2:1 The basic on sugar, and related topics

Again I must state that I don’t like the word “probably”,[2] thus I state the evidence and solution without that word; considered it understood.

Note: in the Fischer projection (right) that the ketone oxygen is on the 2^nd carbon for fructose and the aldehyde form 1^st for glucose & galactose.

Below look at their dominate ring structures both stay in the 6-member ring most of the time; however, fructose stays longer in the less stable furanose form than glucose. This 5-member ring a fraction of the time opens up (exits the ring form) into an open chain form. Fructose is in the open form about a net 325 times more often than glucose. In the open chain form its oxygen is electrophilic and can bond to electron sources such as some amino acids in proteins, DNA, RNA, unsaturated fatty acid, etc., a process called glycation. Both are reducing sugars; fructose dominates in glycation. Note: standard lab test of Hb1Ac doesn’t excludes fructose or galactose.

Glycation is the non-enzymatic bonding, a bad thing. The Hb1Ac is a measurement of that glycation to one of the types of hemoglobin in the erythrocytes. The lab measurement doesn’t distinguish glucose from fructose or the other sugars. Moreover, most of the fructose goes to the liver, not circulating in the blood; therefore, the glycation of fructose upon the liver is not measure. What you need to retain now is that fructose in excess because it is more reactive it is a slow acting poison. Fructose is a poison not just to the liver but through IR that increases the polyol pathway which converts glucose to fructose, thus every cell in the body is being poisoned—retain that please! I will add details later to these key points, key points in the evidence proving that fructose is the number one major CC for CAWD. I will add later several supporting actors. For now, retain fructose is 20 times[3] more reactive than glucose, and on the high sugar diet it overwhelms the repair systems. Fructose is the number-one CC for CAWD.

Pyranose is a term for saccharides in a 6-member ring; furanose a 5-member ring. The pyranose ring exists 76.4% in pyranose, 19.5% furanose ring, and 4.1% open chain.[4] Another study found it to be 70, 20, and 8% open,[5] by contrast glucose is over 90% to 99% in the 6-member ring

“In aqueous solution, however, more than 99% of glucose molecules, at any given time, exist as pyranose forms [6 member ring]. The open-chain form is limited to about 0.25%, and furanose forms exist in negligible amounts” [6] Comparing 8% to .25% entails the open chain is 32 times longer for fructose. Thirty-two time more for glycation.

The Maillard reaction is a chemical reaction between amino acids and reducing sugars (fructose and glucose). Dicarbonyls, methylglyoxal, are formed from the glycated amino acid; they undergo the Milliard reaction. The glycated substrate undergoes further reactions which produce highly reactive compounds dicarbonyls and methylglyoxal. In the MTD being very reactive, they damage the structures of the MTD, some of which results in the release of ROS (reactive oxygen species) that do additional damage the MTD. The MTD have repair-replacement systems, however, when the mtDNA is damaged, that damage is passed on to the next generation of MTD. The western high fructose diet overwhelms the systems and as covered in 1:3 which compared the LSPs to HSPs various biomarkers; this comparison exposed the damage. Listed were fasting glucose, insulin, leptin, blood pressure, and oxygen consumption all of which were worse for those lean health on the western diet.

The open-chain Amadori products undergo further dehydration and deamination to produce dicarbonyls.^[13] This is a crucial intermediate.[7]

Fructose is absorbed by GLUT5 receptors of the enterocytes (intestinal epithelium cells) mainly in the jejunum (second section of 3 of the small intestines). Exits through GLUT2 into the hepatoportal vein from which the liver absorbs most of it through GLUT5 where it is rapidly converted by fructokinase to fructose 1-phosophate, which then in fructolysis then split by aldolase B to produce the trioses dihydroxyacetone phosphate (DHAP) and glyceraldehyde and then phosphorylated to glyceraldehyde 3 phosphate.[8] However, the serum fructose level is over twice that of glucose in a glucose tolerance test because fructose is taken up only by GLUT2 while glucose is taken up by GLUT1, 2, & 4 receptors on cells. I have not found a seminal article covering the complexity of transport. Only a few types of cells have receptors for GLUT 1 and 2. They include the hepatocytes, some of the endothelial cells, some types of pancreatic, nephrotic cells, and some cells in the brain (probably other cell types).[9] GLUT 1 also uptake ascorbic acid which is stored in high levels, one is the leucocytes --I suspect ascorbate has immune functions. Levels get up 100 times that of serum ascorbic acid are in select cells such as leukocytes.

Fructose is absorbed in the intestines and transported to the liver by the hepatic portal vein and there deposited.[10]

The glucose tolerance test consists of a 75 ML bolus of sucrose; for t2d the serum level (area under graph) over a 3-hour period is twice that of those who are IR—depending on degree of IR.[11] In the cytosol the monosaccharides glucose and fructose on entry are phosphorylated at about the same rate, but when there is a heavy load of fructose, it occurs after glucose.[12]

Fructose’s metabolism is after glucose, thus if more ATP is not needed it is converted through de novo lipogenesis (DNL).[13] Alternatively, fructose can also be converted to glucose and then to glycogen.

Fructose is a net 20 times more reactive than glucose. Net twenty times because it is metabolized after glucose and phosphorylated after glucose. Fasting level of blood glucose is 2-3 tsps. and fructose is 1/10^th its level.

Uric acid synthesis in the liver is stimulated by fructose. It is a powerful antioxidant. It Is also produced by the metabolism of purine.

When fructose is repeatedly consumed in excess, it significantly contributes to glycation of HB1Ac at a high rate. Note, the labs which do the blood work when measuring Hb1Ac and fasting glucose, though called glucose it in includes all sugars.

Making fructose, the polyol pathway (PP, also misleadingly called the sorbitol pathway)[14] is a two-step reaction converting the excess glucose which cause harmful osmotic pressure. In response, the glucose is covered to fructose

Fructose causes MTDD in the liver, which slows the metabolism of sugars and often progresses to IR and NAFLD.

The amount of fructose is dependent on type of cell (fructose receptors) and the conversion of glucose to fructose produced in the PP. Want to lower your HbA1c, go on a low sugar diet and low other carbs. With this diet the PP won’t be turned on to lower the glucose in the cells—including in the erythrocytes.[15] Want to greatly reduce your diabetic medications and their side effects, go on a ketogenic diet.

A bit of repetition to drive home the evidence. The foundation for the difference reactivity for fructation is the amount of time in the furanose 5-member ring, from which the reactive open chain form is derived. For glucose the duration in the 5-unit furanose ring is minimal; for fructose is 22% in that ring. The steric stress entails that fructose is 7.5 to 10 more reactive than glucose. This figure is for the western diet doubles or more because fructose metabolism is delayed by glucose metabolism which occurs first. Since with over the limit of the Jejunum for fructose metabolism (2:2), the excess goes mainly to the liver, the liver is damaged through fructation (the percentages are debated). Los doses of fructose are ~90% cleared by the intestine.” [16] When the MTD is damaged the amount of ROS increases and further damages the MTD. Moreover, on a high carb large meal the PP operates to reduce osmotic pressure from overstuffing of the cell with glucose. Excess glucose is turned to fructose, which is a simpler two-step process than the conversion to fats.

In aqueous solution, however, more than 99% of glucose molecules, at any given time, exist as pyranose forms [6 member ring]. The open-chain form is limited to about 0.25%, and furanose forms exist in negligible amounts. The distribution of d-fructose tautomers in solution is related to several variables, such as solvent and temperature.^[16] d-Fructopyranose and d-fructofuranose distributions in water have been identified multiple times as roughly 70% fructopyranose and 22% fructofuranose.[17]

Paleo sugar “For thousands of years, humans consumed about 4-6 g of fructose each day, mainly as fruits and honey obtained from foraging and agricultural activity.” [18] Selective breeding has greatly increased sugars in fruits and some vegetables.

Per capita consumption of dietary fructose and sucrose has increased over 10-fold among the working class over the past two centuries. Fructose now accounts for ~10% of caloric intake (~20% sucrose), and over half the population consume more than the average. The bodily repair systems can’t handle that load of fructation.

Fructation (commonly called fructosylation) is the non-enzymatic bonding of fructose to amino acids. I prefer fructation and general hereafter use glycation for glucose, though in the literature glycation can also include the other sugars—a cause of confusion.

The glycemic index is a rating of 100 grams of food to the insulin response, A glucose curve over two hours is taken on a group of lean students of either 100 grams of glucose or white bread (the two as standard give moderately different curves). If white bread is used then glucose is ~ 140. There are two other less commonly used rating the glycemic load and the insulin index, but glycemic index is enough for here.

Insulin resistance results when it takes a high amount of insulin to lower blood glucose to the normal range (for cause 3:6) assuming they are not diabetic.

With t2d, they are insulin resistant, but are not able to produce sufficient insulin to return their blood glucose to the normal range.

Insulin regulates leptin (among its 16 function) leptin. With IR the leptin is elevated, and eventually that person become leptin resistant

Leptin is a hormone produced by the adipose tissue, it has major role in control hunger and rate of metabolism.

When IR, a high carbohydrate diet is lipogenic because insulin signals cells to stop metabolizing fats, store them as triglycerides, and metabolize only glucose. [19] Carbs are only lipogenic when the person is insulin resistant.

Fibers is resistant to digestion; however, in the intestines bacteria outside their cell digest the fiber, and about 50 to 70% of the glucose will be absorbed by the small intestine—a gradual process that when fasting will not raise insulin.

Adenosine triphosphate (ATP) is the gasoline of the body providing the energy for over 90% of the body’s energy for chemical processes, one of which permits the contraction of muscles. Energy is transferred through the loss of a phosphate, turning ATP to ADP, adenosine diphosphate.

Oxidation phosphorylation is the process in the MTD of reverting ADP (diphosphate) back to ATP in a series of steps. It involves the transfer of electrons. The combination processes of Krebs cycle, beta oxidation, and oxidation phosphorylation occur so rapid that the body’s weight in ATP is produced in one day. Adenosine is also part of the backbone for RNA and DNA.

Krebs cycle (citric acid cycle, CAC; Tricarboxylic acid cycle, TCA) occurs in the MTD where pyruvate or acetyl CoA enters the cycle and in 7 steps in the presence of oxygen (aerobic respiration) that produces NADH + H⁺ for the next cycle in the MTD, the electron chain transport which phosphorylates ADP into ATP. and then transport into the MTD for metabolism. The conversion occurs first to glucose.

Pyruvate is a 3-carbon molecule that is transported into the mitochondria to produce ATP. Glucose is split and converted to 3-carbon pyruvate

Beta oxidation (fat metabolism) occurs in the MTD to generate acetyl CoA, which then enter the Krebs cycle. It is named because the beta carbon of the fatty acid is oxidized to a carbonyl [C = O]

Mitochondrion (MTD), mitochondria plural: is the organelle in which over 90% of the energy ATP (adenosine triphosphate) molecule is produced by adding a phosphate molecule to ADP (adenosine diphosphate). They are tiny, between 0.75 and 3 μm² in area; vary in functions depending on cell type it is in. Has An active cell will have from 500 to over 2,000 mitochondria, which is under 2% of the cell’s volume. They have between 615 to 700 distinct protein types, of which only a few are made in the MTD. The remainder or made in the endoplasmic reticulum and transported to the MTD. There is an inner and outer membrane, and 37 genes in their mtDNA. The production of ATP from AMP and ADP is complex. Below are 2 key chemicals (acetyl CoA and pyruvate) that are transported in the MTD for catabolism. There are several other functions for the MTD (3:1).

[1] Nicholas Pokoluk, Scourage of the AGES: glycation and diabetes, cancer heart disease, Alzheimer’s and aging, “Chapter It is a dicarbonyl compound that can inhibit mitochondrial respiration and other physiological pathways.”

[2] ““Probably in a phrase when repeated often is a mark of verbosity, a poor style of writing, and it detracts from the overall thesis by encouraging the reader to wonder what else. Think of The Origin of Species with a phrase containing “probably” on every second page. A work which presents an alternative thesis is very possible wrong in details, and possible overall wrong

[3] There is great variation in the testing results, and I failed to find a seminal article.

[4] RS Shallenberger 1978, Intrinsic Chemistry of fructose

[5] Funcke, Werner; Clemens von Sonntag, et al Oct 1979, Detection of the open chain forms of d-fructose, L-sorbose in aqueous solution by 13C-n.m.r. spectroscopy

[6] Wiki, glucose. April 2021

[7] Wiki, Maillard_reaction, May 2022

[8] Mark Feldman in Sleisenger and Fordtran’s Gastrointestinal and liver disease (2021)

[9] I repeat again that pharma and food manufacturers hide their gold egg, fructose, through tobacco science. They claim that nearly all of fructose goes to the liver, where the liver handles this reactive sugar (which they don’t of course call reactive). Missing also is that fructose goes to other cell types. Moreover, fructose is produced in every overstuffed with glucose cells by converting glucose to fructose through the polyol pathway (2:5). Diabetics convert around one-third of glucose to fructose.

, P 110[10] From Prof. Robert Lustig Lecture, based on Kim et al, Diab Res Clin Pract 4:281, 1988

[11] Kim, Hae, Hee Paik, et al, April 1988, Effects of several simple sugars on serum glucose and serum fructose levels in normal and diabetic subjects

[12] Clark, Michael, David Blaxham, et al Jan 1974, Estimation of the Fructose 1,6-Diphosphatase-phosphofructokinase Substrate Cycle and Its Relationship to Gluconeogenesis in Rat Liver in Vivo

[13] Common assumed that the conversion of fructose to fat in the liver causes NAFLD. Later (3:5) I will present a more complex development. Pharma uses conversion to fat to argue saturated fats toxicity.

[14] Misleading because industries are protecting their golden age fructose. Thus fructose, is an “F” word. Sorbitol is converted to fructose. The claims of accumulation of sorbitol are not supported, nor its putative causing increased osmotic pressure. Moreover, the alternate name polyol pathway is also misleading because polyol ,means an alcohol with 3 or more hydroxyl (OH) groups. Sorbitol is both a sugar and an alcohol, it has 6 hydroxyl groups and no carbonyl group.

[15] Morrison, Anthony, Rex Clements, et al, July 1970.Glucose utilization by the polyol pathway in human erythrocytes

[16] Jang, Cholsoon, S Hui, et al, March 2018, The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids

[17] Wiki, April 2021, glucose and the fructose articles

[18] Douard, Veronique, Ronaldo Ferraris, Aug 2008, Regulation of the fructose transporter GLUT5 in health and disease

[19] Shafrir, Eleazar, Fructose/Sucrose metabolism, Its Physiological and Pathologic Implications, 1991, p. 73

[1] Wiki, Whitehall_study, August 2022