Fructose pathology
Fructose pathology
Sugar Buzz Lustig & fructose and NAFLD articles
382 day fast
Insulin Reistance and Fatty Liver, at the heart of the storm--Fung
Excess sugar and fatty liver experiment, heart of storm   2/16/17

Exposes standards method for measuring glycation of fructose underestimates it rate.  Compared two methods of measuring glucose fructose glycation products; it occurred for fructose at a 3 fold great rate for formation of carbonyl, and a 15 fold when using fluorescence intensity.

 Journal of Diabetes and its Complications Volume 9, Issue 2, April–June 1995, Pages 87-91

Significance of fructose-induced protein oxidation and formation of advanced glycation end product


To investigate the significance of fructose-induced protein modification, we examined both fructose-and glucose-induced protein oxidation and the formation of advanced glycation end products (AGE) in vitro. Albumin incubated in the presence of 100 mM fructose at 37 C for 1 week showed 5.1-fold and 3.1-fold increases in the content of carbonyl, which is a marker for oxidized protein, when compared with either control incubated without sugar or with 100 mM glucose. Similarly, the same incubation with fructose increased the fluorescence intensity over 100-fold and 15-fold formation compared with that of no sugar and glucose controls, respectively. Both fructose-induced fluorescence and protein oxidation were almost completely suppressed in the presence of the iron chelator; deferoxamine (100 μM), the hydroxyl radical scavenger; MK-447 (1 mM), or aminoguanidine (200 mM), which is an inhibitor of AGE formation. In contrast, the fructose-induced formation of fluorescent albumin was potentiated in the presence of 100 μM FeCl2. This was completely inhibited in the presence of 60 μM or more deferoxamine. These results suggest that fructose promotes both AGE formation and protein oxidation possibly through the formation of hydroxyl radicals.



Kobe J. Med Sci, Vol 48 no 5 pp 125-136, 2002

Experimental Studies on the Role of Fructose in the Development of Diabetic Complications

Supports the finding of Lustig below.  This PDF form wont copy.  Of interest was a comparison of the extent of glycation of collagen after incubation; for glucose it was 86.9% of the collagen was in tack while with fructose it was 15.9%


Fructose & sugar addition from carbs Part 3  /rh/id3.html   (9/23/16)

Fructose, the differences from glucose:  Unlike glucose, which is metabolized widely in the body, fructose is metabolized almost completely in the liver in humans, where it is directed toward replenishment of liver glycogen and triglyceride synthesis.   Fructose is also not metabolized in insulin-sensitive peripheral tissues. Fructose is selectively taken up and almost completely metabolized by liver hepatocytes, while much of dietary glucose passes through the liver where it is metabolized in skeletal muscle to CO2, H2O and ATPWiki. Fructose is often recommended for diabetics[1] because it does not trigger the production of insulin by pancreatic β cells, probably because β cells have low levels of GLUT5 [transport system into pancreas] although its net effect is debated.  Fructose has a very low glycemic index of 19 2, compared with 100 for glucose and 68 5 for sucrose.  Fructose is also seventy-three percent sweeter than sucrose.  Compared with consumption of high glucose beverages, drinking high-fructose beverages with meals results in lower circulating insulin and leptin levels, and higher ghrelin levels after the meal.  Since leptin and insulin decrease appetite and ghrelin increases appetite, some researchers suspect that eating large amounts of fructose increases the likelihood of weight gain.   However there are 2 metabolic pathways in fructolysis:  one produces triglycerides from DHAP and glyceraldehyde 3- phosphate; the other converts DHAP into glucose and glycogen.  “Since fructose consumption has been hypothesized to be a cause of insulin resistance, obesity, … and, leading to metabolic syndrome. In preliminary research, fructose consumption was correlated with obesity.  A study in mice showed that a high fructose intake may increase adiposity.  While a few other tissues (e.g., sperm  cells and some intestinal cells) do use fructose directly, fructose is metabolized primarily in the liver.  Since leptin and insulin decrease appetite and ghrelin increases appetite, some researchers suspect that eating large amounts of fructose increases the likelihood of weight gain.  A preliminary human study indicated that fructose may not influence metabolic activity or blood flow in brain regions regulating satiety ("fullness"), and so may promote overeating.  Excessive fructose consumption may contribute to the development of non-alcoholic fatty liver disease [describe below}Wiki,2015.  Typical findings for effects of high fructose diet include:  Fructose is more lipogenic [fat and cholesterol producing] than glucose or starches, and usually causes greater elevations in triglycerides and sometimes cholesterol than other carbohydrates.  Dietary fructose has resulted in increases in blood pressure, uric acid, and lactic acid.  People who are hypertensive, hyperinsulinemic, hypertriglyceridemic[2], non-insulin-dependent diabetes, or postmenopausal, they are more susceptible to these adverse effects of dietary fructose than healthy young subjects.”  In Fructose, weight gain and insulin resistance syndrome, 2000 journal article states:  Because leptin production is regulated by insulin responses to meals [and fructose  stimulates insulin production only 17% compared to glucose], fructose consumption also reduces circulating leptin concentrations. The combined effects of lowered circulating leptin and insulin in individuals who consume diets that are high in dietary fructose could therefore increase the likelihood of weight gain[3] and its associated metabolic sequelae [injury].”  Corresponding with the rise in CVD and obesity has been fructose’s dietary increase.  USDA chart:  The per-capita yearly consumption of sweeteners was 109 lbs. in 1950 and 152 lbs. in 2000.[4]  With the major reduction in corn syrup (pure glucose), which has been replaced with HFCS (high fructose corn syrup) our fructose consumption has doubles.  Thus the harm done is far greater than the increase in 43 pounds of added sweeteners would indicate.  The USDA states: “The food consumption in 1970 was 2275 calories and in 2000 was 2,750 calories per person per day, 475 calories above the 1970 level.”  Though both glucose and fructose are about equally efficient at producing ATP (the body’s energy source), fructose rate of glycation is 7.5 fold greater [actually 15 fold because of slower clearance than glucose].  This estimate of difference between fructose and glucose has been confirmed experimentally using albumin, “15 fold increased formation compared to glucose” at.   Not surprisingly fructose has a much greater role than glucose in obesity, IR, MeS, fatty liver disease, and numerous chronic conditions. 


Glycation:  its role in the pathologies has been underrated (for reasons relating to the lipid hypothesis).  Glycation (sometimes called non-enzymatic glycosylation) is the result of typically covalent bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose, without the controlling action of an enzyme. All blood sugars are reducing molecules. Glycation may occur either inside the body (endogenous glycation) or outside the body (exogenous glycation). Exogenous glycations and Advanced Glycation End products (AGEs) are typically formed when sugars are cooked with proteins or fats. Temperatures over 120C (~248F) greatly accelerate the reactions, but lower temperatures with longer cooking times also promote their formation.  Glycation may also contribute to the formation of acrylamide,[2] a potential carcinogen, during cooking.  Food manufacturers have added AGEs to foods, especially in the last 50 years, as flavor enhancers and colorants to improve appearance.[4] Foods with significant browning, caramelization, or directly added preformed AGEs can be high in these compounds.  Until recently, it was thought that exogenous glycations and AGEs were negligible contributors to inflammation and disease states, but recent work has shown that they are important (Vlassara, 2005). Enzyme-controlled addition of sugars to protein or lipid molecules is termed glycosylation [part of production of useful bioactive molecules, while] glycation is a haphazard process that impairs the functioning of biomolecules. Much of the early laboratory research work on fructose glycations used inaccurate assay techniques that led to drastic underestimation of the importance of fructose in glycation.[1]  Glycated substances are eliminated from the body slowly, since the renal clearance factor is only about 30%. This implies that the half-life of a glycation within the body is about double the average cell life. Red blood cells are the shortest-lived cells in the body (120 days), so, the half-life is about 240 days. (This fact is used in monitoring blood sugar control in diabetes by monitoring the glycated hemoglobin level.) As a consequence, long-lived cells (such as nerves, brain cells) and long-lasting proteins (such as DNA, eye crystalline, and collagen) may accumulate substantial damage over time. Metabolically-active cells such as the glomeruli in the kidneys, retina cells in the eyes, and beta cells (insulin-producing) in the pancreas are also at high risk of damage” Wiki.  However, it is the accumulation of fat that is the knock-out punch in the process that leads to reduced production of insulin by the beta cells of the pancreas and thus T2D.

 Endogenous glycations occur mainly in the bloodstream to a small proportion of the absorbed simple sugars glucose, fructose, and galactose. It appears that fructose and galactose [from lactose of milk] have approximately ten times the glycation activity of glucose, [actually 15 times see end of previous paragraph] the primary body fuel.[6] Glycation is the first step in the evolution of these molecules through a complex series of very slow reactions in the body known as Amadori reactions, Schiff base reactions, and Maillard reactions; which lead to advanced glycation end products (AGEs). Some AGEs are benign, but others are more reactive than the sugars they are derived from, and are implicated in many age-related chronic diseases such as cardiovascular diseases (the endothelium, fibrinogen, and collagen are damaged), Alzheimer's disease (amyloid proteins are side-products of the reactions progressing to AGEs),[7][8] cancer (acrylamide and other side-products are released), peripheral neuropathy (the myelin is attacked), and other sensory losses such as deafness (due to demyelination).  This range of diseases is the result of the very basic level at which glycations interfere with molecular and cellular functioning throughout the body and the release of highly oxidizing side-products such as hydrogen peroxide.  Long-lived cells (such as nerves and different types of brain cell), long-lasting proteins (such as crystallins of the lens and cornea), and DNA may accumulate substantial damage over time. Cells such as the retina cells in the eyes, and beta cells (insulin-producing) in the pancreas are also at high risk of damage[citation needed]. Damage by glycation results in stiffening of the collagen in the blood vessel walls, leading to high blood pressure, especially in diabetes.[9] Glycations also cause weakening of the collagen in the blood vessel walls[citation needed], which may lead to micro- or macro-aneurisms; this may cause strokes if in the brain [vascular dementia]” Wiki 2015.  We have gone from 15 grams of sugar in 1900 to 188 grams, of which approximate 90 are fructose.  This has overwhelmed the system for repairing the damage caused by glycation.  Advanced glycation end products (AGEs) are proteins or lipids that become glycated as a result of exposure to sugars.[1] They can be a factor in aging and in the development or worsening of many degenerative diseases, such as diabetes, atherosclerosis, chronic renal failure, and Alzheimer's disease…. In clearance, or the rate at which a substance is removed or cleared from the body, it has been found that the cellular proteolysis[5] of AGEs—the breakdown of proteins—produces AGE peptides and "AGE free adducts" (AGE adducts bound to single amino acids). These latter, after being released into the plasma, can be excreted in the urine[24]Wiki.  AGEs in the liver and elsewhere are recognized as foreign substances by the immune system and can in sufficient number produce significant inflammatory response.  The attributing of excess fat in the liver as the primary cause for liver inflammation is questionable given the co-existence of AGEs in the liver and the natural inflammatory response by the immune system.  Also under-rated is the role of glycation in retinopathy, nephropathy, and endothelial dysfunction[6] in diabetics, and the over attributing to reactive oxygen species created by metabolism—see  Protein Glycation, A firm Link to Endothelial Cell Dysfunction:   The incubation of human endothelial cells with specific AGE (carboxymethyl lysine-modified adducts) prompted intracellular generation of hydrogen peroxide, a process suppressed by diphenyliodonium but not by inhibitors of nitric oxide…. The diminution of endothelial cell barrier function was completely inhibited by anti-RAGE antibodies.”  To mention again, the liver is the gateway to the dietary pathologies. “In the second 'hit' [leading to NAFLD], owing to the molecular instability of its five-membered furanose ring, fructose promotes protein fructosylation and formation of reactive oxygen species (ROS), which require quenching by hepatic antioxidants” Nature, Lustig, 2010.  This all takes us to the conclusion that the current average consumption of 152 pounds of added sugar (total sugar is about 25% higher), of which approximately one half is fructose, entails an overload upon our inherited biological protective system for the removal of abnormal proteins, proteolysis, and this accumulation of abnormally functioning proteins is the main driving force that has upset the weight regulatory system, produced NAFLD, obesity, diabetes and their comorbidities. 


Sugar addiction:  “The hedonic pathway comprises a neural conduit between two brain areas:  the ventral tegmental area by (VTA) and the nucleus accumbens (NA also known as the reward center),… Pleasure occurs when the VTA signals the NA to release dopamine, a neurotransmitter…. When the released dopamine binds to its specific dopamine D­3 receptor in the NA, the sense of pleasure is experienced.  [Sugars] are also key players in the hedonic pathway, modulating reward to response to meals.  In normal circumstances, after you’ve eaten a sufficient amount, leptin sends a signal to the VTA to suppress the release of dopamine, thereby reducing the reward of food…. If you feed a rodent a palatable food (e.g., a high-fat, high-sugar food such as cookie dough), the animal experiences reward because dopamine is released from VTA and binds to D­­3 receptor in the NA…. Dopamine stimulation in the NA reinforces the intake of drugs or alcohol and also of food…. After you’ve eaten a sufficient amount, leptin sends a signal to the VTA to suppress the release of dopamine, thereby reducing the reward of food.  That’s what obesity is:  leptin resistance.   What about insulin, leptin’s accomplice?  Normally, people are sufficiently sensitive to insulin.  Insulin’s job is to clear dopamine from the synapses…. Thus the rise in insulin that occurs during a meal blunts the reward of further food intake.  This acts as a servo-mechanism built into the hedonic pathway to prevent overfeeding.  Insulin resistance leads to leptin resistance in the VTA, contributing to increased caloric intake by preventing dopamine clearance from the NA.  Increase pleasure is then derived from food when energy stores are full…. Thus, the combination of high fat along with high sugar is likely to be more addictive than high fat alone.  All the criteria for sugar addiction have been demonstrated in rodent models.   Evolutionary, sweetness was the signal to our ancestors that something was safe to eat“, Prof. Robert Lustig, Fat Chance 2013, p 50-56.  If you doubt the sugar addiction theory, try cutting your sugar intake to 24 grams a day (6 teaspoons).  Use the food labels to determine sugar content and USDA Handbook for the bulk foods (mainly fruits, vegetables).  I tried it, and though fairly good at eliminating sugar added products, I keep nibbling on fruits and dried fruits.  I have eliminated the sugar added foods at the source, the grocery store.  Existing stock isn’t replaced, and the worse of them have been trashed.  Secondly observe the behavior of children between the ages of 3 and 6, most crave sugar added products, and let their parents know it.  Loaded on sugar they become hyperactive.    Another mechanism for this addiction is through the stimulation caused by the neurotransmitter norepinephrine.  Glucose creates alertness through increase in level of norepinephrine—a reinforcer.  Glucose intake was found to significantly increase plasma norepinephrine levels. In contrast, protein and fat intake was found to have no effect” Wiki, and, 1981.  This mechanism operates less efficiently in the obese, thus requiring great consumption of glucose for the response--1983.  As Dr. Lustig observed, obese children have a much lower response to glucose in soda, thus they require a bigger soda to overcome their IR, to produce the sugar buzz.         


Note:  fructolysis can enter the glycogenic pathway and thus be converted to glucoses products including fat and glycogen.  The Wikipedia article is one of the worse as to distortion of material.  It must have been written by the sugar industry since it exonerates fructose, changes its metabolism so that most of it is digested in other tissue than the liver, etc. 

Fructose metabolism [edit]

All three dietary monosaccharides are transported into the liver by the GLUT2 transporter.[44] Fructose and galactose are phosphorylated in the liver by fructokinase (Km= 0.5 mM) and galactokinase (Km = 0.8 mM). By contrast, glucose tends to pass through the liver (Km of hepatic glucokinase = 10 mM) and can be metabolised anywhere in the body. Uptake of fructose by the liver is not regulated by insulin. However, insulin is capable of increasing the abundance and functional activity of GLUT5 in skeletal muscle cells.[45]


Main article: Fructolysis

The initial catabolism of fructose is sometimes referred to as fructolysis, in analogy with glycolysis, the catabolism of glucose. In fructolysis, the enzyme fructokinase initially produces fructose 1-phosphate, which is split by aldolase B to produce the triosesdihydroxyacetone phosphate (DHAP) and glyceraldehyde [2]. Unlike glycolysis, in fructolysis the triose glyceraldehyde lacks aphosphate group. A third enzyme, triokinase, is therefore required to phosphorylate glyceraldehyde, producing glyceraldehyde 3-phosphate. The resulting trioses are identical to those obtained in glycolysis and can enter the gluconeogenic pathway for glucose or glycogen synthesis, or be further catabolized through the lower glycolytic pathway to pyruvate.



[1]  Such advice could only be generated by experts (KOLs) who feed this information to doctors in CME class funded by fund pharma.  The health issues with diabetes come not from glucose (another piece of crap taught by the same KOLs) but from the fructose, which is one half of glucose.  Fructose is from 7.5 to 10 more reactive than glucose and it is cleared from the blood at one half the rate of glucose, thus even further increasing the damage to protein through glycation.  Thus the major damage to endothelial cells lining blood vessels and kidneys is caused almost entirely by fructose.  It is fructose not glucose that is causing the much greater risk for heart attacks, kidney failure, blindness, and amputation of legs.  Fructose overwhelms the body’s system for repairing the damage done by glycation. It get worse, for doctors are taught to monitor glucose, and most of the drugs increase insulin and insulin promotes weight gain and fatty liver, since it causes fat storage/.  And fatty liver results in insulin resistance which leads to T2D.  Even the dietary advice is flaw, but this is what a profit driven system produces, protracted illness and deaths.   

[2] As repeatedly stated “associated with doesn’t mean cause”.  Higher levels of cholesterol are associated with obesity which is associated with NAFLD. high insulin, a high sugar diet and the damage that diet does to the endothelial cells that line the artery wall.  Damaged endothelial cells (called endothelial cells) are strongly associated with CVD--see  the Cholesterol Myth.  

[3] A mere imbalance between energy consumed and metabolized of just 1% will cause through accumulation of fat obesity in 20 years.  For those on a traditional or paleo diet their lack of obesity is an example of the hormonal management of weight. 

[4] In 1950 about half of the inexpensive sweeteners consisted of corn syrup, which is the dietary safe pure glucose.  The amount of fructose thus would be about 20 pounds compared to the year 2000 approximately 70 pounds—reduction is made for the milk sugar galactose, which is one half of lactose, about 10 pounds, average was 1.25 glasses per day. 

[5] Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids.

[6] A high glycemic index diet with its sugars: ”Consuming higher GI diets was associated with > 3 fold higher accumulation of advanced glycation end products (AGEs) in retina, lens, liver, and brain in the age-matched mice, suggesting that higher GI diets induce systemic glycative stress that is etiologic for lesions” at 2011.

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