Recommended Diabetes

Home | Low Carb diet to treat type-2 diabetes | THE CAUSES: Fructose, insulin resistance, ascorbate, and collagen | More Jounral articles on COLLAGEN and its role in diabetic pathologies | Ascorbic acid diabetes studies | Journal articles on polyol pathway and ascorbate | Ascorbate role and not hyperglycemia is pathogenic | Explanatory letter recommending ascorbate supplement
Journal articles on polyol pathway and ascorbate

 

Polyol pathway

“Also called the sorbitol-aldose reductase pathway, the polyol pathway appears to be implicated in diabetic complications, especially in microvascular damage to the retina,[1] kidney,[2] and nerves.[3]

Sorbitol cannot cross cell membranes, and, when it accumulates, it produces osmotic stresses on cells by drawing water into the insulin-independent tissues.[4]

https://upload.wikimedia.org/wikipedia/commons/thumb/4/49/Polyol_metabolic_pathway.png/600px-Polyol_metabolic_pathway.png

Cells use glucose for energy. This normally occurs by phosphorylation via the enzyme hexokinase. However, if large amounts of glucose are present (as in diabetes mellitus), hexokinase becomes saturated and the excess glucose enters the polyol pathway when aldose reductase reduces it to sorbitol.   Sorbitol dehydrogenase can then oxidize sorbitol to fructose, which produces NADH from NAD+Hexokinase can return the molecule to the glycolysispathway by phosphorylating fructose to form fructose-6-phosphate…. 

While most cells require the action of insulin for glucose to gain entry into the cell, the cells of the retinakidney, and nervous tissues are insulin-independent, so glucose moves freely across the cell membrane, regardless of the action of insulin. [This is not pathological as proven by the very high carbohydrate diets of the Highland New Guinea peoples, the Japanese and Katovans.] The cells will use glucose for energy as normal, and any glucose not used for energy will enter the polyol pathway. When blood glucose is normal (about 100 mg/dl or 5.5 mmol/l), this interchange causes no problems, as aldose reductase has a low affinity for glucose at normal concentrationsWiki.   ANOTHER PHARMA SUPPORTIVE ARTICLE STRESSING HIGH GLUCOSE, GLYCATION, OXIDATIVE DAMAGE, WHILE NOT MENTIONING COLLAGEN, LET ALONE DEFECTIVE COLLAGEN. 

And it gets worse in that in the article on collagen there is no mention of diabetes.

Synthesis

“First, a three-dimensional stranded structure is assembled, with the amino acids glycine and proline as its principal components. This is not yet collagen but its precursor, procollagen. Procollagen is then modified by the addition of hydroxylgroups to the amino acids proline and lysine. This step is important for later glycosylation and the formation of the triple helix structure of collagen. Because the hydroxylase enzymes that perform these reactions require vitamin C as a cofactor, a long-term deficiency in this vitamin results in impaired collagen synthesis and scurvy.[20] These hydroxylation reactions are catalyzed by two different enzymes: prolyl-4-hydroxylase[21] and lysyl-hydroxylase. Vitamin C also serves with them in inducing these reactions. In this service, one molecule of vitamin C is destroyed for each H replaced by OH. [22] The synthesis of collagen occurs inside and outside of the cell. The formation of collagen which results in fibrillary collagen (most common form) is discussed here. Meshwork collagen, which is often involved in the formation of filtration systems, is the other form of collagen. All types of collagens are triple helices, and the differences lie in the make-up of the alpha peptides created in step” https://en.wikipedia.org/wiki/Collagen.   

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Background material

Seems like pharma is going down stream AGAIN, rather than dealing with the basic cause of low ascorbate and defective collagen for retinopathy.

Failure to find drugs for aldose inhibitors, one approved was shortly afterwards, in the 90s, taken off the market because of fatal side effects. 

 

Aldose reductase inhibitors are a class of drugs being studied as a way to prevent eye and nerve damage in people with diabetes. Their target, aldose reductase, is an enzyme that is normally present in many other parts of the body, and catalyzes one of the steps in the sorbitol(polyol) pathway that is responsible for fructose formation from glucose. Aldose reductase activity increases as the glucose concentration rises in diabetes in those tissues that are not insulin sensitive, which include the lenses, peripheral nerves and glomerulus. Sorbitol does not diffuse through cell membranes easily and therefore accumulates, causing osmotic damage which leads to retinopathy and neuropathy. 

Diabetic cataract formation follows an increase in sugars in the lens. The excess sugar within the lens is reduced by aldose reductase to its alcohol, but the lens capsule is relatively impermeable to sugar alcohols. Because of the excess sugar alcohol (polyol), the lens imbibes water, causing osmotic imbalance. Eventually, increased sodium and decreased potassium levels and decreased glutathione levels lead to cataract formation. Topical administration of aldose reductase inhibitors have been shown to prevent the cataract in rats.       https://en.wikipedia.org/wiki/Aldose_reductase_inhibitor

A polyol is an alcohol containing multiple hydroxyl groups. In two different technological disciplines the term "polyol" has a special meaning: food science and polymer chemistry. https://en.wikipedia.org/wiki/Polyol

Sorbitol (/ˈsɔərbˌtɒl/), less commonly known as glucitol (/ˈɡluːsˌtɒl/), is a sugar alcohol with a sweet taste which the human body metabolizes slowly. It can be obtained by reduction of glucose, changing the aldehyde group to a hydroxyl group. Most sorbitol is made from corn syrup, but it is also found in apples, pears, peaches, and prunes.[2] It is converted to fructose by sorbitol-6-phosphate 2-dehydrogenase. Sorbitol is an isomer of mannitol, another sugar alcohol; the two differ only in the orientation of the hydroxyl group on carbon 2.[3] While similar, the two sugar alcohols have very different sources in nature, melting points, and uses. https://en.wikipedia.org/wiki/Sorbitol#Laxative

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http://diabetes.diabetesjournals.org/content/32/11/988.short Diabetes 1983 Nov; 32(11): 988-992  

Polyol Pathway Activity and Myo-Inositol Metabolism: A Suggested Relationship in the Pathogenesis of Diabetic Neuropathy

Abstract

Two major metabolic perturbations, increased polyol (sorbitol) pathway activity and reduced tissue myo-inositol content, are induced in peripheral nerve by hyperglycemie. Although they are commonly invoked as alternative biochemical pathogenetic mechanisms for diabetic neuropathy, their possible interrelationship has never been adequately explored. Therefore, we studied the effect of polyol pathway blockade with sorbinil, a specific inhibitor of aldose reductase, on nerve myo-inositol content in acutely streptozotocin-diabetic rats. Sorbinil administration completely prevented the fall in nerve myo-inositol, thereby implicating increased polyol pathway activity as a likely factor in the fall in nerve myo-inositol content in experimental diabetes.

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http://onlinelibrary.wiley.com/doi/10.1002/ana.410080608/full  Annals of Neurology, Dec. 1980 (“Full” is link to paid access of article).

Human diabetic endoneurial sorbitol, fructose, and myo-inositol related to sural nerve morphometry

 

Abstract

Fascicles of the sural nerve from each of 20 diabetic patients, mostly with maturity-onset diabetes, were studied by biochemical and pathological techniques, and results were compared to values found in nerve specimens from 15 healthy persons. The sorbitol and fructose content was much more variable in diabetic than in healthy nerves. More than one-third of the diabetic nerves had sorbitol and fructose values above the highest levels for controls. myo-Inositol and scyllo-inositol content was not reduced in diabetic nerves. The sorbitol, fructose, and inositol concentrations could not be related to clinical, neurophysiological, or pathological severity of neuropathy. [But all three of them cumulative could.]  A comparison of scored symptoms and signs and clinical neurophysiological studies against morphometric and teased fiber studies of sural nerve demonstrated that the former three provide sensitive and reliable measures of severity of neuropathy that can be used for controlled clinical trials of diabetic neuropathy. The presence and type of teased fiber abnormalities could be related to the duration of diabetes and to symptoms of neuropathy. In untreated diabetics without symptoms of neuropathy, a higher than normal frequency of teased fibers showing segmental demyelination and remyelination was found. Untreated diabetics with symptomatic neuropathy showed two kinds of abnormalities: fibers with segmental demyelination and remyelination and fibers undergoing axonal degeneration. In treated diabetics, who often had longstanding neuropathy, the most common abnormalities were fibers undergoing axonal degeneration.

 

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http://diabetes.diabetesjournals.org/content/33/8/712.short Diabetes 1984 Aug; 33(8): 712-716.   

Action of Sorbinil in Diabetic Peripheral Nerve: Relationship of Polyol (Sorbitol) Pathway Inhibition to a myo-Inositol-mediated Defect in Sodium-Potassium ATPase Activity

 

Abstract

The small, but statistically significant, improvement in nerve conduction after treatment of diabetic patients with the aldose reductase inhibitor, sorbinil, suggests that increased polyol (sorbitol) pathway activity may contribute to diabetic nerve conduction slowing. Although classically viewed solely in terms of sorbitol-induced osmotic swelling, polyol pathway inhibition is now speculated to influence a concomitant myo-inositol-mediated alteration in nerve sodium-potassium ATPase activity in diabetic nerve. Therefore, we directly examined the effect of sorbinil treatment on sodium-potassium ATPase activity in crude homogenates of sciatic nerve from streptozotocin-diabetic and non-diabetic rats. We demonstrate that sorbinil treatment, which preserves normal nerve myo-inositol content, prevents the fall in nerve sodium-potassium ATPase activity that has been linked to conduction slowing in the diabetic rat.

  • Received November 3, 1983.

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Harvard Prof. Marcia Angell, MD., former Chief Editor of NEJM wrote: “We certainly are in a health care crisis, ... If we had set out to design the worst system that we could imagine, we couldn't have imagined one as bad as we have.”

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