Abbreviations:    AD Alzheimer’s disease/dementia        ADA  American Diabetic Association   ATP adenosine triphosphate       BMJ British Medical Journal       CVD cardiovascular disease        CAWD conditions associated with the high sugar-fructose Western diet       CME continuing medical education     HSD high sugar diet    IR insulin resistance/resistant      KOL key opinion leader, a thought leader       LSP low-sugar populations/diet     MeS metabolic syndrome        NAFLD non-alcoholic fatty liver disease      NEJM New England Journal of Medicine       RAGE receptors for advanced glycation end-products    ROS reactive oxygen species      t1d type 1 diabetes    t2d type-two diabetes       TOFI  thin on outside fat on inside       Wiki Wikipedia

Mystery:  why peoples who eat life-long low-sugar (fructose) diet including their elderly have very low rates of the conditions associated with the Western diet (CAWD)?  Their diets vary widely thus conflicting with the standard list of major causes:  refined carbs, high protein/meat, high fat, high saturated fats, and sedentary lifestyle; but not sugar.  Where ever those LSPs switch to the Western diet, depending on amount of sugar, CAWD become over 90% of the causes of death and morbidity, a much different list is for the LSP.  A sophisticated analysis of a decade of data on sugar consumption for over 50 countries has been analyzed and it has firmly established the high-sugar diet is the cause for CAWD— refined carbs have a much weaker association. 

This leads to the second question and answer:  why is it that those with type 2 diabetes (t2d) have the same conditions of those on a high sugar diet (HSD), the only difference being the rate?   Answer, both are insulin resistance, differing only in degrees.  Elevated glucose is not the cause but a sign—see    Relying on the work of Joseph R. Kraft MD, there are 4 patterns of IR, the 4^th has progressed to t2d due to a fatty-inflamed pancreas which causes a decline in insulin production.  By using IR as its key marker, it becomes clear that the risk of the comorbidities is dependent upon the degree of IR, and IR is unknown among LSP thus they don’t have CAWD!  Using IR as the measure of risk, I would estimate that about 95%, of Americans are at significant risk for CAWD.  With IR as the marker for risk of CAWD, a light is shine on the chaos created by facts and theories.   What evolution is to nature, IR is to CAWD:  they illuminate their spheres.

What follows is based on publish research on the pathogenic mechanism caused by fructose that affects every cell in the body.  As Prof. Robert Lustig says, “Fructose is ethanol without the buzz.”  While some of you have heard that fructose is safe for diabetic because it doesn’t raise insulin, and that when managed with drugs sugar and refined carbs are safe according to the American Diabetic Association.  The American Heart Association approved for a fee Heart Healthy sticker on high sugar foods including fruit juices and sugar coated cereals.  Now following the World Health Organizations change in recommendations, sugar is to be limited to 6 teaspoons a day for women and 9 for men (24 and 36 grams) all sources.  This message has been buried is billions of dollars of advertising promoting high sugar manufactured foods.  Also buried is the questions about CAWD, the role of sugar, and the scientific evidence explain why fructose (on half of the sugar molecule) is toxic to some at above 20 grams a day, and nearly all at above 100 grams a day. 

Listen and attend my beloved (a phrase repeatedly used by Rudyard Kipling) and I shall the store of the high fructose—glucose is merely a bit actor. 

Terms not in common usage though of importance

TOFI:  thin on the outside, fat on the inside.  This refers to abdominal fat which is associated with MeS, NAFLD, IR, and CAWD.  I hold that it isn’t abdominal fat, but the subclass of fatty liver that is causal.  Fatty liver is strongly associated with IR and the consequences of excessive fructose damaging biological systems.  IR and fructose explain why those people who ate a western diet, even after changing their diet decades before, that most of them are still at risks for CAWD.

Diabesity:  ”used to refer to a form of diabetes that typically develops in later life and is associated with being obese.” Google --derived from the words diabetes & obesity.

Glycation/fructosylation: glycation is the random attachment of a sugar to a protein.  It is often used to refer to glucose bonding, but can include fructose and other common mono-saccharides, while fructosylation refers to the action of fructose.  

Bad pharma, tobacco ethics and tobaccos science, refers to an industry that puts profits before people, and marketing dressed as science, see Appendix ???

As an aide, I highly recommend that you print the outline page--LINK

Sucrose, a disaccharide of glucose and fructose.  Note the 5 member ring of fructose, the angle of the oxygen member of the ring is under greater stress because of it angle than the oxygen in the 6 member glucose ring, and this entails that the frequency of being in the open form (instead of ring) is significant greater for fructose.  In this open form, fructose to a greater extent than glucose react with a several amino acids on proteins in a process called either fructosylation or glycation.  Various source rate fructose as 7 to 10 more reactive than glucose.   Since 95% of fructose is metabolized in the liver, and it is delay while glucose is metabolized first, fructose is a net 20 times more reactive than glucose in the liver. 

Listen and attend my beloved (a phrase repeatedly used by Rudyard Kipling) and I shall tell the story of excess fructose—glucose is merely a bit actor. 

1. Evidence for Conditions Associated with the Western Diet (CAWD) --  an introductory ramble

    

a.    Conditions linked to RAGE  [receptors for advanced glycation end products].  They all are very rare among those on LSP; thus they are all CAWD!    This paper explains that it isn’t caused by glucose by the 10 times more reactive fructose which goes directly to the liver the only major tissue that can metabolize fructose, and which those on a western diet consume more than cellular receptors can repair, thereby damaging the liver to cause IR and other abnormalities that increase the risk for CAWD.

• Alzheimer's disease

• Arthritis^[14]

• Atherosclerosis

• Congestive heart failure

• Diabetic neuropathy

• Diabetic nephropathy

• Diabetic retinopathy

• Myocardial infarction [and other ischemic events including strokes]

• Peripheral vascular disease  [includes coronary heart disease]

• Psoriasis

• Rheumatoid Arthritis^[15]

• Takayasu's arteritis^[16

  Wikipedia (12/17)

  All of these are linked to CAWD, others have added cancer, insulin resistance, non-alcoholic fatty liver disease, dysregulation of the weight control system (weight gain), type-2 diabetes, most types of dementia, gout, acne, hypertension, strokes, varicose veins, palsy, macular degeneration, inflammatory bowel diseases, appendicitis, osteoarthritis and all other conditions not named above which are associated with t2d.  Compared to the low sugar populations (LSP), their rates are below 1/20^th the rate the rate of those on the western high sugar diet, and that includes cancer and CVD which were unknown among aboriginal Negroes, the Kitavans, and others before the introduction of highly portable sugar and refined grains.  Population evidence of a low sugar diet--LINK

  b.   Hyperglycemia, saturated fats, and cholesterol--the scapegoats:  sadly to say, industries intrusion has most researchers looking under the wrong tree for what has gone wrong, because pharma profits from illness and the food manufacturers profits from replacing whole foods with manufacture foods,  which are high in sugars to reach the bliss point.[1]  What we have is a situation in which in a fire-pump truck has a crew of 2 (fructose and glucose) known as the sucrose brothers, and one of them, fructose, is a pyromaniac, so instead they (pharma and food manufactures) pay the media, scientist for hire, politicians, and the medical and dietary associations to blame saturated fats and cholesterol for the fires of CAWD.  This “villain” fructose, along with his brother sucrose, is still in the fire station watching the news about the conflagration they started.  The building material cholesterol and saturated fats used to repair cell build cell walls, make hormones, insulate nerves, fuel for ATP, etc. is charged with the fires.  The repair workers, physicians and dieticians, are monitoring blood cholesterol, triglycerides, glucose, and glycated hemoglobin (HbA1c), and pharma pushes drugs that block the production of cholesterol and for diabetics, drugs that lower blood glucose by stuffing more into overloaded cells.  The industries are in bed with the sucrose brothers along with those whom they influence.  What follows are the mechanisms on fructose that causes IR, MeS, t2d, and CAWD.  Obviously, prevention of the fire is to reduce sugar; and in Section VII is on how to reverse NAFLD, IR and t2d by diet, and to allow the cells toasted in the fire to heal naturally.     

  c.   Basic explanation:  Fructose is one-half of the disaccharide sucrose--the other half is glucose. Fructose is quite different than sucrose because its pentose ring is less stable than glucose’s hexose ring:  fructose is a net 20 more reactive than glucose in the liver where fructose is metabolized.  On a high sugar diet there is a dual assault that damages the liver by accumulation of excess fat through de novo lipogenesis within the hepatocytes and stored in the liver’s adipocytes and by fructosylation.[2]  This assault of excessive storage of fat in the hepatocytes and the damage done to proteins by fructose attaching to proteins in the hepatocytes (fructosylation) overwhelms the liver’s cellular repair systems.  With the damage to the hepatocytes mitochondria (visible as deformation) which results in the underproduction of ATP  and because of the underproduction of ATP the energy molecule, there is reduction in the rate of cellular repair systems such as superoxide dismutase, MTOR, and others, and this results in the lower rate of replacement of collagen, increased sensitivity to the damage cause by uric acid, upsets the hormonal regulatory system that control appetite, metabolism, and from continued fructosylation to name the major contributors to CAWD.   This combination affects the hepatocytes ability to metabolize glucose and convert it to glycogen, thus the hepatocytes to avoid excessive glucose with its increased osmotic pressure become resistant to the uptake of more glucose.  In the liver insulin’s the transport of serum glucose is down regulated; this is known as insulin resistance (in the liver).  Eventually with the reduced liver function because of the damage to the hepatocytes for reasons needing further research the  other tissues become resistant, especially the myocytes and the adipocytes (the major users of glucose, along with the brain). 

  Excess fructose is part of a vicious cycle, on a high carb diet it lipogenesis is increased, because the glucose has supplied sufficient ATP, so it is conversion to fat is increased compared to a meal lower in carbs.  Also a product of fructose metabolism is uric acid.  Fructose this is both very lipogenic and is a major source for the sharp uric acid microcrystals.  For now remember that long-term excess fructose is comparable to excess long-term ethanol drinking, but worse.  Worse because  downstream from liver damage and IR are further changes including the under production of collagens, cellular ROS, kidney damage, endothelial dysfunction, glycation and fructosylation of proteins, hypoxia, defective  mitochondria[3], reduced production of ATP  which  reduces the rates of cellular repair systems, and this increases the amount of other compounds (such as beta amyloid) that are pathogenic, increased sensitivity to uric acid, lipophilia (weight gain), fatty liver and pancreas, leptin and insulin resistance, and t2d, MeS and thereby CAWD.  On top of this it lights up the dopaminergic pathway (seen under imaging) in the addiction center, the nucleus accumbens, to causes sugar addiction.  Homo sapiens are poisoned by their high fructose western diet.  

  d.    Sources for material on CAWD, LSP, and fructose:  The best short source summarizing the evidence for CAWD that I have found is in chapter 5, Good Calories, Bad Calories (2002) by the highly rated science writer Gary Taubes and his The Case Against Sugar (2016) chapter 11—see LINK.  Hugh Trowell and Denis Burkitt’s, Western Diseases Their Emergence and Prevention, 1981 is the most complete source:  21 contributors present articles on the health conditions of peoples in different regions around the world who are on a traditional diet—see link.  In the journal article The Western Diet and Lifestyle and Diseases of Civilization[4] are measurements of blood pressure, fasting insulin, fasting leptin, and oxygen consumption for the Kitavans whom Staffan Lindeberg studied and compared to healthy Swedes—see link.  Other peoples are included in at that link by me.  However, Trowell, Burkitt and Lindeberg’s beliefs as to causes for CAWD suffer from swallowing the current cornucopia of causes—Lindeberg promotes the paleo diet as fix, and Trowell and Burkitt, low fat, cholesterol, low salt, and high fiber. 

  Sugar was singled out as starting point for over a century, but it was based on the observation that there are conditions of the rich.  Observations don’t prove causation, and books such as Low Blood Sugar and You, Carlton Frederick, Ph.D., 1969, lacked science.  Often sugar was grouped with refined carbs and still is ( I reject the charge against glucose, see Section VI).  The phrase fattening carbs was in common usage.  However, based upon the research of John Yudkin, founding Professor of the first department of Nutrition in the UK, Queen Elizabeth College, London, a strong base in science blaming sugar was established.   Yudkin popularized the science in  Pure, White, and Deadly,1972, which is still in print.  Science since has refined the cause to that of the fructose molecule, to which  Prof. Robert Lustig, science writer Gary Taubes, and nephrologist Jason Fung are leading voices in the US and Canada.  In Europe, Australia, and Canada, their public broadcast networks have done documentaries exposing the role of sugar—see my documentary page for links to YouTube.  Taubes’ latest book 2016, The Case Against Sugar, settles the issue, as does Lustig’s journal article which reviews the science behind his claim that fructose is toxic to the liver in ways that parallel’s ethanol.  A summary of that evidence is in a 15 minute college-level documentary.  It was Lustig’s lecture on UCTV on fructose, which I saw in 2012, that started me researching full-time all aspects of the western diet and its role in causing the diabetes and obesity pandemics.  Prior to that I assumed fructose was like glucose, just empty calories.  I pasted parts of the 2005 Wikipedia article on fructose and sucrose on my website at link.  In 2017 it was because of Taube, I began researching how fructose causes CAWD.  This expansion now includes an inventory of the ways in which fructose is a slow acting poison very similar to ethanol—a point made by Prof Lustig repeatedly—his Buzz article.   The major theme in this paper is an expansion of his list with inclusion of the biological processes that has pathogenic consequences.  Thousands of journal articles have been published on the role of fructose in the development of insulin resistance (IR), its progression to metabolic syndrome (MeS), fatty liver disease (NAFLD), obesity, and t2d.  I’ve added CAWD a consequence of biological changes that fructose causes to the cellular repair systems functions.  The science is conclusive:  fructose in excess is toxic in ways that causes far more than other candidates the CAWD.  Of course the industries which profit are trying to keep the pig in the bag. 

  e.   Cognitive dissonance and framing beliefs:  Without knowing what the main cause, minor causes are elevated to fulfill that role.  Thus there is a long list of causes to which supposed major or refined carbohydrates, gluten, saturated fats, meat, cholesterol, hypertension, stress, salt, GMOs, processed foods, food additives, industrial chemicals, pesticides, and sedentary and lifestyle.  The looking of finding mice while missing the elephant in the room has long history built upon industry’s cash, scientists for hire and government and media support.  Earlier notable examples include cigarettes, industrial pollution, cigarettes, exposure to chemicals at work, pharmaceutical drugs, tetraethyl lead, GMOs, and sugar. Given the dispositive evidence against fructose/sugar, it should be first before global warming.   And it gets worse in that the comparison of causes for death among population life-long on a low sugar diet is verboten.  Instead the message is the healthy foods and drugs has extended our lives decades.  The 1871 UK population study of men found that if taking only those age 21 and older (dropping out childhood morality) that their life expectancy was just 3 years longer than for men in men in the US (2010 census); their average age of death was 75-- see   link.   I say this because understanding causes requires a realization that the media implants pernicious memes.  How can we fail to realize that “the consumption of fructose and the fructose-containing disaccharides sucrose for decease is at ~130 lb./year or 6.5 oz./day  for the average American”[5] is causing our health disaster and that LSP are free of those conditions?  To quote Just So Stories by Kipling:  “Listen and attend my beloved” and I will take you down the Fructose river to the lassie fare port that permits food manufactures to cause CAWD , and you shall know the place for the first time.[6]  It is the story of tobacco retold.  The scientific evidence was in by 1922 (see link), but it took until 1964 for the Surgeon General to warn Americans about lung cancer; but he skipped extra death from all cancers and from coronary artery disease, which causes more extra deaths than cancer—see link.  The message of tobacco was already out around the world, and now Americans got the minimal federal government warning. 

f.   Cognitive dysfunction:  Industry’s response and thus our corporate media is to have us looking under the wrong trees, thus they don’t mention CAWD or fructose as toxic to the liver.  Their tree’s main branches are hypercholesterolemia, saturated fats, salt, hypertension, ratio of omega 3 to omega 6 fatty acids, trans-fats, sedentary life-style, stress, gluten, sun shine, low vitamin D and calcium, and a dozen more; and an even longer list of miracle foods as fixes.  Industry’s favorite phrases:  breakfast is the most important meal, energy rich foods (avoid), artery clogging cholesterol and saturated fats, a calories is a calorie, eat less and move more, and ask your doctor;  It’s all bad advice, and if doctors knew the answer then we wouldn’t have the diabesity and MeS pandemics.  For over 40 years we have been following theirs and the NIH advice to eat low fat, and to eating less and move more.  The mountains of tobacco science spouted by key opinion leaders (KOLs) and carried by corporate media as to causes of chronic and acute conditions and their fixes/prevention creates cognitive dissonance; it smothers the evidence fingering fructose and sucrose in our western diet.  For example over and over again I read journal articles where researchers investigating the health of LSP were measuring cholesterol and triglycerides--only one measured serum insulin.  What follows is about fructose and how in excess it mucks up our mammalian systems.  The last section is on how best to promote healing.   The ability to heal is in our DNA, and there are ways to promote that process. 

        g.  Health biomarkers of populations on a low sugar diet  Lindeberg found that comparing insulin levels of an aboriginal people--the Kitavan--to a western society, only 5% of the Swedes had plasma insulin level below  that of the average Kitavan;[7] and the Kitavans get 70% of their calories from carbs, most of which are easily digested—see link.  Based on Lindeberg’s[8]  and Dr. Kraft’s.[9] work, I estimate that over 80% of adults and over 90% of seniors have IR.[10]  Dr. Joseph Kraft starting in the 1970s  tested over 15,000 patients for IR[11] by measuring for 5 hours insulin secretion in response to 75 grams of glucose.  He found that 80% of Americans back then were IR, and that IR was strongly associated with atherosclerosis and ischemic events; the degree of risk depended on degree and duration of IR.  The work of Kraft and Lindeberg confirm the association of CAWD with IR.  Other key measures of issues are the reduced oxygen consumption of American, the fasting leptin increase and blood pressure increase—see tables.  The lower maximum oxygen consumption is an indication of an issue with the mitochondria for those on the Western diet (see Section IV k).  Seminal works have shown that IR is a marker for cancer and another for CVD, and numerous other works for t2d and MeS, and another for age related conditions[12].  It is time to get off of the glucose & lipid paradigms and focus on IR and fructose.  The elevated insulin continuum from TOFI to diabetic explains why both groups have the same set of CAWD—see section III.  T2d is the extreme form of IR, a form which is caused by excessive fat accumulation in the pancreas (YouTube and Newcastle U 2015) resulting in pancreatic inflammation and a pathological drop in the production of insulin.  Type 2 diabetics have the most severe form of IR and thereby a greater risk for CAWD.  The case against fructose and IR as the major cause for CAWD has the support of an ever growing number of researchers and physician—see my video section #3    Other than lipid measurements, comparisons of biomarkers are few and limited.   

h.   IR in the liver and fructose:  Is IR pathogenic?  Or is it just a marker for the damage caused by fructose?  I and others put the main blame upon fructose, because fructose causes IR, see Section II.  In various ways IR is not only a sign of excessive long-term dietary fructose, but also a contributor to CAWD.  Insulin is a major regulatory hormone, thus elevated insulin affects several other hormones and its abnormal elevation form IR has many pathogenic consequences.  IR is causal through leptin resistance for weight gain:  leptin lowers the rate of metabolism 25 to 40% when on a calorie restricted diet, and causes increased hunger by down regulating the action of leptin in the hypothalamus.   IR increases insulin like growth factors (IGFs) of which IGF-1 is associated with the growth of cancer.  IR increases fat storage, and thus is causal for the accumulation of fat in the liver thus a casual factor for NFALD, and there is a strong link between IR and weight gain.    Defects in the mitochondria result in underproduction of ATP, which has many effects of which one is the underproduction of collagen (Section IV i).  Uric acid, a byproduct of fructose metabolism, is responsible for hyperuricemia uric acid which promotes nephropathy, endothelial dysfunction, and other conditions (see Section II f ).  IR inhibits the express of FoxO1, a key autophagy gene, 2009.   This compromises the cellular repair system in the liver and thus promotes damage to the liver by glycation and liver inflammation, thus IR is causal for NAFLD and other conditions associated with the western diet.  In these and other ways, IR is pathogenic, and in other ways not mentioned.  These topics will be at length developed in subsequent sections.   Note A fasting serum insulin level greater than 25 mIU/L or 174 pmol/L is considered insulin resistance. The same levels apply three hours after the last meal.  

 The path to CAWD starts with high sucrose diet, in which fructose--one-half of the disaccharide sucrose--when consumed long-term and in excess damages the liver by its conversion into fat and by glycation,[13] non-enzymatic bond.  This combination leads to inflammation in the liver, fatty-liver, and liver insulin resistance.  IR will then develop in other tissues, mainly adipocytes and myocytes.  This combination of IR and liver inflammation mucks-up the various regulatory and healing systems whose down-stream effects result in CAWD.  Two major pathogenic effects are an over production of uric acid and an underproduction of collagen—see below.  The evidence for the role of fructose as the first (starting) cause is compelling; while the concern over glucose is the result of bad pharma pushing their drugs—Section VI

II.        How Fructose Causes Insulin Resistance

a.  Introduction:  The road to IR starts with fructose’s whose effects in the liver in 5 ways differ from glucose, for which the end result is IR in most tissues.  The main source of fructose is the disaccharide sucrose; its other half is glucose.  While it is net 20 more reactive than glucose:  net in that is cleared from the blood by the liver slower than glucose and is metabolized after glucose, thus though 10 more reactive (see IV e) its presence as a liver toxin is twice as long as glucose and longer depending on amount of glucose in the meal.[14]   This is further compounded by the fact that the clearance of fructose is reduced in those who are diabetic compared to the non-diabetic and presumable to a lesser extent by those who are IR, though not address in research that I know of.[15]   “These results suggest that fructose is closely involved not only in glycation but also in the polyol pathway [making cellular fructose] and peroxidation reactions through free radical formation. Thus, fructose is considered to be a more critical reducing sugar associated with the progression of diabetic complications than it has been thought until now” Kobe 2002.   Because of the CAWD, it is reasonable to assume that the pathological findings for t2d extend to those who are merely insulin resistant or had been because of the western high fructose diet.

 b.    Metabolized by the liver:  One of the livers functions is to dispose of toxic chemical, thus fructose is transported to the liver for disposal.   A high sugar diet overwhelms first the first protective system the small intestines (Science 2018) that metabolizes small amounts of fructose.  Overloaded the excess is sent via the portal vein to the liver where it is stored until glucose in the liver is sufficiently low.  On the Western diet ninety-five percent of serum fructose is handled by the liver.  Unlike glucose there is no storage (glycogen) form for fructose.  Fructose being a net 20 times more reactive than glucose can overwhelm the cellular repair systems in the liver (and in other tissues).  While only about 20% of glucose goes to the liver for metabolism an estimated 95% is metabolized in the liver.[16]  Glucose is metabolized first in the mitochondria, thereby delaying the metabolism of fructose.  This delays fructose’s metabolism when part of a high-carb meal; thereby, increasing fructose’s toxic effects. 

c.    Fructosylation of proteins:  in a non-enzymatic reaction of the reducing sugar fructose (often called glycation).[17]  Fructose attaches to certain amino acids mainly on proteins. Fructose and galactose are the most reactive of the common monosaccharaides. “Reducing sugars have an affinity for the amino acids lysine, methionine, and cysteine, of which the latter two [can] undergo a reversible oxidation, and thus act as an antioxidant—at 2013.[18]  Fructose because if forms a 5-unit ring (4 carbons and an oxygen) while glucose forms a 6-unit ring (5 carbons & an oxygen); thus there is greater strain upon the carbon to carbon bonds in the smaller ring; and as a consequence, fructose goes into an open straight chain form significantly longer and more often than glucose.  In this open form, fructose is capable of latching on to certain amino acids in a process known as glycation to form a fructosamine, which are further modified by reactive oxygen species—see 1989.  Non-enzymatic attaching to proteins alters their functions—a bad thing.  Since fructose is more reactive and its clearance is delayed by glucose by metabolism, a reasonable estimate of the amount of glycation in the liver by fructose compared to glucose is a net 20 fold greater (10 x 2 because of delayed clearance from liver—(depending on method of measurement).    “Fructose undergoes the Maillard reaction, non-enzymatic browning, with amino acids.  Because fructose exists to a greater extent in the open-chain form than does glucose, the initial stages of the Maillard reaction occur more rapidly than with glucose” Wiki, 2017. “Some of the products of this reaction (acrylamides) are known carcinogens” Wiki.  “The Maillard is a step in the formation of advanced glycation end products (AGEs).  It has also shown a correlation in numerous s different diseases in the human body….  In general, these diseases are due to the accumulation of AGEs on nucleic acids, proteins, and lipids” Wiki 2017.   The mechanisms which have evolved to protect mammals from the damage by glycation from glucose on a high carbohydrate diet, such as superoxide dismutase and autophagy, are overwhelm by our western diet high in fructose—not glucose see II j below. This excessive formation of these end-products in the liver to adversely effects liver function and causes a higher rate of complication associated with t2d, and those with insulin resistance.    

                d.    Fatty liver:  In the liver fructose is converted to fat at a much higher rate than glucose.  “By liver metabolizing glucose first, this will when there is sufficient ATP, cause the conversion of fructose to fat by de novo lipogenesis. Thus, fructose-generated ROS species are abundant (66, 67) and require quenching by a hepatic antioxidant (e.g., glutathione, ascorbate, superoxide dismutase, et al) or hepatocellular damage will result (Fig. 4). The hepatotoxic effects of fructose via ROS formation have been demonstrated in both cultured hepatocytes (68) and animal models (69). Although mechanistic data in humans are difficult to obtain, case-control studies demonstrate that fructose consumption correlates with the development of hepatic steatosis and nonalcoholic steatohepatitis (70–72)” Lustig 2013.  Uric acid a product of fructose metabolism generates ROS which stress the mitochondria and thereby has a role independent of fructose in the development of fatty liver—a seminal article at 2012,  “[U]ric acid upregulates frictokinase expression thus leading to the amplification of the lipogenic effect of fructose”, 2012.   Gradually with long-term high sugar diet this will lead to excessive storage of fat in the liver.  The rate of fat storage in the liver is controlled by the level of insulin, level of glucose, and the level of fatty acids in the liver.  Excess free fatty acids are converted to triglycerides, the water insoluble storage form, made up of 3 molecules of fat bonded to glycerol.  With sufficient accumulation the condition is known NAFLD –certain drugs including ethanol can also cause a fatty liver.  NAFLD can progress to NASH (Non-alcoholic steatohepatitis) in which there is the combination of inflammation and fibrosis—estimates run between 2-5% in the US.    Over a 10 year period about 20% of those with NASH will progress to cirrhosis of the liver.  But much more is at stake with development of fatty liver, for example liver fat and hyperinsulinemia are the two best markers along with C-reactive protein for MeS at Sept 2007 abstract.  In summary 2007:  “We conclude that increased liver fat is associated with both impaired insulin clearance and hepatic insulin resistance. Hepatic insulin sensitivity associates with liver fat content, independent of insulin clearance.”

e.   The two hit hypothesis for NAFLD and hepatic inflammation:  The two processes above, conversion to fat and the production of reactive oxygen species as a result of glycation by fructose are the main causes for the inflammation of the liver leading to NAFLD—see 2009[19]  If fructose was comparable to glucose in the rate of glycation, then the 15% of calories from fructose that a fair number of sugar addicts consume would be comparable to 70% of calories that the Kitavans consume as carbs, yet the Kitavans have very low insulin and fasting glucose (see section I).  But these sugar addicts test much worse than the Kitavans, the difference stems from the glycation by fructose.  The same argument can be made for the traditional Japanese and other high starch diet peoples.  It isn’t just de novo lipogenesis in the liver.  Fructose is 10 times more reactive than glucose.  The major difference is glycation (fructosylation), the 2^nd essential punch.  Among the signs of damage to hepatocytes includes reduction in size of mitochondria and thus reduced production therein of ATP, which is observed with t2d.   Others include reduced production of collagen in the polyol pathway.  Even though fructose is transported to the liver and is more reactive than glucose, many authorities assume only one hit, fatty liver (Fung, Lustig, and Taubes et al.), and a few add a third uric acid (urate), which is a product of fructose metabolism.

f. Uric acid from fructose metabolism promotes IR   “ Fructose is a major component of added sugars and is distinct from other sugars in its ability to cause intracellular ATP depletion, nucleotide turnover, and the generation of uric acid”, at 2013   “Here, we show that fructose also stimulates triglyceride synthesis via a purine-degrading pathway that is triggered from the rapid phosphorylation of fructose by fructokinase. Generated AMP enters into the purine degradation pathway through the activation of AMP deaminase resulting in uric acid production and the generation of mitochondrial oxidants. Mitochondrial oxidative stress results in the inhibition of aconitase in the Krebs cycle, resulting in the accumulation of citrate and the stimulation of ATP citrate lyase and fatty-acid synthase leading to de novo lipogeneis.  These studies provide new insights into the pathogenesis of hepatic fat accumulation under normal and diseased states” at 2012.   The study shows how de novo lipogenesis is promoted by a product of fructose metabolism, uric acid.  Another study shows that uric acid also stimulate fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes.  The study (supra) takes us from association to causality—2014, again with Richard J. Johnson et al—he was on the team that produced the other 2 sites supra.  Since fatty liver is causal for insulin resistance and insulin resistance for obesity and diabetes, this work adds a major pathway for major conditions associated with the Western diet through the action of uric acid upon the mitochondria, and upon stimulating de novo lipogenesis. 

g.  Defective mitochondria:  Type 2 diabetics have defective mitochondria, at 2005, 2006.   “A reduced basal ADP-stimulated and maximal mitochondrial respiratory capacity underlies the reduction in in vivo mitochondrial function, independent of mitochondrial content. A reduced capacity at both the level of the electron transport chain and phosphorylation system underlies this impaired mitochondrial capacity”, at 2008.   As maintained those with IR in the liver which is caused by the high fructose diet will develop in other tissues defective mitochondria similar the diabetic but to a lesser degree.  This will causes a decrease in the production of ATP through the Krebs cycle, and as a consequence an increase in cellular and serum glucose.  In the liver and conversion rate of glucose to glycogen and the production of ATP has decrease due to defective mitochondria and the effects of inflammation caused by a fatty liver, thus slowing the utilization of glucose and raising serum glucose, the hallmark of IR—see 2008 and 2011.  Cells throughout the body already load with glucose become resistant to the uptake of more glucose as the liver’s functions decline. Through a feedback mechanism these body cells become resistant to the uptake of more glucose. Added to this is the Crabtree effect:  a high level of glucose down regulates glucose metabolism (inhibition of respiration), “that effect was strongly antagonized by fructose 1,6-bisphosphate (F16bp). . . .  as able to inhibit mitochondrial respiration. . .” at 2008. This combination of factors explains the development of insulin resistance in tissues besides the liver.

In the liver some of the fructose enters the Krebs cycle to produce ATP.  Though fructose is invisible to insulin by entering the Krebs cycle and thus slows the cellular and serum uptake of glucose.  This explains why fructose though invisible to insulin, has a glycemic index (which measures glucose uptake from foods) of fructose is between 19 to 23, while glucose is rated at 100, and sucrose at 60 (thus not 50).  The rise in insulin is because of the slower metabolism of glucose and slower uptake through the GLUT-5 transport system.  Unfortunately I could not find any articles on the mechanism by which mitochondria become defective.  The most likely cause is excessive production of ROS and glycation by fructose (fructosylation) within the mitochondria.  Whatever the process, the lowered rate of production of ATP causes a slowed clearance of glucose and thus reduced rate of uptake of blood glucose.  Thus the beta cells release more insulin; viz., excessive insulin is by definition insulin resistance.

h.    Inflammation of the liver:  This damage to the liver is by glycation and compound by the excessive storage of 2-3 pound of fat; this causes an inflamed liver and thus elevated C-reactive protein 2007.  This condition is known as non-alcoholic fatty liver disease (NAFLD).   This combination of two process has been established in animal and human experiments; however, most authorities stress the 3^rd factor fat storage (it is easy to measure with a sonogram of the liver), while missing the additive role of fructosylation—see protein oxidation, 2013, and 2008.        

            j.    Insulin resistance in the liver:  This is a response by hepatocytes to the excess storage of fat in the liver and the damage caused by glycation mainly by fructose, and compounded by the hepatocytes having sufficient glucose and fructose, and thus resisting the uptake of more plasma glucose (a point made by Dr. Jason Fung in his 2016 books, see supra).  The damaged hepatocytes are not clearing the cellular sugar at the rate prior to damage.  As liver functions decline the liver cells become resistant to insulin signal for the uptake more glucose than fructose; they both use the GLUT 5, GLUT 2 and possible SLC2A9 transport system and with insulin  resistance these transport system don’t work as well.  Moreover the level of fructose, in a vicious cycle, increases with increasing insulin resistance, the highest level being among type-2 diabetics.   

j.   Insulin resistant in other tissues:  Eventually IR in the liver, depending on lifestyle, genes, hormones, and age, can develop into IR in other cells especially the myocytes and adipocytes—along with the brain & liver, these cells consume most of the glucose.  Insulin resistance is the result of a feed-back system protecting the cell from having glucose in excess of what it needs.  Also causal is “elevated lipolysis and the release of free fatty acids into the blood stream which contributes to further insulin resistance via increasing hepatic gluconeogenesis and preventing insulin dependent uptake in tissues” Wiki. 

k.    Fatty pancreas causes t2d:  the work of Joseph Kraft and 3 decades later Roy Taylor  and team at Newcastle University  have shown that as insulin resistance progress, it drives fat storage into tissues throughout the body, and eventually excess fat will be stored in the pancreas and result when sufficient in excessive stores like the liver the pancreas becomes inflamed and the production of insulin dramatically declines to become symptomatic hyperglycemia which is treated with drugs or through a low carb diet.[20]  Healthfully articles on t2d and Roy Taylor’s work. {need to paste his journal article.

I.  Metabolic syndrome (MeS):  MeS its cause is the western diet.  Not surprisingly the list of signs associated with increased risk of CVD events should be spun to promote the sales of drug.  Nevertheless, It merits discussion because the conditions have become accepted by physicians and public though the consequences for most of the markers don’t put the person in the high risk group for CVD.  It  is defined by the American Heart Association as 3 of the 5: 1) unmedicated fasting plasma glucose greater than 100 mg/dL, 2) HDL cholesterol under 40 mg/dL, 3)Triglycerides greater than 150 mg/dL, 4)waist circumference greater than 40 inches men, and 35 for women, and 5) unmedicated systolic blood pressure of 130 mm Hg.  Of the five associated with CVD, all of these are grossly flawed, for example #3; includes a significant percentage of people at lower risk for CVD such as those who as part of physical because they eat lots of high carbohydrate foods in their diet while in physical training.  And number #4 is flawed because many obese short people would be missed.   missing short people who would be considered at low risk but aren’t.  The cholesterol myth has been amply debunked in the literature and summarized at link.  Systolic blood pressure of 130 to 140 would include athletes and other fit people.   Having said this, the markers associated with ischemic events are the western high fructose diet, insulin resistance, elevated plasma glucose without medications, systolic blood pressure above 150 mg/dL, associated with atherosclerosis, angina pain, sedentary lifestyle because of being incapable of run and swim laps, polypharmacy, overweight, abdominal fat, and all the conditions associated with western diet when past the age of 50. 

M.  Not refined grains (glucose) alone:   Given those populations that eat or once ate a high-carb easily digestible, low-sugar diet don’t experience CAWD (Kitavans, Japanese, Okinawans), this is strong evidence glucose isn’t by itself causing CAWD, but rather that at some point there must be a protracted period of intake of fructose averaging over 50 grams a day (less for the elderly and inactive). Many authors are not aware that fructose is a reactive sugar, and that it damages the liver to cause IR.  A second error is the claim that real foods are much more healthful, and foods high in refined carbs aren’t because of their low fiber content.  However, the populations named above consume foods low in fiber, but this doesn’t mean that fiber is not of value when on a Western diet; but its value is small when on a low sugar diet.  This is like the error concerning antioxidants supplements, they are helpful for those on a western diet. On a life-long low sugar diet, the over 50 cellular repairs system, a number of which utilize cellular manufactured antioxidant such as glutathionene and CoQ10.   

 About 3 hours later, on a meal with half carbs, the mitochondria begin taking up the fructose and metabolize it into the trioses dihydroxyacetone and glyceraldehyde which can enter the  glycogenic “pathway leading to glycogen synthesis as well as fatty acids and triglyceride synthesis” wiki 2018 and fatty acids from the production of pyruvate which is converted to acetyl-CoA and then fatty acids or through glycerol-3 phosphate to fatty acids. Unlike glucose, fructose’s end product can also be uric acid:  “The fructose component of sugars increases serum levels of uric acid.  “The striking increase” in those levels with an infusion of fructose was first reported in the late 1960s by Finnish researchers. . . .”  Taubes The Case Against Sugar p 241-2.  He goes on to describe how through its effect on ATP breakdown through “adenosine a form of adenine, a purine” and “the effect of fructose on works to stimulate the synthesis of purines, and the metabolism of fructose leads to the production of lactic acid, which reduces the excretion of uric acid by the kidney and thereby raises uric acid levels indirectly.” Supra 241.[21] The amount of fatty acids and triglycerides is controlled by the cellular need for glucose. Fructose is far more pathogenic than glucose, and too many authorities fail to mention the differences.  As Prof. Ben Goldacre repeatedly writes in Bad Pharma “The devil is in the details.”    

n.  Summation:  While the journal evidence is weak other processes that are causal for CADW, in particular uric acid, lowered rate of replacement of collagen, and glycation by fructose, they are likely also contributing causes for the issues leading to beta cell dysfunction resulting in t2d and IR.  On point is the over expression of fructose-1-6-bisphosphatease in pancreatic beta cells causing reduced secretion of insulin and increased pancreatic fat are causal for t2d--2008.  Moreover through glycation and thus oxidative stress fructose promotes apoptosis (but not glucose)[22] in beta cells, the more so with fructose being the most reactive 96, and in a higher level in the pancreas.  

The progression to t2d is associated with a list of comorbidities, and as insulin levels go up through medications to lower glucose, these comorbidities increase, especially weight gain, due to insulin’s function of promoting fat storage.  The elevated glucose both stimulates the polyol pathway which produces sorbitol and fructose and slows by selective metabolism of glucose first, an increase in the level of fructose.  This focus on managing glucose while good for pharma, this is another misdirection of treatment and research which should focus on lowering fructose.  That the ADA has among others recommended replacing sucrose with fructose, while lowering the need postprandial medication in the long-run is pathogenic.  Management should be on lowering fructose.  And this can best be achieved both for t1d and t2d by lowering carbs, which among other things doesn’t turn on the polyol pathway that produces fructose.  In section VI, this topic of dietary control and cure will be briefly developed. 

 III. Consequences of Insulin Resistance (IR)

            a.    A review of the role of excess fructose:   Insulin resistance starts with the Western high fructose  diet.  Although sugar cane was grown since the 7^th century, the mass important into Europe occurred in the 18^th century.  France is the early 19^th century, under the direction of Napoleon selectively bred beets for higher sugar content.  Today sugar beets account for about 20% of sugar.  In the 19^th century, the consumption of high sugar products became affordable to all.   “In the US in 1830 went from less than 15 pounds [18.7 gram/day] a person yearly to 100 pounds in the 1920s and 150 pounds . . .by the end of the century.”[22]  About 20% of glucose and all of fructose is transported into the liver.  Fructose is a net 20 times more reactive than glucose,[23] and it nearly exclusive metabolized in the liver.  Our high fructose diet overloads the systems that repair glycated proteins and their oxidized end products.[24]  Glucose alone being less reactive can’t cause insulin resistance.  With a high carb meal, the excess glucose causes a delay in fructose metabolism, and also increases its conversion to fat in the liver by de novo lipogenesis—also 2010.  The production of ATP is controlled by need, and with a high carb diet, when sufficient ATP is produced, the excess is converted to fatty acids which are converted to triglycerides.  To promote glucose metabolism, insulin also signals fat storage; this gradually leads to a fatty liver (similar to that caused by ethanol).  There is very strong evidence supporting the role of fructose; for example, in a trial in which young-healthy volunteers were fed 40% of calories from fructose; within 2 weeks they developed insulin resistance and fatty liver.  This is consistent with animal studies using a lower dose.  Prof. Robert Lustig has done a sophisticated population study of over 100 populations; they controlled for confounding variables.  His team found that only for the disaccharide sucrose is there a strong association with metabolic syndrome—the same type of population study done to prove that cigarettes cause lung cancer. This one two punches of fructosylation damaging hepatocytes and fatty cells drives insulin resistance in the damaged liver as it lowers the import of glucose into the hepatocytes.  The liver plays a major role in controlling plasma glucose which is down regulated, thus increasing serum glucose, and thus more insulin.  This eventually this will lead to IR in the myocytes and adipocytes as they resist excess glucose uptake and thus become IR.  Insulin promotes fat conversion to the storage form of triglycerides and also regulates other hormones that are part of the weight-regulatory system, of which insulin is an antagonist of leptin at the hypothalamus (see leptin resistance Section III d), thus insulin resistance is the major cause for weight gain.[25]  See rmb/5Figure 1 for insulin levels of LPS and healthy Swedes whose level is 90% above the LSP, and Swedes have a much lower rate of obesity.     Even moderate weight gain (TOFI) is strongly associated with IR, high sugar diet, and CAWD.

b.     storage:  IR not only promotes the uptake of glucose, but also shuts down the metabolism fat to promote cellular glucose metabolism.  The fat is then converted to the storage form of triglycerides, and IR potentiates that effect of insulin thus the fundamental cause for excessive (not natural) weight, typically averaging about 1% of caloric intake, about 25 grams a day.  “Just a 1 percent excess of e nergy consumption (over expenditure), for instance, could cause an average size man to gain 60 pounds over 30 years” (What Fuels Fat, JS Flier Dean of Medicine Harvard University, and EM Flier MD, Scientific American, 2007, p 73).  With long-term weight gain, the adipose tissue functions to maintain its adiposity when weight is being loss by lowering metabolisms and increasing appetite—click on link for journal articles on point. 

b.  Weight regulatory system:  Humans, like all mammals, have a complex system of regulatory hormones that controls appetite, metabolic rate, fat storage, glucose storage, nutrient absorption, and like, therefor there are over 80 hormones involved in these systems regulation.  That system is set promote the ideal weight for seize, circumstances, and age.  In the wild, an overweight animal among their species is exceedingly rare, even during food surpluses.  It is exquisitely controlled: animals only in preparation for hibernate or migration is weight put on.  For humans, like other processes such as wound healing and growth, weight too is tightly controlled for those lifelong on a low-sugar diet (with the rarer exceptions driven by societal norms).  Even the elderly aboriginals retain their natural weight, for example, a man weighs an average of 7 lbs. less as they lose muscle mass and women over twice loss through muscles and the loss of fat-stores from their fertile years. 

The two most important of the regulatory hormones are insulin and leptin, and insulin regulates in part leptin.  IR not only directly promotes excess fat storage but also through other hormones including leptin causes the regulatory system rest as “normal” the gained weight.  Without insulin resistance this wouldn’t happen.  (As stated prior over 90% of those on a western diet are IR using the measurements of those on a traditional diet as a standard.)  There are at least 4 other hormones besides leptin secreted by adipose tissue.  Though regulation is complex, the initiating cause is our high fructose diet—all else is downstream. 

d.  Leptin and leptin resistance:   insulin up regulates leptin thus insulin resistance eventually in response to the excess of leptin the  receptors for leptin in the hippocampus become resistant to leptin.  Leptin is also responding to hormone from the adipose tissue, and functions to keep a biologically determined amount of fat.  With insulin resistance, a signal is sent to increase the amount of fat.   Excess leptin increases hunger to cause weight gain, and that fails, typically at 2 months it will reduce the rate of metabolism. When weight is being lost, leptin resistance through its action in the brain causes increase in appetite as first response then a couple months reduction in metabolism.  This reduction in metabolism, adversely affect how that person feels both physically and mentally, and through these negative effects creates the urge to eat more so as to feel better.  This leptin driven effects is why nearly all dieters with significant long-term weight will gradually gain back most of the weight they had lost over several years, and some even more than when they began their diet.[23]  This confirms what Prof. Lustig says, “biology rules.”  He uses the example of obese babies.  Insulin resistance through leptin and other regulatory hormones is driving the obesity epidemic, thus weight gain is a sign for the high fructose diet, or past fructose amounts that caused the fatty inflamed liver that plays a key role in developing insulin resistance. 

Leptin is a hormone secreted by adipose tissue which regulates appetite, metabolism, & functions to restore fat storage to its set level through reducing the rate of metabolism from 25% to 40% and increasing appetite.  With long-term excess weight, the normal weight (level of fat) is reset; thus making eating less and exercise more is futile—the yo-yo diet.  Leptin, typically during the second month of a diet will lower metabolism and increase appetite for to maintain “normal weight”.  If leptin-insulin system is working right, that person without efforts stays at normal weight—like the aborigines.  Weight gain is strongly associated with IR[24].  Pharma profits from having doctors focusing on lowering plasma glucose and treating CAWD; thus their ignorance about the weight regulatory system and how to fix it.[25]  And pharma through their KOLs recommend “eating less and moving more” advice that doesn’t work in 95% of the cases; thus doctors are taught that diabetes is a progressive condition.[26]   

e.  Cellular hyperglycemia:   By using the measure of the lsp, the level of glucose is well above that of those people and is a sign, like hypertension, one in the main a sign of insulin resistance, the other in the main of atherosclerosis. I thus hold both abnormalities in themselves as only moderately pathological, though pharm treats these sign, and consistent with its business model, the benefits aren’t there.[27] Dr. Jason Fung and others have developed this topic.  In chapter 11 of his Diabetes Code, pages 138 to 150  uses clinical trial shows that tight management of glucose confers no important benefits such as lower death and prevent heart attacks, and given that these are pharma funded studies, adjusting for scientific fraud, the results in the real-world population is negative.  He found 2 possible exceptions (assuming fraud isn’t extreme) in the dipeptidyl peptidase-4 inhibitors (DPP-4) and the sodium glucose cotransporters inhibitor (SGLT 2)).    Note after 3 hours of searching I was not able to find serum glucose levels for those populations on a low sugar diet.  Lindeberg in is studies of the Kitavans used insulin and leptin levels, which is superior to fasting glucose and HbAIc because excess insulin (IR) keeps these markers in the normal range.  Only with an insulin assay reveals the underlying IR consistent.[28]   Using insulin levels, the Kitavans on a traditional diet have levels 45 to 50 % below those of healthy Swedes.          

f.  Type-2 Diabetes:  Insulin resistance causes t2d through the accumulation of fat in the pancreas, which when it reaches a critical point cause a significant decline in the product of insulin, an effect similar to that of excess fat in the liver causing NAFLD and its subsequent reduction in liver functions.  This process parallels that in the liver of glycation by fructose which causes oxidative—1996.  The IR which causes weight gain, fatty liver, also causes accumulation of fat in the pancreas—watch Prof. Roy Taylor’s lecture and, Dr. Jason Fung, and in Taylor 2015, Science News.  Thus the combination of oxidative stress and fat accumulation causes t2d.  The other pathological process such as underproduction of collagen, stress by uric acid, etc. are all likely contributory. 

Pharma teaches that the problem lies in insulin receptors on cells which have become  resistant to insulin signaling for uptake of glucose, thereby causing the pancreas to release more insulin, and that over time the beta cells in the pancreas become (permanently) exhausted from their increasing production of insulin and production declines sufficiently to cause t2d.  Pharma hold that t2d is progressive requiring ever increasing medications to stabilize serum glucose.  Pharma and the ADA[29] teach that their isn’t a cure, thereby they ignore the counter examples or “explain” them away.  One is that with significant weight loss there is a reduction of medications.  Pharma also teaches that the consumption of carbs is not pathogenic, and that the patient should eat frequent snacks with carbs to stabilize their insulin level and avoid hypoglycemia caused by their medications.  They also hold that the morbidly obese type-2 diabetics who undergo bariatric surgery, that their reduction in medications is because of weight loss. And pharma holds that tight management of glucose based on DCCT Trial and the EDIC Trial prove that tight control of glucose avoids major adverse events; however, the trial was done with type 1 diabetes, and type 1 is the near zero production of insulin, while type two there is significant production of insulin but not enough to keep glucose in the desired range.[30]  As Prof. Ben Goldacre says in Bad Pharma, “The devil is in the details.”  To arrive at these conclusions resulted from “cherry picking” the evidence, used 2 inappropriate trails and others of very low quality, ignored counter examples and scientific fraud which is buried by the fact that pharma won’t share the raw data when submitting a trial for journal publication.  The article was published in the NEJM and is based upon raw data.  Four professors found the average bias was 32% in journal articles—that amounts to scientific fraud.  

Contrary to pharma and the ADA, as for no cure there are many examples to the contrary including that 80% of diabetics are cured of t2d or have a major reduction in medication, and the improvement occurs before major weight loss.   The Bata cells are not burnt out but rather producing less insulin because of fat and inflammation--Fung 2017.  Unfortunately, most of the patients aren’t warned about sugar, and thus that they would revert to weight gain and t2d through consumption of sugar.  Critics[31] of pharma hold that the issue isn’t the receptors’ resistance to insulin, but rather the cells that have become resistant to taking on more glucose than needed.   They hold that it is much better to go on a very low carb diet and lower their need for medication—the opposite of guidelines, ADA, and pharma’s recommends.  That 80% of diabetics who subsequent to bariatric surgery are cured is attributed by pharma KOLs to their weight loss; however, the reversal of the condition occurs before substantial weight loss, most within the two month.[32]  The IV feeding subsequent to the operation is essential a fast, one in which calories average under 600 per day.   The dietary fix for t2d, though successful for over a century, is the knife in the back of pharma’s spin.   Fredrick Allen reported cures of some of his patients on a ketogenic diet in 1913.[33]

This treating of symptoms instead of the conditions is a common business practice of pharma, like treating fever instead of infection.  The consequence is that pharma frames the understanding of the diabetes and the search for treatments to lower the sign, high glucose, rather than search for what has gone wrong with the weight regulatory system, how best to cleanse the liver and pancreas of excess fat, and thereby cure type-2 diabetes with diet, and.   And they blame the comorbidities of t2d on glucose toxicity, thus requiring tighter control of glucose.  However, by razing insulin level these conditions become more common, which leads some to refer to insulin toxicity, though I hold that it is mainly the downstream effects of fructose that is the main causal factor, and insulin resistance is a consequence of fructose toxicity—a position held by Prof. Robert Lustig and others.

f.  Elevated Insulin like growth factors (IGF):  When insulin goes up so does IG-1.  The significant of this and the other IGFs are not clear.  IGF-1 (the best studied of them) promotes of the utilization of amino acids, at 2014.  It is on this basis that thought to accelerate the growth of cancers.  Given that there are six binding ligands, at least two IGF, and that they function mainly “part of a complex system that cells use to communicate with their physiologic environment” (Wiki) even though they promote the growth of cancer, their net overall effect as to health and their being over produced by those  insulin resistant, the overall net effects has not been worked out—as far as I know.  Moreover, the connection to the growth of cancer might be just a marker for plasma level of amino acids, and the putative growth of cancer might not be promoted by the IGFs, but rather by the availability of amino acids used in cell growth.  For the sake of completeness, I have included a reference to the possible role of IGFs.  

h.   Downstream changes caused by IR:  Insulin functions in a number of regulatory systems affecting metabolism of carbohydrates, fats, and amino acid, and thus affects their serum levels, glycogenesis, lipogenesis, conversion of glycogen to glucose in the liver, and the converse glucose to glycogen, synthesis of proteins, decreases proteolysis, decreases autophagy, increases secretion of hydrochloric cells by parietal cells, increases potassium uptake, and decreases sodium excretion.  Insulin affects the level of other hormones, among them leptin, adiponectin and ghrelin—and this is not a complete list, see appendix 4?. These hormones then have an effect upon the formation of advanced glycation end produces (RAGE), the functions of endothelia nitric oxide synthase (eNOS), glyceraldehnyde-3phosphage dehydrgenase, increased production of fructose and sorbitol in the polyol pathway and regulation of intracellular osmotic pressure, manganese superoxide dismutase (MnSOD), nuclear factor kB (NFkB), poly(ADP-ribose) polymerase, protein kinase C, I GF-1 (Insulin like growth factors), uric acid, delaying replacement of collagen and endothelial cells, rate of metabolism in the tricarboxylic1 acid (TCA)  cycle, uncoupling proteins, and others.  The complexity of compromised functions caused by excessive dietary fructose causes a long list of CADW.  This contrasts with the simple clinical consequence of a deficiency of thiamine (vitamin B1), beriberi.  There is need for major research efforts to sort out the role of insulin resistance in CAWD.   A similar effort is need for the effects of glycation of proteins and the oxidation of unsaturated fatty acids.  And we need to keep businesses out of funding scientists for hire to sullying the evidence base on which medicine is practiced.  You’d be surprised at how many drugs are not worth their side effects—far more than Evans and Debree claimed, link.

The third points turns upon what is being measured and that the reactive sugars is not being measured. Fraud http://healthfully.org/index/id9.html

i.   Fetal environment promotes IR:  a mother with IR--elevated postprandial glucose- significantly increases the risk in her offspring of being born with or developing IR and thus obesity and other CAWD.[34]    The elevated glucose and insulin cross the placenta and affect the fetus production of GLUT receptors for insulin an glucose and fructose transport.  This increase in receptors increases the response to sugars thereby increasing the risk for IR.  Each generation, as we have observed, has a higher rate of obesity and IR than the previous. 

IV.   How excess fructose causes CAWD

a.    Introduction:  As shown in Sections I through III, the conditions associated with the western diet are caused by fructose, and not refined carbs.[1]  The four ways I have stressed are the diminished the production of collagen, hyperuricemia, hyperinsulinemia, and fructosylation hepatic and cellular via the polyol pathway. In this section how these and other effects of fructose are stressed. The body of evidence both biological and epidemiological shows that fructose causes the diabesity (obesity & diabetes) pandemic and by extension MeS and CAWD.[2]  The evidence is more than mere association; the biological processes have uncovered several major ways in which fructose promotes CAWD.  Downstream of fructose are many pathogenic and potentially pathogenic changes.  Below is developed tersely those changes receiving significant journal space and which are consistent with the major role of fructose, other I find the evidence weak.  For every major biological process there are many functions that are affected:  some such as associated with nitric oxide, cortisol, micronutrients, PYY, pollutants, and hormone mimics I consider not fundamental to understanding the issues before us.  Too many pathways and actors obscure through complications the main issues.    

As covered in Section I, CAWD are rare to extremely rare among the elderly aboriginals[3] and other peoples who consume life-long their traditional low-sugar diet (under 40 grams a day—32 lbs. year--all sources).  With few exceptions, wild fruits are both low in sugar and seasonal.   A second healthful practice of most of the LSP is their not eating.  While sleeping (thus not eating) autophagy is turned on.  “Autophagy is normally suppressed by amino acids and insulin” at 2009[4].   The western dietary pattern of snacks and 3 meals a day contrasts with other population that do not get CAWD:  they eat less frequently and skip meals when traveling or working.  Their major causes of death in population with very low CAWD are infections, communicable diseases, parasites, physical trauma, and pregnancy.  The case for dietary fructose being the main cause IR & CAWD is beyond being a theory.   

b.   Insulin resistance:  As stated above (see II c, d, & e), the de novo lipogenesis and fructosylation in the liver causes IR and fatty liver.  IR by many is considered relatively benign; however, it isn’t.  Insulin is a major regulatory hormone that affects many other hormones and thus plays key roles leading to the diseases of western society[5].  Given the many functions of insulin (see appendix, Insulin), it is causally associated with biological markers and a direct contributor to NAFLD, obesity, t2d.  The epidemiological of the CAWD to LSPs and the difference is biological markers are strong evidence for the case against fructose. 

c.  Hyperuricemia & uric acid crystals (gout)  Having looked for some months at the literature concern the pathological consequences of uric acid, I find for a confluence of reasons that other effects of IR act synergistically to sensitize the patient to the effects of uric acid microcrystal and very possible other effects of serum uric acid.  Of those likely to be significant would be the delayed replacement of collagens, mitochondrial defects resulting in a reduced production of ATP with its effects upon cellular repair systems,  , low ascorbate.  How fructose raise blood uric acid and urate and thereby increases the incidence of gout.is firmly establish.  Also established is the role of uric acid in endothelial dysfunction and nephropathy.  Uric acid is derived from the metabolism of fructose and, which with excessive glucose causes gout, a condition where micro uric acid crystals form, and when sufficient cause inflammation, most often pictured as in the joint of the big toe,

 and can occurs in other parts of the body and form a tophi.  By 2013 nearly 6 million were affected.  These sharp crystals travel the blood and damage other tissues;

 of particular concern are the epithelial cells lining the arteries, capillaries and nephrons of the kidneys.

Diabetic nephropathy affects over 6 million people and often progresses to end-stage kidney failure.  It is a common among those who have had diabetes over 20 years.   Uric acid is the major driving cause  THewre is a synergic relationship to defective collagen to which uric acid promotes, turning on of the polyol pathway with the subsequent fructosylation, high osmotic cellular pressure, hypoxia and defective mitochondria.  All of these are present in the type-2 diabetic.  Further basic research is needed to measure the significant or uric acid crystal upon the kidney for those with late stage IR and also upon endothelial cells lining arteries.  Damage causes a viscous cycle since the kidneys are the principle method of elimination from the blood of uric acid crystals, and with damage to the kidneys the rate of excretion declines.  These crystals also damage endothelial cells lining the arteries, and since they are the gate way to in the interior of the arteries there function as gatekeeper is compromised in ways that promote atherosclerosis and therefore CVD.  Consistent with the increased consumption of sugar and the diabetes epidemic “Rates of gout approximately doubled between 1990 and 2010” Wiki.  By 2013 nearly 6 million were affected and increasing.  The causal role of excess fructose and the subsequent elevated uric acid and t2d has been established in a seminal article—Oxford Academy 2009. 

The belief that pyruvates from meats are the cause gout--once for decades accepted--is lacking in compelling evidence (see Taubes supra p 238-249 for the burial of that belief).^[19]  “Fructose also inhibits the excretion of uric acid, apparently by competing with uric acid for access to the transport protein SLC2A9”^[20]  Wiki 2018.  “Dietary causes account for about 12% of gout,^[3] and include a strong association with the consumption of alcohol, fructose-sweetened drinks, meat, and seafood.^[12][15] Among foods richest in purines yielding high amounts of uric acid are dried anchovies, shrimp, organ meat, dried mushrooms, seaweed, and beer yeast.^[16] Other triggers include physical trauma and surgery. . . .^[4]   About 10% of people with hyperuricemia develop gout at some point in their lifetimes.^[14] In purine metabolism this interference [by fructose] has a dual action, both increasing the conversion of ATP to inosine and hence uric acid and increasing the synthesis of purine.^[19] ” Wiki gout 2018 and also.  The old belief that gout is a sugar disease has been confirmed.  Gout is like hypertension a sign that there is some very wrong on a cellular level. 

The role of fructose and uric acid crystals in the pathologies associated with CAWD is based upon diminished kidney function and endothelial dysfunction.  It is more than theory.  “Under excretion of uric acid by the kidney is the primary cause of hyperuricemia in about 90% of cases, while overproduction is the cause in less than 10%.^[4]   High intake of fructose contributes significantly to hyperuricemia. . . . . Fructose also inhibits the excretion of uric acid, apparently by competing with uric acid for access to the transport protein SLC2A9”^[20]  Wiki 2018.  The risk, however, varies depending on the degree of hyperuricemia. When levels are between 415 and 530 μmol/l (7 and 8.9 mg/dl), the risk is 0.5% per year, while in those with a level greater than 535 μmol/l (9 mg/dL), the risk is 4.5% per year”.^[11]  Wiki 2018.  I maintain that a cofactor is the degree of insulin resistance.  “Fructose rapidly raises uric acid . . . . Lowering uric acid in fructose-fed rats ameliorates much of the metabolic syndrome,” 2006.   “Uric acid causes hypertension, atherosclerosis, and ischemic events, through several pathogenic processes.  Among them is the lowering of nitric oxide (NO)” “. . . many aspects of endothelial function and occurs not only in the kidney.  The close linkage between micro-albuminuria and endothelial dysfunction in diabetes is an attractive explanation for the fact that microalbuminuria is a risk marker for atherothrombosis” Clinical Science 2005.  “Asymptomatic hyperuricemia in humans is also associated with endothelial dysfunction (107)”, a seminal review 2009.   Endothelial dysfunction probably occurs at least in part from the same processes that cause glomerular dysfunction in the kidney and by an anti-proliferative effect which would include ROS and other pathogenic modalities, see 2005, and 2005.  The formation of sharp microscopic uric acid cause abrasion to the fine structures in the kidneys, and I suspect such micro-crystals, damage the endothelial cells lining the arteries to promote endothelial dysfunction, and thus atherogenic.[6]  The damage to glomerulus result in reduced clearing of uric acid, which thereby promotes the formation of more microscopic crystals that further damage the kidneys that can progress to nephropathy which would cause hypertension.  

This role becomes pathological with other conditions and life-style factors besides excess fructose consumption.  “Alcohol consumption has long been associated with hyperuricemia and gout” as has diabetes and insulin resistance at 2002.  Thus a combination of factors all associated causally associated with excess fructose works synergistically to promote CAWD, most starting with excess fructose. 

This leaves me with one last question:  Why is gout is virtually unknown for LSP, yet unlike other makers, such as for insulin, serum glucose, blood pressure, adipose tissue, that of uric acid in the Kitavans and healthy Swedes have only about a 10% difference--Lindeberg et al 2004?  (I couldn’t find measures of uric acid in other LSP).   However, a subset of about 10% of the healthy Swedes have significantly elevated uric unlike the Kitavans for whom there were none.  This subset of elevated level correlates with the incidence of gout.  Unfortunately the study by Stefan Lindeberg doesn’t follow to find out the long-term consequences of the subset of Swedes.  Based upon the Kitavans it appears that the level of uric acid that is considered normal of those on a western diet is not pathogenic in itself; but is when the population is on a high fructose diet because of their other factors.  That health Swedes are only slightly above the level of uric acid of the Kitavans supports the role of the afore mentioned other causal factors for CAWD.  Science is a long way from putting the pieces of the puzzle together (see journal articles pasted at Healthfully uric acid.) 

In summary:  The role of uric acid is complex:  it is not associated with pathologically until IR and NAFLD are present, at which point the ability to handle the stress of uric acid has been compromised.  Then the micro-sharp crystal form which damage endothelial cells and kidney cells. Other factors such as the underproduction of collagen, compromised proteins due to fructosylation, and reduced production of ATP by the mitochondria could all function synergistically with uric acid crystals.  Thus though the level of uric acid is only about 10% higher for the healthy Swedes than the Kitavans, the ability to handle uric acid has been compromised, 2004 Lindeberg (an explanation Lindeberg doubts).  There is no doubt ”that excessive fructose intake (.50g/d). . . . There are now extensive experimental and clinical data supporting uric acid in the pathogenesis of metabolic syndrome” (Richard Johnson et al, 2009, seminal article) and much more.   

d.  Fructosylation and cytotoxicity:   Tissues with frequent pathological developments in those with t2d are the kidney, retina, neurons and related cells, and capillaries, arteriole, and endothelial cells, thus an examination of the literature on the pathology and abnormalities involving these tissues is often fruitful.  Like much of the journal literature seminal articles are off not available; an example is the basic research on fructose and fructosylation.  I have yet to find a seminal summation article; thus I must proceed with articles each of a limited scope, and also interpret oxidative stress as a result of end product of fructosylation where context supports this reading—few researchers are aware of this process outside the liver.  There test for glycation is based mainly on end products of the Milliard reaction, which occurs also with fructose, and given it 10 fold increased reactivity compared to glucose, that is sufficient reason to consider as very possibly why it is mainly fructose that is responsible for overwhelming the repair system, and this is one more pieces as thy for CAWD. 

Allow me to restate this:  the role of pathological role of fructose is underestimated for 2 reasons.  One is that the testing for end-products of bonding by sugars is often grouped as glycation, rather than perform further testing for the bonding of fructose to proteins.  Second many researchers knowing that the blood level of fructose is much lower than glucose assume that assume that nearly all of fructose is in the liver, thus no needs to test for it; they are only dimly aware of the polyol pathway (e below). This is further compounded because of the lack of awareness of the toxic nature of fructose.  Moreover, the current testing for HbA1c doesn’t reveal fructosylation at 1992 and 2013.[7]  Too often research is done with the goal of finding a drug. 

 When the glucose levels are high, a significant amount of glucose is converted to fructose in the polyol pathway—see e below.  This has been shown to significantly contribute to fructosylation of proteins and other suitable substrates such as polyunsaturated fats.  This is further complicated in that several tissues take up fructose directly from the blood plasma without active transport.  This includes the kidneys, eye lenses, neurons, and the endothelial cells in the intestines, thus making these tissues more vulnerable to fructosylation.  For neuropathy elevated levels of sorbitol and fructose have been reported for diabetics, and “the most common abnormalities were fibers undergoing axonal degeneration” at 1980.  Among the finding was that fructose-modified-HSA (human serum albumin, the most abundant protein in human blood plasma).  It is an important marker for diabetic pathophysiology at 2016.[8]  Similar finding for bovine serum albumin (BSA) are widely reported; e.g. Oxford 1993. Biochemistry 1988.  The same can be expected for other proteins and other receptive chemical including polyunsaturated fats—see section VI.   Fructose being more reactive (in the endol form)[9] undergoes glycation with proteins (amino acids) at 10 times the rate of glucose (see II b above) in the Maillard reaction to from mutagenic compounds and play a role in the conditions associated with CAWD, at 1993.  Because of the intermediate and end products from by fructose’s reaction with amino acids, its role in the pathologies associated with t2d has been grossly underestimated “Compared with glucose, fructose increased the fluorescence intensity and the cross-linking of glycated collagen, and promoted the polymerizations of proteins… accelerated the production of advanced glycation end-products more than glucose” (Experimental Studies on the Role of Fructose in the Development of Diabetic Complication, 2002 and 2003 on the contribution of the polyol pathway to t2d through oxidative stress.

e.  Polyol pathway produces sorbitol and then fructose thus cellular fructosylation

The polyol pathway is a 2 step conversion of glucose to sorbitol (an alcohol sugar) and then to fructose.  It is turned on when within a cell there is excessive glucose,[10] can damage (toxic) the cell by excessive osmotic pressure—see 1990.  The polyol pathway is a quick way of lowering the amount of glucose by conversion to two other sugars, in a two-step process, first to sorbitol and then some of that to fructose, both of which can be further metabolized to produce the energy molecule ATP.  For LSP the frequency of the production of cellular fructose is a fraction of what occurs on the western diet, thus fructosylation (also grouped with glycation) occurs sufficient to contribute to CAWD. 

 Certain tissues, the retina, kidney, and nerves do not take up glucose by the GLUT 5 transport system as this system is missing only in those tissues, but rather glucose is absorbed by diffusion across the cell membrane, thus that tissue will absorb an excess of glucose when it is very high in the blood.  Turning on the conversion of cellular glucose is a quick way of lowering the excess glucose and avoiding the consequences of high osmotic cell pressure.  However that process doesn’t work right or in excess thereby creating intercellular pressure, which happens at a higher rate among the insulin resistant, since the starting point before eating has higher level of glucose, and even more so for the diabetic.  Among the diabetic the tight controlling the serum glucose has in trials failed to show endpoint benefits, and the degree of damage depending on the drugs used.   

Moreover the end product fructose present problem similar to that for hepatocytes.  The missing of the endogenous production of fructose enables pharma to stress glucose and slow management.   The polyol pathway has therefor adverse synergistic effect t throughout the body.   

f.   Low ascorbate in the polyol pathway  “The pathway is implicated in diabetic complications, especially in microvascular damage to the retina,^[2] kidney,^[3] and nerves.^[4] Wiki.  One issue arises because diabetic have low-level of ascorbate in those 3 tissues and the others which store a high level of ascorbate,[11] thus the lower level of ascorbate in diabetic could be a major contributory factor for the microvascular damage of the retina, kidney, and cause neuropathy--see 1990.  One pathogenic way is in the glutathione-ascorbate cycle which “detoxifies hydrogen peroxide” and other reactive species-see Wiki.  Thus diabetic given their low-level of ascorbate would likely have a low-level of glutathione (possible the most important of the body’s antioxidants) which is need to quench the ROS including from the fructose produced in the polyol pathway.  The lower level of glutathione in diabetics would promote damage from fructosylation.  This lack of glutathione explains why diabetics suffer from the effects of ROS.[12] 

g. Osmotic pressure from excess sorbitol, glucose and fructose, These sugars are hydroscopic within cells, and thus an excess cause an influx of water.  “As sorbitol does not easily dissolve across cell membranes this increases cellular osmolarity, ultimately leading to cell damage” Science Direct. The level of sorbitol is controlled by the next and final step in the polyol pathway, the synthesis of the reactive sugar fructose.  Thus we have a protective system, one which lowers intercellular glucose and thus osmotic pressure in the vulnerable tissues (kidneys, nerve and retinal cells which lack glucose transporters) gone wrong because of afore mentioned issues and likely other systems that are functionally compromised.[13]  The same functional issues, but to a less extent; I aver, applies to those who are insulin resistant including diabetics.  There are reasons why osmotic cellular pressure is regulated and this in part explains why cells become Insulin resistant through a feedback system that prevents excessive cellular osmotic pressure.   

h.   LSP on high carb diet avoids CAWD, why?  So why do those peoples on a high-carb, low-sugar diet not at the same risk levels as the TOFIs (excessive visceral fat but of normal weight)?  Their polyol pathway is turned on like those with TOFI when there is excessive glucose in a cell so as to lower the level and thereby lower osmotic pressure--2000 and 1977.  With TOFI, they have developed insulin resistance, have fatty liver compromised liver and kidney functions, and thus are metabolically different the LSP.   TOFIs are producing cellular fructose though the a safety valve that works fine among LSP who are on a high carb diet, but not when fructose is excessive and there is IR and fatty liver, as a study of rats feed a high fructose diet demonstrate—see 1990[14]  To this we have the other compromised cellular process associated with insulin resistance and diabetes including underproduction of collagen.  The detail as to which of the many effects associated with IR are most important is in need of further research.  

i.   Under-production of and oxidative damage to collagen:  Collagen is the foundation protein for many tissues:  there are 18 types of collagen and they make up over 35% by weight of the proteins.  The high sugar diet affects the production of collagen in several ways.  Attention to collagen occurred when it was found out that diabetics are vulnerable to the effects of lower ascorbate; which as a co-enzyme affects the production of collagen.  Other contributory factors for diabetics include the elevated uric acid, abnormal mitochondria causing lower ATP production, and reduced cellular repair rates for ROS.  All four just named—and likely others--reduce the synthesis of collagen.[15] These changes affect the function of ascorbate in the production of collagen.  This is through the hydroxylation of lysines and prolines on polypeptides.[16]  Among the suggested causes for this under-product of collagen is the depletion of NADP in the polyol pathway.  Though the research is incomplete for want of funding and faulty causal models, there is sufficient evidence to support the conclusion that that lower production of new collage to replace older, defective collagen is a vector in the comorbidities associated with diabetes IR and CAWD. 

An assortment of pathogenic consequence has been obtained experimentally in rats (Diabetes Jan 1989.   “Diabetes induced a greater defect in collagen production than food restriction and a greater decrease in collagen than non-collagen protein production within each group, suggesting a specific effect on collagen”[17] June 89 Diabetes.   “(1), decreased bone mass  and rate of formation (2), and thickening of the vascular basement membrane, (3) Abnormalities in the connective tissue of one organ may in fact be a signal of more generalized defects, which are seen in patients in whom increased skin thickness was correlated with an increased incidence of retinopathy and neuropathy (4) and in the limited joint mobility syndrome, which was associated with an increased risk of microvascular disease (4,5)… the widespread nature of connective tissue alterations in diabetes suggests that abnormalities in collagen metabolism may play a role.” at Diabetes 1988. See also Diabetes Jun 1989 and following on “endothelial dysfunction” and “bone fragility in aging, osteoporosis and diabetes” at link.  Collagen defects are the big piece in the puzzle that explains the wide variety of conditions associated with the high fructose diet.

j.  Fructosylation occurs to collagen.  The need for replacement collagen is increased because of the much higher rate of glycation by fructose, compared to glucose.  This ”leads to the formation of advanced Milliard products in the polyol pathway” at 89 and 2002.  Since the polyol pathway produces fructose throughout the body, this production affect collagen throughout the body. 

  In summation I hold that the association of CAWD with elevated glucose, which occurs among those who are diabetic or insulin resistant, because the polyol pathway is turned on to lower the level of glucose and thus osmotic pressure and as a consequence fructose is produced which results in fructosylation, and thus it is not the glucose but fructose that ultimately is pathogenic.  More research is needed because the extensive research on collagen during the golden era of medicine is now a trickle replaced by the search for marketable drugs.  Clinical trials of ascorbate and myo-inositol supplements for diabetics are lacking.  This hypothesis is made stronger by extensive evidence that fails to support a significant role of glucose in diabetic’s associated conditions—see section, VI.  The failure to follow up with a study showing the benefits of mega dose of ascorbate or myo-inositol for diabetics is one more example of the role of pharma in the practice of medicine:  standard of care is to threat diabetes with patented drugs that lower glucose mainly by raising insulin, a practice which harms patients.  There is a need for research into the level of ascorbate in cells that accumulate it among those with IR compared to those without IR, and also to do studies on the quality of collagen in those with IR.  The underproduction of collagen as a consequence of IR and explain in part CAWD in those without t2d.  For articles on collagen and ascorbate click on healthfully/rca.

k. Hypoxia and defective mitochondria  “Perturbations in the regulation of glucose and lipid metabolism are both involved in the insulin resistance in skeletal muscle in obesity and type 2 diabetes (2,3). Previously, our laboratory (30) as well as others (31) have observed that the severity of skeletal muscle insulin resistance in type 2 diabetes and obesity is related to diminished activity of oxidative enzymes. In addition, accumulation of triglycerides in skeletal muscle is also correlated with the severity of insulin resistance and with diminished oxidative enzyme activity in these disorders.(23) . . . The mitochondria area was reduce by ~35% in type 2 diabetes and obesity.” at 2002.  Size and shape of mitochondria are strong associated with compromised functioning of the mitochondria—see for example the work of Nobel Laureate Otto Warburg.  Research is needed to find out if this change also occurs with IR.

l.  Endothelial dysfunction and atherosclerosis and peripheral artery disease  “Endothelium plays a central role in atherogenesis” at 2002.  “Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease” at 2009. “Therefore, we hypothesized that uric acid induces endothelial dysfunction by inhibiting nitric oxide production” at 2005.  Another contributory factor is that following apoptosis the “regenerated endothelial cells are dysfunctional”, at 2009, which parallels the dysfunctional replacement collagen discussed IV I & j.  The synergistic effects of excessive fructosylation, under-production of collagen, and hyperuricemia and the others mentioned in this section, they compromise the gatekeeper functions of the endothelial cells lining the arteries in ways that promote atherogenesis—see jk, and for a 2016 summation of endothelial dysfunction.  You need to put out of your mind the industry causes of saturated fats, cholesterol and hyperglycemia, and replace them with the afore-listed consequences of the high fructose diet.      

V.  Diabetes a window on causes of CAWD

a.  Introduction:   T2d is quite different than type 1 diabetes(t1d).  T1d is caused by the destruction of most of the insulin producing bête cells; t2d is the result of IR that causes the excessive accumulation of fat in the pancreas which causes underproduction of insulin.  Type 1 causes a pathological accumulation of glucose which in the era before insulin was fatal in over 90% of the cases, while type result merely in elevated glucose, a condition that often is not significantly symptomatic.  This period of lowered production of insulin is altered by many of the drugs given to lower serum glucose most often though elevating insulin.[18]  The pathological association with t2d is complicated by the effects of having for years elevated glucose and from elevated insulin (IR) and all the effects listed about IR.  Many of these with t2d are diagnose as having MeS, and thus many have been taking for years statins and hypertension drugs.  Once diagnosed as diabetic, to the mix is add the side effects from the medications that lower level of glucose.  Of course the doctors will attribute all the side effects from being diabetic; pharma’s mantra is safe and effective.  And it gets worse among the hypertension drugs are those which effect cognitive functions, as does statins which lower ATP 40%.  Being in a mental cloud creates reliance upon their physician.  Using LSPs as a standard, 95% of those above the age of 40 in the US population are IR.  Thus we have a complex system of causes at work in which more research is needed to sort out the causal processes and their degrees.  I will assume that though the literature associates the 4 below (and other not listed) as a result of t2d, I will presume that in a significant degree they are also present with IR.  With more research the list will change.  For now I will start with biological difference that are associated with t2d, that have not been investigated or the literature is thin to see if it occurs with IR.

b.  NADPH depletion:  There are other ways in which diabetes (and I would aver IR) have pathogenic consequences by reducing NADPH used in other metabolic processes to the inactive NADP+.  “Increased polyol pathway activity also alters the redox state of the pyridine nucleotides NADP+ and NAD+, thus reducing their concentrations. Since these are important factors in many enzyme-catalysed reactions, many other metabolic pathways may be also affected”  Science Direct.  The depletion of NADPH oxidase is associated is caused by fructose and its causing the production of ROS, 2004.  “NADPH is also the essential cofactor for regenerating a critical intracellular antioxidant, reduced glutathione” Diabetes 2005.  By reducing the amount of reduced glutathione, the polyol pathway increases susceptibility to intracellular oxidative stress, compounded by other biological consequences.   High blood glucose elevates the production of sorbitol and thereby can significantly reduce the level NADH; however, more research is needed to show this potential issue has in fact pathological consequences, and the significant tor a real-world population on the western diet.      

c.   Lower NO (nitric oxide) causes endothelial dysfunction:  There a number of articles supporting lower NO to causal for CVD through the endothelial cells.  The causal pathway is through elevated glucose:  “in vitro with high concentrations of glucose activates protein kinase C (PKC) and increases nitric oxide synthase (NOS III) gene expression as well as superoxide production” Circulation Research 2011.[19]  I haven’t sufficiently research this theory; nevertheless I have a gut feeling that this isn’t a major cause or it’s a sign, like elevated triglycerides rather than a cause.  This gut reaction is based on its putative connection with hyperglycemia others offer an explanation based upon the lipid hypothesis and hypertension hypotheses, neither of them are causes.  Association doesn’t prove cause.  The NO-endothelial dysfunction hypothesis fits into marketing goals of pharma.  Over and over again I have come across pharma’s KOLs and others gathering evidence to support a pro-drug explanation; but upon examination of the totality of evidence I almost always reject the industry favored analysis and side with the chorus of critical professors--sometimes the chorus is quite small. The chorus is small for NO, but it seems to me that the reduced arterial dilation is a sign of damaged endothelial cell rather than a cause of the damage.  Even if I am wrong, the roll of NO is less than the major factors I stress. I consider both NO and the microbiome examples of deliberate misdirection by industries.      

d.  Microbiome:  It is known that the microbiome has a role in diabetes pathophysiology”, Science May 2018, [20] Seems farfetched for two reasons, one there is a known healing process which is turned on when insulin is low, autophagy, and second the theory supposes that the pathogenic bacteria are adversely effected by their reduction in glucose supply more than the benign bacteria, and that in this weakened state the benign bacteria will eliminate colonies of the t2d causing bacteria. As stated in the footnote this misses the role of fructose, fatty liver and pancreas.  Given the complexity of the microbiome with millions of species and subspecies of bacterial, I don’t think given the present research will produce answers.  Moreover, this fails to explain why LSP don’t develop t2d.

Fasting is good, but not for the microbiome, but because of autophagy, which permits the metabolism of the excessive fat in the pancreas and liver. Fasting subsequent to bariatric surgery explains why over 80% of diabetic are cured or  greatly reduce their medication within weeks of the surgery—this occurs before significant weight loss. 

e.   Fructosylation:  The third step is the end-product of the polyol pathway, the conversion of sorbitol to fructose and the fructose bonds to amino acids and other receptive molecules such as unsaturated fats.  This production of fructose occurs significantly in the kidney, retina, and nerves.  All these organs have been shown to have elevated fructosylation end products and elevated health issues among the diabetics. In additions through the polyol pathway fructose is the end product in cells, and these cells—but for the liver-cannot metabolize fructose; thereby causing fructosylation at a high rate.  Given the general lack of awareness of this issue, many researchers attribute the damage to proteins and polyunsaturated fats as the result of ROS, and their testing doesn’t distinguish the two possibilities.  Though there is little research, the lack of a metabolic pathway for fructose outside the liver and our high sugar diet support its cellular role in CAWD.

f.  Defective mitochondria:  Type 2 diabetics have defective mitochondria, at 2005, 2006.   “A reduced basal ADP-stimulated and maximal mitochondrial respiratory capacity underlies the reduction in in vivo mitochondrial function, independent of mitochondrial content.  A reduced capacity at both the level of the electron transport chain and phosphorylation system underlies this impaired mitochondrial capacity”, at 2008,  see 2010 for more systems.  The reduce capacity of mitochondria entails a lower rate of metabolism of both fats and glucose.  This lower rate of turnover of glucose entails higher level of glucose in cells and blood, which entails in the cell resistance to transport into the cell-- which is increased insulin--and thus an increase release of insulin by the pancreas into the blood.  A studied compared 10 lean persons to 10 type-2 diabetic, and their insulin levels were nearly 5 fold higher and their fasting glucose 63% higher for the diabetic at 2001 see Tables 1 & 2 below.  The cause for the reduction in metabolism of glucose is that the mitochondria of type-2 diabetics are about 1/4^th the size of a lean person This results in reduced ATP production, and since ATP is the energy source for about 90% of synthesis processes, this reduction has numerous negative cellular consequences.  With lower production of ATP the over 50 processes that promote cellular healing are down-regulated, and thus the increased damage by ROS—see 2008, 2012[21], and 2011.  On top of this insulin when low turns on those process (many of which are in the healing category of autophagy), thus IR reduces the window of time for those healing processes.  The deformed mitochondrion, because of their lower production of ATP, is a major cause for CAWD.  I believe that many of the lean like those of the LSP are at very low risk for CAWD in part because both have normal mitochondria.  By extension given the diabetics and normal weight people on the western diet get the same conditions, only the diabetics at several fold the rate, I propose that  many in the former to groups have smaller mitochondria but to a lesser extent than the diabetics.  Reduction in ATP I hold is more significant that ROS, since ATP is essential for cellular repair of non-enzymatic oxidation.  Research is needed to confirm what appears logical.    

Table 2 from 2001

^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

Table 1 from 2001

Tables from Dysfunction of Mitochondria in Human Skeletal Muscle in type 2 diabetics, at 2002

 g.  “ Hyperosmolar hyperglycemic state (HHS) is a complication of diabetes mellitus in which high blood sugar results in high osmotic concentration  without significant ketoacidosis.^[4] Symptoms include signs of dehydration, weakness, legs cramps, trouble seeing, and an altered level of consciousness.^[2] Onset is typically over days to weeks.^[3] Complications may include seizures, disseminated intravascular coagulopathy, mesenteric artery occlusion, or rhabdomyolysis^[2]” Wiki.  This tights in with the above material on the polyol pathway as nature’s way of lowering increased cellular osmic pressure caused by excessive cellular glucose. “ Triggers include medications and combinations of medications, infections, trauma, and major stroke or heart attack.  Diagnosis is based on blood tests finding a blood sugar greater than 30 mmol/L (600 mg/dL), osmolarity greater than 320 mm/kg, and a pH above 7.3.^[2][3]  Older people are most commonly affected.^[4] The risk of death among those affected is about 15%.^[4] It was first described in the 1880s^[4]”  Wiki.  Hyperosmolar thus hyperglycemic state is only weakly associated with death once the confounding variable of degree of IR is adjusted for.  Hyperglycemic state is greatly over-emphasized by pharma.  Tight management of glucose doesn’t not for most types of drugs confir benefits for patients.  This conclusion is based on the failure of studies to show that drugs which lower serum glucose while raising cellular glucose lower mortality.[22]  I couldn’t find a single study on diabetics who aren’t treated, even though there a many who go years before diagnosis, and other who manage their T2D with diet. See Section VI for more on glucose.   

g.  Uric acid role in pathology has been as much as the research permits developed in Section II f and Section IV b.  The complexity of its functions, the thinness of research to the other conditions besides CVD and nephritis, and lack of a seminal article putting it all together are the reasons I am not again developing this topic.

h.  Cortisol Is a steroid hormone produced by the zona fasciulata of the adrenal cortex.  When used as a medicine is it known as hydrocortisone. It is elevated in diabetics.  After spending a week looking at the evidence in support of elevated cortisol as a major cause of pathologies weak.  Its association with diabetic complications is based upon the degree of diabetes Thus its elevation in diabetics I hold to be a response to the conditions associated with IR, rather than a cause of those conditions.  In fact it might be, like with the immune system, a response to stress.  “[C]ortisol secretion was found to be associated with complications and metabolic control of diabetes, at 2007.  And again I must suspect that pharma has sullied the evidence base because of the use of off-patent hydrocortisone.

i.  mTOR

j.  Summation:  I hold there is a continuum of IR, with t2d being the most advanced and pathogenic.  Based on the continuum, the increased risk for nearly all of the CAWD is part of that continuum, and thus the finding for t2d can be extended to IR.  

VI.   Blaming elevated glucose for the comorbidities of t2d, obesity, and MeS—association doesn’t prove significant causality but profits industries

            a.  Evolutionary question:  evolution does a very good job of protecting mammals from common environmental hazards.  Why don’t LSP on a high starch diet have high fasting glucose and HbA1c?  And why don’t they have conditions associated with the western diet in proportion to their serum glucose level? Their level is below 95% of Swedes in 1999, see Section 1c, yet the conditions are virtually unknown?  These questions suggest that dietary glucose e is not the problem, nor elevated serum glucose, but rather recent dietary changes, in particular fructose. 

The pattern repeats:  Pharma profits from treating a sign and searching for new drugs to treat signs while burying the major causes under a stack of KOLs’ journal articles.  Managing glucose and the chronic conditions that develop is very profitable.                                             

B .  Glycation by glucose is not a major cause for CVD and other CAWDs:  This bromide of medical wisdom was born out of t1d study, however, it is much different condition than t2d:  one condition has near zero production of insulin, the t2d patients have IR, insensitivity to insulin.  When their pancreas production of insulin declines (because of fat accumulation), their IR becomes mildly symptomatic.  The response to drugs that raise insulin or promote its activity are much different for these patients. 

 Dr. Jason Fung points this out in the Obesity Code, p. 80 that pharma used a trial for t1d the lower side effects, to “educate” doctors with this trial (and other subsequent trials); however, the logic is flawed because most t1d patients were never insulin resistant.  And it gets worse in that pharma ignored the weight gain of 9.8 pounds more for the tight control group—insulin promotes fat storage.  By not following the long-term consequence, pharma avoids the side effects associated with MeS including obesity including cancer.  This and in other ways they produced results which supported the role of glucose as the major pathogenic factor, and thus that diabetics both type 1 and 2 needed to tightly control the level of glucose.   

Several types of evidence presented here show that glucose alone is not pathogenic.  For example those life-long low-sugar diet high starch diet:  traditional Japanese diet which is high in the refined carbohydrate white rice; they have a low rate of CAWD—and it would have been lower if they didn’t smoke and drink.  So too does other societies such as Kitavans and Okinawans who eat starchy root crops as a staple.  All of them average less than 30 grams of sugar daily from all sources.  A high glucose/starch diet doesn’t cause IR, t2d, MeS, or CAWD.  Thus the association of the western diet doesn’t prove causality for refined carbs--merely removing the nutritional parts from grains is not causal.[23]  As shown above it is the fructose mainly obtained from sucrose that is causal. 

Another consideration is the lack of linear association of CADW with the increase in serum glucose:  the normal level of serum glucose for those on a western diet and the elevated level of prediabetics.  The diabetic is not considered because their level is now similar to the prediebetic.  START

c.   A historical prospective:   Gary Taubes in The Case Against Sugar reviews the biological effects of fructose and how industry has deflected criticism.   Sugar came into the 20^th century with a bad rap, that of causing the health problems of the upper class, since until about the 1850s only the affluent could afford those luxury foods.  Then with the extraction of sugar from cane and beats the price dropped, but usage was for most of the working class limited.  The market for sugar laden product grew but was still one third of our present consumption.  Gout and obesity were the most visible conditions of the affluent, and it was popularly held to be caused by sugar.   

____________________________???

 The difference is about 30%, but for most conditions the risk is doubled or greater.   When that person drifts toward t2d, the period of elevation is typically under a year, which is two short a period for the pathologies that normally develop after 10 years and longer.  The biological evidence for cause of those conditions as being linked to glucose is weak, made all the weaker when compared to the same type of evidence for fructose.  Thus elevation of the less reactive glucose is insufficient to account for the increase in CAWD. 

,??? this pales in comparison to the Kitavan thus the pathological consequence I would place behind uric acid, underproduction of collagen, and polyunsaturated fats (see below) on the list of causal factors for CAWD.  One reason is based on results of tight management of glucose for type 1 and type 2 diabetics doesn’t have positive endpoint outcome.[24]  Pharma holds diabetes is a lifelong progressive disease and that their comorbidities are caused by high plasma glucose through glycation and its subsequent oxidation (ROS), thus ideal treatment is to keep glucose low with drugs.  But rather then cut back on drugs, carbohydrates are not restricted:  their KOLs including those in ADA (American Diabetic Association) hold that eating carbs (glucose) is necessary to avoid hypoglycemia caused by their drugs, and this should be done 6 times a day.  But clinical Trials have failed to show that tight management of glucose, compared to standard treatment for diabetics reduces the elevated pathologies associated with t2d.  Glycation, as stated in II b, is the non-enzymatic attachment of a monosaccharide to a protein (amino acid), and this both compromises both the functions of the protein and through further reactions by ROS produces pathogenic products.  Again sadly I must mention the norm for industry–funded studies is scientific fraud NEJM.  A second norm is for pharma to expand the market for their drugs.  As a consequence, doctors are told by KOLs and given handout reprints of journal published clinical trials which “demonstrate” that for t1d and t2d tight management of blood glucose results in lower adverse advents.  “This [UKPDS] reported three endpoints:  it found no benefit for the first two, which were dearth and diabetes-related death; but it did report a 12 percent reduction in composite endpoint [of 14 items]” (Ben Goldacre, p 196).  Other studies have confirmed this.  The Cochran Review meta-analysis found using industry studies that with tight control compared to standard control, “treatment in 1,000 adults would lead to between zero and two people avoiding non-fatal myocardial infarctions”.  And it gets worse, in that with tight management the increase in drugs diabetes is accelerated and thus if tracked until the endpoint of death, tight management significantly shortens life and quality of life.  Tolerance to insulin results in a spiraling increase in insulin injections and with that increased fat storage (weight gain), and the comorbidities of t2d; it is why t2d is called a progressive disease.  The studies of pre-diabetics--ADA criteria for fasting glucose 100 mg/dL to 125-- have failed to justify the use of drugs even though the pre-diabetics have substantial increased risk for all the CAWD compared to those who se level is in the bottom 20%.     

d.  Fructose is safer than sugar for diabetic and doesn’t cause MeS--Wikipedia:  An expert panel of the European Food Safety Authority concluded that fructose is preferred in food and beverage manufacturing to replace sucrose and glucose due to the lower effect of fructose on blood glucose levels following a meal.^[11] However, as a common sweetening agent for foods and beverages, fructose has been associated with increased risk of obesity, diabetes, and cardiovascular disorders that are part of metabolic syndrome.^[9] Clinical research has provided no or only limited direct evidence that fructose itself is associated with elevated LDL cholesterol and triglycerides leading to metabolic syndrome,^[53] but rather indicates that excessive consumption of sugar-sweetened foods and beverages, and the concurrent increase in calorie intake, underlies metabolic syndrome.^[9] Similarly, increased consumption of sweetened foods and beverages raises risk of cardiovascular disease, including hypertension,^[54][55] but there is no direct cause and effect relationship in humans showing that fructose is the causative factor.^[9]

Fructose is often recommended for diabetics because it does not trigger the production of insulin by pancreatic β cells, probably because β cells have low levels of GLUT5,^[56][57][58] For a 50 gram reference amount, fructose has a glycemic index of 23, compared with 100 for glucose and 60 for sucrose.^[59] Fructose is also 73% sweeter than sucrose at room temperature, allowing diabetics to use less of it per serving. Fructose consumed before a meal may reduce the glycemic response of the meal.^[60] Fructose-sweetened food and beverage products cause less of a rise in blood glucose levels than do those manufactured with sucrose or glucose.^[11]‑  Wiki 2018, June.  This is another case of industry’s experts writing the articles and framing the topic for dieticians, physicians, and media--welcome to United States Inc. 

VII  Prevention and signs of insulin resistance

a.     Prevention: Prevention is easy simply limit sugar.  How much depends on metabolism.  An elite athlete can consume about 4 times the average 70-year old without developing insulin resistance.  For a person who isn’t IR the average male, active 30-year old can consume can consume about 60 grams a day, and a woman about 40 grams.   Teens can consume more.  Activity level and rate of metabolism make a big difference.  But why endure the fate of Prometheus?[25] damage the liver with fructose and then have it repaired Of course the best diet is to stay low fructose.[26]

b.    How to tell if you are insulin resistant:  A person who is insulin resistant can have normal HbA1c and normal fasting glucose because they are secreting excessive insulin to lower blood glucose.  Only in more advanced state of IR dose that person have a rise in both of the glucose measurements.  The gold standard is to perform a glucose tolerance test in which insulin is measured, not the serum glucose.  See below the Joseph R. Kraft section; he performed this test on over 14,000 patients.  Other signs strongly associated with IR are 1) a fatty liver (NAFLD) for which a sonogram is the preferred test; 2) elevated HbA1c and/or fasting glucose; 3) to gain weight and need to diet to lose it; 4) yo-yo diets; 5) a non-smoker who has atherosclerosis thus CVD; 6) hypertension, which is a sign of atherosclerosis and kidney damage; 7); elevated uric acid which is causal for kidney damage and ED; 8) and CAWD—see  Section I.  Given that when compared to the Kitavans who eat a high starch diet which is low in sugar, by their standards about 90% of adults by the age of 30 are insulin resistant—see Staffan Lindeberg, are the work of Joseph Kraft in appendix. 

VIII The error of blaming palmitic acid or other saturated fats for CVD

“Since the 1990s, these researchers have established certain findings unambiguously.  First, feed animals enough pure fructose or enough sugar (glucose and fructose) and their liver converts some of the fructose into fat—the saturated fat palmitic acid, to be precise, which is the one that supposedly gives us heart disease when we eat it, by raising LDL cholesterol [see cholesterol myth].  The biochemical pathways involved are clear and not particularly controversial.  Feed animals enough fructose for long enough and this fat accumulates in the liver, cause the kind of fatty liver seen in obese children and adults.  The fat accumulation accompanies insulin resistance, first in the liver and then other cells as well, resulting in metabolic syndrome, at least in laboratory animals.  . . . The effects may take several months to appear if the animal are fed something closer to what humans in America actually consumer—around 20 percent of calories in their diet.  Stop feeding them the sugar and the fatty liver goes away and with it insulin resistance .  In a 2011 study in which twenty-nine rhesus monkeys were given the opportunity to drink a fructose-sweetened beverage along with their unusual monkey chow, every last one of them developed “insulin resistance and many features of the metabolic syndrome” within a year, and four had progressed to type 2 diabetes”--Taubes, p204-5.  De novo lipogenesis produces palmitic acid[27].  The association with CVD is through the fructose which is converted to palmitic acid, thus it is the fructose that is causing CVD.  This is one way that palmitic acid and in general saturated fats get blame form CVD and ischemic events.  The fire caused by the high starch plus fructose in the liver is ignored while the blamed is placed upon their conversion product palmitic acid. 

XI  Dietary fix   insulin resistance, type-2 diabetes,  obesity, fatty liver,  TOFI, and CAWD

a. What doesn’t work:  eat less and move more   Pharma’s and food manufacturer’s fix is to eat less, exercise more, frequent small portions, and replace energy dense fats with carbs; thus a high insulin diet.  It work for those who don’t have long-term (over 2 years) weight issue, because by the end of 2 years most with the exception of some children, have had their weight regulatory system rest through the hormones secreted by the adipose tissue to the increased weight.  The standard advice  doesn’t fix the mammalian weight-regulatory system because it doesn’t cure IR; thus, we have the yo-yo diets.  Yo-yo because—as mentioned above—leptin secreted by the adipose tissue functions to restore the amount of fat to a set point, and in this case because of insulin resistance, that point has been set in their recent past.  Leptin then will cause an increase in appetite and a reduction in metabolism of 20—40%; and with that reduction the dieter will fell that he needs to eat more to feel better.  This is why for most gradually over the next 6 years their weight increases to the set point and frequently higher if that person is sufficient insulin resistant; this is the fate of nearly all those who attempt to restore their health by the caloric-restricted diet recommended by physicians. 

b.  Obesity and t2d are dietary problems with a dietary fix.  The path to health is illuminated by the results of bariatric surgery.  Bariatric surgery is able to cure 80% of the diabetics, and 51% at 12 year follow up.  Most diabetics following the surgery are off their medication in the first two months, before major weight loss.  Following surgery the intravenous feeding limits calories to around 500 per day; this indicates that the forced fasting is curative vector—not weight loss.  Other studies have shown that fasting and for some the ketogenic diet cures through metabolism of excess stored fat in the liver, and for diabetics in the pancreas.  Following surgery they are on an extremely low calorie, low insulin diet; their body metabolizes the excess fat in the liver and pancreas which cures their diabetes and insulin resistance—excess insulin increases fat storage.[28]  The long-term cure rate would be higher if those surgery patients had been warned of the roll of fructose and had a low carb diet in the hospital and afterwards.  A small but growing group of physicians (Dr. Jason Fung and Dr. Michael Mosley[29] are the best known) are now advocating fasting (both intermittent and alternate day) and lowing carbs or a ketogenic diet.  They have been able to cure type-2 diabetes and obesity by curing insulin resistance and fat storage in the liver and pancreas.  With low insulin, the body continues the process of autophagy—started while sleeping—that metabolizes the excess fat in the pancreas which causes the reduction in the production of insulin for those with t2d.  The metabolism of the excess fat in the liver cures NAFLD and IR.  Since insulin causes fat storage, the low insulin diet accelerates weight loss.      

Mediterranean diet is healthy because of the high consumption of olive oil; wrong, it is the low consumption of sugar.  This is part of the mountains of proposed causes and fixes currently circulating.  That which explains what has gone wrong and the fixes are buried within the mountain of media stimulated social twaddle.  Switching to a Mediterranean diet won’t fix the fatty liver, insulin resistance, and diabetes, thus what is offered as a fix, isn’t: nor will it cure IR, because of the failure to warn about sugar.      

Good and bad fats:   “The type of fats in the diet are important, with saturated fats and trans fatty acids increasing the risk, and polyunsaturated and monounsaturated fat decreasing the risk^[26]” Wikipedia (contrary to the mass of evidence, see rancid fats and saturated fats). The only way to sort out the tobacco science is to question everything, and rely upon the modus operandi.  The modus operandi:  Polyunsaturated and to a lesser extent monounsaturated fats because of their double bond(s) have free electrons which is available for attachment to by reactive chemicals, which when in sufficient amounts and occurring within cell walls, it becomes a healthy issue.   Because of oxidation, milk is high in saturated fats.   

The Dietary Fix and in concise, some links:  The question isn’t how can I lower my risk factor for CAWD to that of those who live on Crete (Mediterranean diet),[30] but to lower it to the level of the Kitavans (footnote 11).  This requires undoing the damage done to our complex weight regulatory system, and then not damaging it again by excessive fructose.[31]  The simple answer is fasting made more effective with a low carb diet.   To learn more I highly recommend reading the two books by Dr. Jason Fung and watching his lectures on YouTube.  In a more concise form then his books, you will find my dietary advice and a longer version (my advice was arrived at prior to reading and watching his lectures).  It is easier not to eat than to significantly reduce calories long term.  With fasting the body burns fats, not conserve it, and increases metabolism to promote searching for foods.   It is as Dr. Fung wrote in Obesity Code, “It is more important not to eat than what you eat.”  In one clinical trial, skipping breakfast resulted in a reduction of 539 calories per day.  An easy start is intermittent fasting (skipping a meal or 2) and progress into alternat e day fasting and thereby avoid the metabolic consequences of being in the starvation mode.   Going on a low carb (insulin) extends autophagy and accelerates the rate of weight loss.   

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