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First article:  Though it doesn’t mention damage by glycation, the attachment of fructose to proteins, it is described: “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.´ This has to be the first hit, since it occurs when fructose is transported to the liver, the process of fat accumulation is gradual over years, and thus doesn’t become pathogenic for years, while from the start protein in the liver are compromised by fructose.

http://www.nature.com/nrgastro/journal/v7/n5/abs/nrgastro.2010.41.html

Nature Reviews Gastroenterology and Hepatology 7, 251-264 (May 2010) 

 The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome

Jung Sub Lim, Michele Mietus-Snyder, Annie Valente, Jean-Marc Schwarz & Robert H. Lustig  About the authors

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Abstract

The often cited article comparing excess glucose consumption to that of excess fructose consumption in a group of paid volunteers.  Only fructose damaged promoted insulin resistance.  This is consistent with the observation that a high glucose traditional diet does not cause insulin resistance and it comorbidities 

One important point is the putative association of high LDL with cardiovascular disease is putting the cart before the horse.  The horse is fructose and its casual role in NAFLD, insulin resistance, damage to endothelial cells that line the arteries (and thus promotes atherosclerosis), etc.  Bad pharma ones to treat a sign high LDL rather than the cause fructose and the liver damage it causes which through off the regulation of weight, blood glucose, etc.  Remember that pharma profits from chronic conditions.  They should have measured the increase in fat in the liver with a sonogram and blood insulin for Insulin resistance.  But pharma has them looking under the wrong tree, probably through funding of trial and thereby setting up the primary endpoints (protocols). 

https://www.jci.org/articles/view/37385#sd    complete (only abstract copied here)

Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans

Abstract:

Studies in animals have documented that, compared with glucose, dietary fructose induces dyslipidemia and insulin resistance. To assess the relative effects of these dietary sugars during sustained consumption in humans, overweight and obese subjects consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Although both groups exhibited similar weight gain during the intervention, visceral adipose volume was significantly increased only in subjects consuming fructose. Fasting plasma triglyceride concentrations increased by approximately 10% during 10 weeks of glucose consumption but not after fructose consumption. In contrast, hepatic de novo lipogenesis (DNL) and the 23-hour postprandial triglyceride AUC were increased specifically during fructose consumption. Similarly, markers of altered lipid metabolism and lipoprotein remodeling, including fasting apoB, LDL, small dense LDL, oxidized LDL, and postprandial concentrations of remnant-like particle–triglyceride and –cholesterol significantly increased during fructose but not glucose consumption. In addition, fasting plasma glucose and insulin levels increased and insulin sensitivity decreased in subjects consuming fructose but not in those consuming glucose. These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.

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Criticism of Dr. Lustig on the cholesterol myth:  Dr. Lustig proposes the lipid hypothesis as to the start of the atherogenic process leading to cardiovascular disease (CVD).  This is another case of pharma treating signs of a condition, rather than its cause.  This is the power of an industry to frame a topic (in this case CVD) and through KOLs (key opinion leaders) to get their junk science accepted as medical science.  If you are interested in the cause, then I click on Cholesterol Myth.  There is a chorus of critics, but pharma’s KOLs won’t debate the issue, or even write of it in the medical textbooks.  Fortunately their control has limits and journals will publish quality articles present the real major cause of CVD and a few documentaries and lectures. Possible he has his march points, go after cholesterol and UCTV et others will black-list you and USF will cut off research funding.  Or possible he doesn’t want to raise an issue which will distract from his main theses, that fructose is poison. 

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SUMMARY:  Fructose unhealthy consequences:  1) Causes metabolic syndrome (high blood pressure, atherosclerosis, and insulin resistance/type ii diabetes).  At 7 times the rate of glucose, fructose causes glycation of proteins through its keto group.  This process of glycation also causes oxidative damage and both promote cellular dysfunction, atherogenesis through oxidative damage to endothelial cells that line the artery walls, and affects the brain reward system in a way that promotes weight gain.  A second effect is upon the metabolic system for which fructose’s metabolism is quite different from that of glucose.  Among the results of this difference is hepatic insulin resistance, and elevated blood sugar level.  Fructose in the body is metabolized similar to ethanol. Glucose’s contribution to atherogenesis is a small fraction compared to fructose “Only 2% of ingested glucose will find its way into VLDL; thus, glucose contributes extremely slowly to cardiovascular disease and other aspects of metabolic syndrome.” 

doi: 10.3945/​an.112.002998Adv Nutr March 2013 Advanced Nutrition, an international review journal, vol. 4: 226-235, 2013   http://advances.nutrition.org/content/4/2/226.full then click on “full”.  10 pages Condensed by JK

Fructose: It’s “Alcohol Without the Buzz”

This paper compares the metabolic actions of fructose with those of glucose and ethanol to make the point that fructose is “alcohol without the buzz.”

http://advances.nutrition.org/content/4/2/226.full 2013  

Abstract

What do the Atkins Diet and the traditional Japanese diet have in common? The Atkins Diet is low in carbohydrate and usually high in fat; the Japanese diet is high in carbohydrate and usually low in fat. Yet both work to promote weight loss. One commonality of both diets is that they both eliminate the monosaccharide fructose. Glucose is the molecule that when polymerized forms starch, which has a high glycemic index, generates an insulin response, and is not particularly sweet. Fructose is found in fruit, does not generate an insulin response, and is very sweet. Fructose consumption has increased worldwide, paralleling the obesity and chronic metabolic disease pandemic.  However, fructose is unlike glucose. In the hypercaloric glycogen-replete state, intermediary metabolites from fructose metabolism overwhelm hepatic mitochondrial capacity, which promotes de novo lipogenesis and leads to hepatic insulin resistance, which drives chronic metabolic disease. Fructose also promotes reactive oxygen species formation, which leads to cellular dysfunction and aging, and promotes changes in the brain’s reward system, which drives excessive consumption.  Thus, fructose can exert detrimental health effects beyond its calories and in ways that mimic those of ethanol, its metabolic cousin. Indeed, the only distinction is that because fructose is not metabolized in the central nervous system, it does not exert the acute neuronal depression experienced by those imbibing ethanol. These metabolic and hedonic analogies argue that fructose should be thought of as “alcohol without the buzz.” 

We are in the midst of a global pandemic of chronic metabolic disease, 30 y in the making. The UN Secretary General in 2011 declared that metabolic syndrome (type 2 diabetes, hypertension, dyslipidemia, heart disease) and other noncommunicable diseases (e.g., cancer, dementia) are now a greater threat to both the developed and developing worlds than is acute infectious disease, including HIV (1). Most people blame obesity as the driver of these other diseases; however, 20% of obese subjects are metabolically normal, whereas as many as 40% of normal-weight people manifest specific components of metabolic syndrome (2–4). Obesity is not the cause of metabolic syndrome; rather, it is a marker for the metabolic dysfunction that is occurring worldwide. Furthermore, there are now >30% more obese people on the planet than those who are malnourished. Two decades ago, it was the opposite. Is it really possible, even in the most impoverished countries, that so many people became gluttons and sloths in such a short period of time? The ever-onward progression of these diseases in countries that also witness severe malnutrition is more reminiscent of an exposure than it is an alteration in behavior.

Most people blame obesity as the driver of these other diseases; however, 20% of obese subjects are metabolically normal, whereas as many as 40% of normal-weight people manifest specific components of metabolic syndrome (2–4)   Currently, per capita consumption of fructose or fructose-containing disaccharides is at ∼130 lb/y (almost 60 kg/y) or 6.5 oz/d for the average American. Although America is the greatest sugar consumer, other countries are not far behind (6).  Indeed, patients with hereditary fructose intolerance, who are missing the enzyme fructose-1-phosphate aldolase B, and cannot consume fructose lest they become hypoglycemic, do not only have fewer dental caries (8), but they are quite healthy provided they continue to restrict their fructose exposure (9, 10).  Second, fructose exerts 3 different negative impacts on human metabolism, each of which is exclusive of its calories. Most people compare fructose with its isomer glucose, which is so essential for life that your liver will produce it when it is in short supply via the process of gluconeogenesis. [Not dietary essential, for Eskimos live without plants, and thus carbohydrates, yet they are healthy.]  Although fructose is an energy source, the actions of fructose on the body more closely resemble those of ethanol (grain alcohol), another nonessential energy source.

Although most people consider fructose, and sugar in general, as “empty calories,” there is nothing empty about these calories. First, there is not 1 human biochemical reaction that requires dietary fructose. The only place in the body that fructose is of physiologic import is in semen, and the fructose is manufactured de novo from glucose using the aldose reductase/sorbitol pathway (7).

Hepatic Insulin resistance and metabolic syndrome:  One reason for this puzzle is trying to explain the phenomenon of “selective hepatic insulin resistance” (13). Insulin normally exerts its effects on hepatic energy metabolism via 2 metabolic pathways.  Insulin also activates the lipogenic pathway by stimulating sterol regulatory element binding protein 1c (SREBP-1c), which activates the enzymes of de novo lipogenesis (DNL) to turn excess mitochondrial energy substrate into fatty acids, which are then linked to apolipoprotein B100 and packaged into VLDL for hepatic export.  Rather, metabolic syndrome results from “selective” hepatic insulin resistance in which FoxO1 is not phosphorylated yet SREBP-1c is still activated to promote triglyceride synthesis and dyslipidemia. If there is only 1 insulin receptor, how can it activate 1 pathway and not the other (17)? To parse this dichotomy, the hepatic metabolism of glucose, ethanol, and fructose are considered in turn. 

Hepatic glucose metabolism:  This leads to the conversion of the majority of glucose molecules as hepatic glycogen for storage. The small amount that undergoes glycolysis reaches the mitochondria as pyruvate and is quickly esterified into acetyl-CoA.  This allows any excess acetyl-CoA that cannot be β-oxidized for energy and exits the mitochondria to be rebuilt into FFAs, which then are packaged into VLDL for hepatic export and storage in adipocytes. This VLDL can promote atherogenesis and/or obesity, but only ∼2% of ingested glucose will find its way into VLDL; thus, glucose contributes extremely slowly to cardiovascular disease and other aspects of metabolic syndrome. 

 Hepatic Fructose metabolism   Only the liver possesses the Glut5 transporter (30), and the liver has a very high fructose extraction rate (31); thus, virtually an entire ingested fructose load finds its way to the liver.  In contrast to the majority of hepatic glucose being converted to glycogen in the liver under the influence of insulin, fructose does not get converted to glycogen directly [although in case of glycogen depletion due to starvation or exercise, it can be converted to fructose-6-phosphate, which is isomerized to glucose-6-phosphate, which can rebuild glycogen (32)]. Rather, fructose is phosphorylated independently of insulin to fructose-1-phosphate by the enzyme fructokinase (Fig. 3), which undergoes glycolysis, and is metabolized to pyruvate, with the resultant large volume of acetyl-CoA entering the mitochondrial tricarboxylic acid cycle,  which activates carbohydrate response element binding protein (35), stimulating the activity of DNL [causing lipogenesis].  The attachment of hepatic triglyceride to apolipoprotein B by MTP completes its conversion to VLDL, which is exported out of the liver to contribute to fructose-induced hypertriglyceridemia (39, 41–43), along with the production of “small dense” LDL (44), which is particularly atherogenic because it can be oxidized rapidly and is small enough to get under the surface of vascular endothelial cells to start the foam cell process (39, 45–47). [Disagree: the evidence supports active transport where LDL functions as a source for triglycerides and cholesterol for a process of repair to damage tunica media due to inflammation in that layer of the artery caused by the presence of pathogens.  The second function of LDL is that of an antibody which absorbs toxins and reactive products caused by the pathogens.  There is amply journal articles supporting this process, see Prof. Uffe Ravnskov, Ignore the Awkward pgs. 133-146, or my articles at Recommended long.] Some of the fatty acyl-CoA products from DNL escape packaging into VLDL for export and instead accumulate as lipid droplets in the hepatocyte (48), driving hepatic steatosis, similar to ethanol.  The end result is preventing normal insulin mediated … thus promoting insulin resistance.  {Disagree:  I hold based on ample journal articles that the process of glycation of which over 90% is from fructose damages the liver in ways that hinders it’s metabolic functions and that leads to insulin resistance in the liver.]  This drives hyperinsulinemia (51), with resultant obesity causing worsening insulin resistance. Furthermore, fructose increases the expression of FoxO1 (52). In the face of hepatic insulin resistance, FoxO1 is not phosphorylated to maintain its exclusion from the nucleus, with resultant transcription of gluconeogenic enzymes and hyperglycemia, requiring an even greater β-cell insulin response.

Hepatic metabolic profile and substrate burden: fructose vs. ethanol:  Thus, fructose and ethanol are analogous qualitatively in terms of hepatic metabolism. In small doses, neither will overwhelm hepatic mitochondrial capacity.   Both fructose and ethanol uniquely drive DNL, generating intrahepatic lipid, inflammation, and insulin resistance. Through the phenomena of enhanced DNL, JNK-1 activation, and hepatic insulin resistance, the hepatic metabolic profile of fructose is analogous to that of ethanol. Furthermore, fructose and ethanol are also analogous quantitatively.  [Can of beer equals a can of soda.]

ROS [reactive oxygen specie] formation and aging:  Any nutritional substrate with a free reactive aldehyde or ketone can induce ROS formation when that reactive moiety binds to an ε-amino group of lysine found in proteins or DNA bases or with a free hydroxyl group found in lipids.  Because glucose forms a 6-member glucopyranose (5 carbon ring with only 1 hydroxymethyl group), the ring form is stable, thereby reducing the availability of the free aldehyde [fructiose a 5-carbon ring].  However, fructose forms a 5-member fructofuranose ring with 2 axial hydroxymethyl groups, which forces fructose at greater frequency into its linear form with the free ketone moiety (60).

Effects of glucose:  Each glycation generates 1 superoxide radical that must be quenched by an antioxidant or cellular damage will occur (62). However, at 37°C and pH 7.4, the majority of glucose molecules are found in the stable 6-member glucopyranose ring form, limiting aldehyde exposure and reducing ROS generation.

Effects of ethanol:  Acetaldehyde induces hepatocellular damage through several different mechanisms (20), including mitochondrial damage, membrane effects, hypoxia, cytokine production, and iron mobilization.

Effects of fructose:  Because fructose forms a 5-member fructofuranose ring with steric hindrance from the 2 axial (abutting) hydroxymethyl groups, more molecules find themselves in the linear form, which exposes their reactive keto group and leads to fructation of proteins 7 times more rapidly than with glucose (64, 65). Thus, fructose-generated ROS species are abundant (66, 67) and require quenching by a hepatic antioxidant (e.g., glutathione) 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).

Central nervous system effects to increase consumption:  The hedonic pathway that motivates the “reward” of food intake consists of the ventral tegmental area (VTA) (the home of the dopamine perikarya) and the nucleus accumbens (NA) (the destination of the dopamine axons, also referred to as the “pleasure center” of the brain). Food intake is a “readout” of the reward pathway; for example, administration of morphine to the NA increases food intake in a dose-dependent fashion (73). Dopamine neurotransmission from the VTA to the NA mediates the reward properties of food (74), whereas obesity results in decreased density of dopamine D₂ receptors as measured by positron emission tomography scanning (75). Indeed, any process that reduces dopamine receptor density or occupancy can drive increased food intake and weight gain (76)….For both ethanol and fructose “Neuropharmacologic analyses demonstrate a reduction in D₂ receptors in the NA, consistent with the fostering of reward and behavioral changes seen in addiction.

Most people consider sugar (i.e., fructose-containing compounds) to be just “empty calories.” However, this paper reports 3 separate ways that fructose exerts negative effects beyond its caloric equivalent. First, in the hypercaloric state, fructose drives DNL, resulting in dyslipidemia, hepatic steatosis, and insulin resistance, akin to that seen with ethanol. This should not be surprising because fructose and ethanol are congruent evolutionarily and biochemically. Ethanol is manufactured by the fermentation of fructose — the big difference is that for ethanol, the yeast performs the glycolysis, whereas for fructose, we humans perform our own glycolysis. Second, through production of reactive carbonyl moieties, both fructose and ethanol generate excess ROS, which increases the risk of hepatocellular damage if not quenched by antioxidants. Last, by downregulation of D₂ receptors in the reward pathway, chronic fructose exposure contributes to a paradigm of continuous food intake independent of energy need and exerts symptoms of tolerance and withdrawal, similar to chronic ethanol abuse. Therefore, it should not be surprising that the disease profile of fructose and ethanol overconsumption would also be similar (Table 2).

Fructose also exhibits notable social and market similarities with ethanol. Both have been “fetishized” by various cultures in times past. Of course, today both sugar and alcohol are legal commodities and are traded freely. The problems of overuse and related health harm tend to occur in lower socioeconomic groups. Those who overconsume either substance are stigmatized. Finally, within public health circles, alcohol clearly evinces the 4 criteria of unavoidability, toxicity, abuse, and negative impact on society, which warrant consideration for personal intervention (e.g., “rehab”) and societal intervention (e.g., “laws”). Sucrose/HFCS satisfies those same 4 criteria as well (6).

Although fructose does not exhibit the same acute toxic effects of ethanol (i.e., central nervous system depression and resultant auto accidents), it recapitulates all the chronic toxic effects on long-term health. It is time for a paradigm shift in our societal treatment of fructose, recognizing that fructose is “alcohol without the buzz.”

Table 2.

Phenotypes of long-term energy substrate exposure¹

• ↵1 Presented at the symposium “Fructose, Sucrose and High Fructose Corn Syrup. Modern Scientific Findings and Health Implications” held April 22, 2012 at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2012 in San Diego, CA. The symposium was sponsored by the American Society for Nutrition and supported in part by an educational grant from the Corn Refiners Association. A summary of the symposium “Fructose, Sucrose and High Fructose Corn Syrup. Modern Scientific Findings and Health Implications” was published in the September 2012 issue of Advances in Nutrition.

• ↵2 Supported in part by NIDDK grant R01DK089216.

• ↵3 Author disclosure: R. H. Lustig, no conflicts of interest.

• ↵4 Abbreviations used: DNL, de novo lipogenesis; Foxo1, forkhead protein O1; HFCS, high-fructose corn syrup; IRS-1, insulin receptor substrate 1; JNK-1, c-jun N-terminal kinase 1; MKK7, MAP kinase kinase 7; MTP, microsomal transfer protein; NA, nucleus accumbens; NO, nitric oxide; ROS, reactive oxygen species; SREBP-1c, sterol regulatory element binding protein 1c; VTA, ventral tegmental area.

• © 2013 American Society for Nutrition

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