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Journal articles on polyol pathway and ascorbate
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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]
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 retina, kidney, 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 concentrations” Wiki. 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.
^^^^^^^^^^^^^^^^^^^^ 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 (/ˈsɔərbᵻˌtɒl/), less commonly known as glucitol (/ˈɡluːsᵻˌtɒl/), 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.
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
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.
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
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.
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Enter supporting content here
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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The information,
facts, and opinions provided here is not a substitute for professional advice. It only indicates what JK believes, does, or would do. Always consult your primary care physician for medical advice, diagnosis, and treatment
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