow.

Grains Are Unhealthy

One of the biggest problems with food processing is separating the inflammatory parts = starch and omega-6 oils, from the nutritive parts, the so-called anti-oxidants, vitamins, proteins, etc. Grains, even so-called whole grains, are simply too enriched for starch and inflammatory oils to be healthy. They are not safe to eat in large amounts. Leafy plant parts are healthy, but even those parts are not good in large amounts from a single plant species. Humans are browsers, because the plant secondary compounds are uniformly toxic, but can be tolerated better in a mixture of different toxicities.

Starch Is Inflammatory

Starchy foods should be treated like a fish. The starch should be pared away and discarded, like the fish gut and bones. (The guts and bones could actually be processed to make them nutritious. Not so with the starch. The starch should be fermented.) The potato skin should be eaten and the rest discarded, just as an aphid secretes as honey dew the extra sugar it sucks in from a plant leaf.

Cereals Are Inflammatory

Breakfast cereals are a dietary abomination. They contribute immensely to obesity, inflammation and chronic disease. Oatmeal for cardiovascular health is a total fraud. The fiber might be useful, but the high starch causes cardiovascular disease. Grains/cereal are the foundation of the chronic disease pyramid.

Fructose is Toxic

Fruit juices are another fraud. The juice (fructose) should be removed and discarded. The fructose is very unhealthy. Mice are given type II diabetes for research purposes by feeding them fructose (especially high fructose corn syrup.) Fructose is avoided in the beef industry, because it causes rapid cross-linking of collagen and leads to tough meat. The same thing happens in humans who eat fructose, it causes aging of the skin and other tissues. High fructose corn syrup is a commercial addiction -- it is hugely profitable as a sweetener -- and that is why it is still used, even though it is grossly unhealthy. It will eventually be removed from the market after the industry is protected from subsequent law suits. It is equivalent to the tobacco industry -- too lucrative to eliminate.

Phytic Acid

The active ingredient in fiber that provides its benefits is phytic acid, the same chemical that people are trying to eliminate. Phytic acid acts as a chelator. I don't think it is actually a problem. The problem comes from extracting cations from the phytic acid before it is eaten. Phytic acid should go in saturated, so that it doesn't contribute to deficiencies. The actual problem is that the diet is already low in minerals, because of eating processed foods that are mineral deficient.

Enzymatic Detoxification: P450, Glycosylation and Secretion

Humans are adapted to plant secondary metabolites by the abiltiy to enzymatically detoxify [using p450 and glycosylating (adding glucuronic acid)] and secrete the toxic compounds. These chemical modifications that occur in the intestines and liver are usually effect. They also work on drugs and that is how we eventually clear these compounds from our systems. Grapefruit and black pepper inactivate these enzymes and alter the way we metabolize plant toxins and drugs. The detox enzymes can also convert innocuous compounds into toxins and carcinogens. That conversion is the basis for using liver enzymes in the Ames Test for carcinogens. The activity of the enzymes is dependent on recent diet, so it would make sense to gradually change the amount and type of vegetables that are eaten in a meal to permit the detox system to adjust.

Glucose and Insulin Cause Fat Accumulation

Fat accumulation is dependent on dietary carbohydrates and insulin. Fat and serum lipids accumulates with a high carbohydrate diet and decrease on a low carbohydrate diet. This is more important than the number of calories consumed.

Inflammation Not Serum Lipids Cause CVD: Statin Are Unnecessary

Inflammation is the source of chronic degenerative diseases. Serum lipids are only secondary factors. Statins lower serum lipids, but do not impact cardiovascular health unless they also lower inflammation. Lowering inflammation lowers serum lipids and decreases cardiovascular disease. Statins appear to be a very expensive way of treating cardiovascular disease dependent on their side effect on inflammation. Modest dietary and lifestyle changes are much more effective, cheap and safe than statins.

Honey, Hydrophobicity and Biofilms

A reader (Jay Bryant) recently pointed out a PNAS article on the structure of a bacterial enzyme that uses sucrose to make the glucan matrix of dental biofilms.  This article released a cascade of associations in my mind and illustrated why honey does not contribute to dental plaques, but is antimicrobial and aids wound healing.  People forget that sugars combine both hydrophilic and hydrophobic properties, and thereby act as soaps.

The starting point of the chemical versatility of carbohydrates is the inability of the central portion of a sugar ring structure to form hydrogen bonds.  Each sugar is made of  a linear chain of carbon atoms with each carbon linked also to a hydrogen and a hydroxyl.  Only the hydroxyl can participate in hydrogen bonds, so each carbon has a hydrophilic side (bonds with water to make hydrogen bonds) and a hydrophobic side (that makes van der Waals bonds with other hydrophobic molecules.)  The sugars circularize and the rings have faces that are predominantly hydrophobic and perimeters with hydroxyls that are hydrophilic.  Polysaccharides (long chains of sugars), such as cellulose, can sometimes form long fibers that form a hydrophobic context for hydrogen bonds between the hydroxyls of adjacent polymers.  These cellulose fibers are very resistant to chemical or biological attack and accumulate as the most abundant biological molecules on Earth.

The PNAS article provides another example of how protein enzymes interact with carbohydrates, in this case sucrose and a polymer of glucose.  Typical weak bonds between the amino acid residues of proteins and other molecules are hydrogen, ionic or van der Waals bonds with energies of a couple of kcals/mol.  In contrast, the bonding of the hydrophobic face of a sugar to the hydrophobic face of an hydrophobic amino acid, e.g. tryptophan, phenylalanine, histidine, lysine or arginine, releases more than ten kcals/mol of energy.  Thus, the structure of the bacterial enzyme that makes biofilm glucan chains from dietary sucrose, the sucrose is bound to the enzyme on the face of a prominent tryptophan.  Examination of enzymes that bind to polysaccharides will show a series of tryptophans arrayed across the surface of the enzymes with spacing appropriate to bind to the individual sugars of the polysaccharide.

Biofilms are communities of multiple species of bacteria held together by a polysaccharide matrix.  In the case of dental plaque, the polysaccharide is made of glucose links, whereas many other matrix polysaccharides are negatively charged and held together by positively charged metal ions.  The bacteria bind to the polysaccharides using protein receptors that exploit the display of hydrophobic binding sites of the polysaccharides.  It takes energy to make polysaccharides and the dental plaque bacteria use the energy already expended in the formation of sucrose to produce a polymer of glucose, an alpha-glucan, and free fructose.  Thus, sucrose is essential in forming this type of biofilm and without this sugar, the dental plaque cannot form.  Milk lactose, or glucose would be a more appropriate sweetener.  Unfortunately, high fructose corn syrup would be a poor substitute, because of the high liver toxicity of the fructose (it causes fatty liver, just like alcohol) and very high activity in forming advanced glycation end products (AGEs), which contribute to the symptoms of  diabetics.

Honey seems to be magical, because at low concentrations the sugars present in honey  (mostly glucose and fructose, and not sucrose) are nutrients for bacteria, but at high concentrations honey is anti-bacterial and useful as a wound treatment.  I think that the explanation for its antimicrobial activity is that sugars are amphipathic, that is they have both hydrophilic and hydrophobic properties, just like soap, and at high concentrations they kill bacteria, just as soaps at high concentrations kill bacteria.  In fact, the gentle soaplike properties of sugars are exploited experimentally to dissolve proteins that are normally embedded in cellular membranes.  This explanation predicts that corn syrup, which can also be used to form very stable soap bubbles, should also be useful in wound healing.

Frankincense and Myrrh, Terpenoids

 --- the other 200 posts ---

Frankencense Resin

 'Tis the season to discuss phytochemicals.  Plants produce a vast array of organic chemicals starting from molecules produced by all organisms, including humans.  Essentially all of these phytochemicals are potent adaptations to kill.  Phytochemicals kill plant pathogens, bacteria and fungi, as well as insects.  Thus, the natural, plant extracts that humans use for flavor enhancers (herbs, spices, and teas), fragrances, recreational/medicinal mind and attitude modifiers (alkaloids, psychopharmaceuticals, etc.), herbal medicines, etc. are present in plants, first and foremost, as antibiotics and insecticides.  Humans have evolved to taste (bitter) and smell phytochemicals to avoid their toxicity, and have adapted culturally to exploit the impact of phytochemicals on body and mind.  In this seasonal post, I focus on the terpenoids in Frankincense and Myrrh, to explore how plant biochemistry contributed to the gifts of the Magi.

It All Starts with Central Metabolism

Phytochemicals are complicated plant chemicals that are produced by a series of enzyme-controlled reactions (Central Metabolism) from the array of chemicals used by plants to convert photosynthetic carbohydrates (fructose and glucose) into the molecules (sugars, amino acids, fatty acids, nucleic acids) used to make the macromolecules of cells (polysaccharides, proteins, fats, DNA/RNA).  Alkaloids and phenolics, e.g. phytoalexins, are made from amino acids (phenylalanine) and terpenoids are made from fatty acids (acetyl CoA/Mevalonate) or other intermediates in glycolysis.  Thus, central metabolism that converts glucose/fructose into pyruvate and the acetyl CoA (see mevalonate pathway left) of mitochondrial fatty acid metabolism, is further converted into amino acids and plant secondary compounds, phytochemicals.  I am going to talk mainly about terpenoids in Frankincense (triterpenoid Boswellic acids) and Myrrh, and many related molecules (steroids) also produced by humans.  

The major thesis here is that carbon dioxide is converted by photosynthesis into either sugars used to build the cell wall polysaccharides (soluble fiber) or larger toxic defensive chemicals, e.g. phytoalexins, resins, essential oils or lignin.  Phytoalexins, e.g. the natural antibiotic resveratrol in wine, are made from phenylalanine along the same biochemical pathway used to produce lignin.  Glyphosate, the herbicide, kills by blocking this unique plant pathway.  Essential oils and resins are another group of natural antibiotics produced by converting acetyl CoA into a five carbon unit, IPP, which is then linked into larger and larger (10, 15, 20 carbons) molecules, terpenoids, that can rearrange into multiple ring structures.  Only the smallest chemicals in the series evaporate to provide identifiable smells, e.g. Frankincense and Myrrh, while larger forms, e.g. cholesterol or testosterone in animals, are odorless solids.

Acetyl CoA to IPP

IPP

For those who enjoy the beauty of biochemistry:  The most abundant enzyme on earth is RibisCo (ribulose bisphosphate carboxylase), the plant enzyme that combines carbon dioxide from air with a five-carbon phosphorylated sugar, ribulose bisphosphate, to produce two, three-carbon intermediates of glycolysis that can be converted into glucose or into acetyl CoA, the starting chemical for fatty acids, the mitochondrial TCA cycle, or via mevalonic acid to isopentanyl pyrophosphate (IPP), the building block for terpenoid synthesis.

In brief:  Photosynthesis uses the energy from sunlight to convert carbon dioxide into sugars (glucose and fructose).  Those sugars can be converted into a five-carbon, molecular building block for terpenoids, IPP.  IPP molecules can then be linked together to make increasingly longer chains and those chains can be ultimately twisted into rings to make resins in plants and steroids in humans.

Five, Ten, Fifteen, Thirty; IPP (5), GPP (10), Sesquiterpenoids (15), Triterpenoids (30)

Terpenoid Polymerization

Terpenoid synthesis begins with IPP, which has five carbons in a branched chain and has a pair of phosphates, pyrophosphate that provide the energy to form chains of 5, 10, 15, etc.  In plants, molecules of each of the incremental lengths are produced together and additional enzymes in different species of plants result in mixtures of molecules with different rings and functional groups.  The smaller molecules evaporate more readily, so that mixtures are extruded from damaged trees as oils and gradually form resins as the remaining larger molecules predominate and solidify.

Shark Livers and the Horn of Africa

IPP with five carbons, an isoprene, is used to make GPP with ten, a monoterpene.  Common monoterpenes are geranol and limonene that make the characteristic odors of geraniums and lemons. Sesquiterpenoids (15 carbons made from three IPPs) include the fragrance of patchouli. Diterpenes, such as sweet steviol, have twenty carbons, which can be chemically twisted into the chemicals that predominate in Myrrh resin, the Balm of Gileade.  The triterpenes with 30 carbons can be rearranged with five rings to form steroids, such as cholesterol in animals or Frankincense.  Linear squalene, is the major component in shark liver oil and provides the same function as a swim bladder in a boney fish.

Essential Oils Are Mixtures of Distilled Terpenoid and Phenylpropanoid Phytoalexins

Boswellic Acid

Phytoalexins and terpenoids have evolved as plant defenses against bacteria, fungi and insects, and they are toxic, because they interact aggressively with proteins through their chemical ring structures that are hydrophobic.  These ring structures make the smaller versions volatile and soluble in organic solvents.  Many of these chemicals have properties similar to petroleum products and may be used as solvents themselves, e.g. paint strippers or thinner.  Steam distillation of plants produces mixtures of phytoalexins and terpenoids commonly called essential oils, which contain the volatile components “essential” for the odor identity of a plant.

Statins Block Cholesterol Synthesis

Statins were identified among a group of fungal antibiotics for their ability to block an early enzyme (marked in the mevalonate pathway above) in the production of cholesterol.  The toxic side effects of statins derive from wholesale disruption of all of the essential pathways (everything below the inhibited enzyme) that are related to cholesterol, such as blood heme A found in hemoglobin, and ubiquinone (CoQ) found in mitochondrial electron transport and needed to reduce oxidative stress and glucose intolerance.  Thus, for these examples, statins would contribute to anemia and type II diabetes/metabolic syndrome.  The side effects are not surprising, since statins are fungal antibiotics that target pathways common to bacteria and human mitochondria.  It is also not surprising that statins have unpredictable impacts on gut flora and the immune system.

Anti-inflammatory Diet

Components of an Anti-inflammatory Diet (focus on meats, fish, eggs and leafy vegetables)
Note:  All food is unhealthy without gut bacteria adapted to the food.  See other posts on repair of gut flora.

• Low starch and other simple sugars -- insulin and high blood glucose are inflammatory; so use complex polysaccharides (not starch); starch only in small portions (1/2 banana or one side of a hamburger bun) and preferably in unprocessed, less available forms, e.g. coarse ground or fat coated -- bread with butter; less than 30 gm in any meal, less is healthier, grains are frequently a problem -- gluten intolerance
  
• No high fructose corn syrup -- high free fructose (in contrast to sucrose) is inflammatory and contributes to crosslinking of collagen fibers, which means prematurely aged skin; sucrose is much better than alternative sweeteners
• High ratio of omega-3 to omega-6 fats -- most vegetable oils (olive oil is the exception) are very high in omega-6 fats and are inflammatory and should be avoided; omega-3 fats from fish oil cannot have their full anti-inflammatory impact in the presence of vegetable oils; omega-3 supplements are needed to overcome existing inflammation -- take with saturated fats
  
• No trans fats -- all are inflammatory
• Probiotics and prebiotics -- the bacteria in your gut are vitally important in reducing inflammation; most of the bacteria that initially colonize breastfed babies and are also present in fermented products seem to be helpful; formula quickly converts baby gut bacteria to inflammatory species and should be avoided completely for as long as possible to permit the baby’s immune system to mature (at least 6 months exclusive breastfeeding.)
• Saturated fats are healthy and reduce the peroxidation of omega-3 fatty acids at sites of local  inflammation, e.g. fatty liver.  Saturated fats should be the major source of dietary calories.
• Vegetable antioxidants -- vegetables and fruits, along with coffee and chocolate supply very useful, anti-inflammatory anti-oxidants
• Sensible daily supplements: 1,000 mg vitamin C; 2,000-5,000 i.u vitamin D3 (to produce serum levels of 60ng/ml); 750 mg glucosamine
• Associated anti-inflammatory lifestyle components:

exercise (cardiovascular and muscle building),

minimizing body fat,

dental hygiene
vagal nerve stimulation

Last Week of the Eades Cure

Week 6 of The 6 Week Cure for the Middle-Aged Middle

It feels like I have established a new set point ten pounds lower than my start.  I dropped ten pounds easily in the first two weeks and then bounced around plus or minus two pounds for the next month.  The Cure is simple and effective.

The First Weeks of The Cure

The 6 Week Cure for the Middle-Aged Middle was written by Drs. Mary Dan and Michael Eades to efficiently lose abdominal visceral fat and tone the abs.  It starts with two weeks of three whey protein/cream/leucine shakes and one high fat/protein-low carb veggie meal per day.  This surprisingly tolerable regime (without all but essential medications, no alcohol and no grains) helps to reduce fatty liver and use up visceral fat around the abdominal organs.  I noticed the impact immediately and lost about a pound a day.  This also eliminated hunger and exposed snacking habits.

The Middle Weeks of The Cure

The second two weeks of The Cure permits occasional alcoholic beverages and three low carb meals per day, but without dairy.  That is basically meat/fish/eggs and low carb veggies for each meal.  Most calories were from fat rather than carbs.  Portion control became a new issue, but hunger was still not a problem.  The meals were very satisfying.  Energy for exercise returned, but weight loss ebbed.  It was harder to stay away from old snacking habits, since meals were back to a more normal pattern.

The Last Weeks of The Cure

During the last weeks of The Cure there is a final turn to what may be for some a new, low carb, higher fat eating style.  I chose The Cure, because I already knew that the eating philosophy of the Drs. Eades was consistent with my own anti-inflammatory diet and lifestyle.  I did not expect to be surprised by The Cure, but I was.  I learned a lot about my own eating habits.

Gut Flora Matter

I started The Cure, because I thought that the progression of dietary components would destabilize my gut flora and simultaneously destabilize my weight set point.  I anticipated that my gut flora would reorient, and they did.  There were all kinds of changes and some of the weight loss and gain was probably elimination of a pound of gut flora and reestablishment of a new bacterial order.  The new order also came with a lower body weight.

Hunger Comes with Carbs

For the first month of the diet, I was only hungry if I went longer than six hours without eating or if I slipped on the diet and introduced some extra carbs.  Straight protein early in the morning can cause an insulin rise and a blood sugar dip that leads to a little hypoglycemia, but it produces dullness, rather than hunger.  The only problem with the easy weight loss first two weeks, was that there was less energy with the protein shakes.

BMs Are Bacterial Motivated

The noticeable changes in bowel movements during The Cure, should have been expected, but they forced me to contemplate stools.  When I first realized the absurdity of eating breakfast cereals, because of their high carb/grain content, I went in search of alternative day-starters in other cultures.  At that time, I was still hesitant to embrace saturated fats, so I ran across salsas and stewed tomatoes.  The addition of stewed tomatoes to my breakfast (usually stewed tomatoes on a poached egg) made my gut happy and regular. 

The point in this context, is that my studies of BMs and constipation brought pectin to my attention again.  I had previously considered pectin (poly galacturonic acid) as a competitor for biofilm acidic polysaccharides, but in this context pectin is also recommended to aid the development of probiotic biofilms.  Thus, I added apples to The Cure, to help the establishment of a new bacterial order.  The rapid result was a return to a happy, regular gut.  This was the duh moment.  Apples = pectin, tomatoes = pectin, and pectin = happy gut flora.  Adding either apples or tomatoes to your diet can make your gut flora happy.  An apple (or tomato) a day keeps the antibiotics away.

The Cure Works

The Cure did what I expected and more.  My wife was also pleased with the rapid initial weight loss and an ongoing loss of about a pound per week.  The continued loss is due to alteration of diet with a further reduction in carbs.  The Cure makes the connection between weight retention and a high carb diet.  Elimination of grains/starch makes weight loss much easier.  Absence of sugar, high fructose corn syrup and other sources of fructose also makes weight loss easier.  The inclusion of saturated fats and elimination of omega-6 vegetable oils is anti-inflammatory and provides an improved sense of well being.  I recommend The Cure, because it simply works.