Recommended GLYCATION, Advanced glycation end-products, ROS (13)

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Polyol Pathway makes fructose

The polyol pathway functions to prevent excess glucose is stuffed in cell from causing high osmotic pressure in the cell by reducing glucose which is converted in 2 steps into the reactive sugar fructose.   With insulin resistance the polyol path is turned up, and for those with type 2 diabetes on the high carb diet about 30% of glucose is converted to fructose.  Pharma spreads the myth that high serum levels of glucose cause all the associated increased risks from type 2 diabetes.  The money is in lowering glucose; however, the harm is caused by the conversion of glucose to fructose.  As established the fructation (fructosylation) of mainly mtDNA, mtRNA, proteins, and unsaturated fatty acids in the mitochondria or in transport to the mitochondria is the cause for the associated conditions risks for those with type 2 diabetes.   The issue the damage to the mitochondria which causes insulin resistance. 

Contribution of Polyol Pathway to Diabetes-Induced Oxidative Stress

ABSTRACT. Diabetes causes increased oxidative stress, which is thought to play an important role in the pathogenesis of various diabetic complications. However, the source of the hyperglycemia-induced oxidative stress is not clear. It was found that the polyol pathway is the major contributor to oxidative stress in the lenses and nerves of diabetic mice. The first enzyme in the pathway, aldose reductase (AR), reduces glucose to sorbitol, which is then converted to fructose by sorbitol dehydrogenase (SDH). Transgenic mice that overexpress AR specifically in their lenses showed a significant increase in oxidative stress when they became hyperglycemic, as indicated by a decrease in GSH and an increase in malondialdehyde in their lenses. Introducing an SDH-deficient mutation into these transgenic mice significantly normalized the GSH and malondialdehyde levels. [This increasing by SDH deficiency, the amount of sorbitol—block conversion to fructose—and as a consequence normalizing GSH, indicates—as I maintain given sorbitol is the most stable of sugar—that fructose is the cause of the oxidative stress and thereby increases malondialdehyde.]   These results indicate that both enzymes of the polyol pathway contributed to hyperglycemia-induced oxidative stress in the lens. In the wild-type mice, diabetes caused a significant decrease in GSH in their sciatic nerves, indicative of oxidative stress. In the AR null mutant mice, diabetes did not lead to any decrease in the nerve GSH level. These results indicate that similar to the situation in the lens, AR is also the major contributor to hyperglycemia-induced oxidative stress in the nerve. Although increased flux of glucose through the polyol pathway leads to diabetic lesions in both the lenses and nerve, the mechanisms may be different. AR-induced osmotic stress seems to be the cause of diabetic cataract, whereas AR-induced oxidative stress is probably the cause of neuronal dysfunction. 

In Vitro evidence that fructose is much more reactive than glucose

Hamada, Yoji, Norie Araki, et al, Jan 1996, Rapid Formation of Advanced Glycation End Products by Intermediate Metabolites of Glycolytic Pathway and Polyol Pathway

Rapid Formation of Advanced Glycation End Products by Intermediate Metabolites of Glycolytic Pathway and Polyol Pathway



To clarify roles of intermediate metabolites of the glycolytic pathway and the polyol pathway in nonenzymatic glycation under physiological conditions, we incubated bovine serum albumin with intermediates of both pathways in the micromolar range as well as with 20 mmol/l glucose, and observed the formation of advanced glycation end products (AGEs). We found that triose phosphates, glyceraldehyde, and a novel polyol pathway-related metabolite, fructose 3-phosphate along with its breakdown product, 3-deoxyglucosone were extremely potent glycating agents that at nearly physiological concentrations on incubation with albumin produced substantial amounts of AGEs as early as 24 hours, while 20 mmol/l glucose afforded trace amounts of AGEs after two week incubation. The results along with the previous evidence of the increased level of intermediates in diabetic states may suggest that the intermediate metabolites [OF POLYOL PATHWAY, VIZ. FRUCTOSE] rather than glucose contribute to enhanced glycation in diabetic tissues, inspite of the much lower concentrations compared with glucose.

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Dr. Relman another former editor in chief of the NEJM said this in 2002
“The medical profession is being bought by the pharmaceutical industry, not only in terms of the practice of medicine, but also in terms of teaching and research. The academic institutions of this country are allowing themselves to be the paid agents of the pharmaceutical industry. I think it’s disgraceful”