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| Home | Polyol pathway, neuropathy, myo-inositol, t2d, etc | Decreased collagen production with t2d, bone fragility, etc. | Low ascorbate is more significant than glycation in t2d | abnormalities of ascorbic acid metabolism and t2d | Ascorbate supplement recommended for t2d--2 grams | ascorbate polyol pathway abnormal metabolism et. | ascorbate deficiency reduced collagen polyol pathway | Insulin Resistance and Atherogenesis |
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recommended COLLAGEN, ASCORBATE (vitamin C) |
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ascorbate deficiency reduced collagen polyol pathway
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https://www.researchgate.net/profile/Beat_Steinmann/publication/16557404_Ascorbate_deficiency_results_in_decrea sed_collagen_production_Under‐
hydroxylation_of_proline_leads_to_increased_intracellular_degradation/links/0a85e53b002cdb1053000000/Ascorbate‐
deficiency‐results‐in‐decreased‐collagen‐production‐Under‐hydroxylation‐of‐proline‐leads‐to‐increased‐intracellular‐
degradation.pdf FULL Ascorbate
deficiency results in decreased
collagen
production: Under‐ hydroxylation
of proline leads to increased
intracellular degradation Abstract Collagen production by
cultured human
lung fibroblasts
was examined when the cells were
made deficient in ascorbate. Cells grown
in the absence of ascorbate produced
30% less
collagen during a 6‐h labeling period
than cells incubated with
as little as 1 μg/ml ascorbate during the labeling period.
Cells grown without
ascorbate produced under‐hydroxylated
collagen which was subject to increased
intracellular degradation from a basal level of 16% to an enhanced level of
49% of all newly synthesized collagen. The likely mechanism for increased intracellular degradation is the inability of under‐hydroxylated collagen to assume a triple‐helical conformation causing it
to
be
susceptible to intracellular degradation. Measurement of collagen production
by enzyme
linked immunoassay (ELISA)
using antibodies directed against triple‐helical determinants of collagen showed that both types I
and III collagens were affected. In contrast, another
connective tissue component, fibronectin, was not affected.
Analysis by ELISA showed a greater decrease in collagen production than
did analysis by the collagenase method, suggesting that some non‐helical collagen chains
(detected by collagenase but not by
ELISA)
were secreted in the absence of ascorbate. These
results provide a mechanism to account, in part, for the deficiency of collagen in connective tissues which occurs
in a state of ascorbate deficiency. ^^^^^^^^^^^^^^^^^^^^^^^^
At id2, 5th in
location short -- long at rca id7
Ascorbic Acid Metabolism and Polyol Pathway
in Diabetes Completely understood. This study confirmed
the ability of the aldosereductase
inhibitor tolrestat to normalize plasma AA (ascorbic acid) level .The observation that
treatment with myo‐inositol
is also effective
in this regard is further
evidence
that the polyol pathway is involved in the abnormal metabolism of AA in
diabetes (14). myo‐lnositol supplementation can
reverse some of the polyol‐related functional
derangements in diabetes,
apparently by preventing the depletion
of a small intracellular pool
of myo‐inositol
(14). This has the
secondary effect of preventing decreased activity
of Na+ ‐K + ‐ATPase,
an enzyme required for many
cellular functions, e.g.,
generation of transmembrane
electrical potential. One site where aldose reductase inhibitor and myo‐inositol may act to affect
AA metabolism is the renal
tubule, which reabsorbs AA by a
Na+‐gradient‐dependent mechanism (15).
Supporting this hypothesis is
the observation that in diabetes
urinary excretion of AA greatly increases but is substantially reduced by
treatment with tolrestat or myo‐inositol, with simultaneous
restoration of plasma AA concentration. This pattern is distinct from that seen in animals treated with AA, in which the normalization of
plasma AA is achieved with a
further increase in urinary AA excretion. The ability of tolrestat
to normalize sorbitol level
in the renal medulla
of diabetic animals is consistent with the
possibility that its action on AA metabolism is at least
partly mediated at the renal
tubular level. Although our data
do not demonstrate decreased
myo‐inositol
concentration in the medulla
of diabetic kidney, this does not exclude myo‐ inositol
deficiency in the renal tubular
cells. This may occur because a subpool of rapidly turned‐over intracellular myo‐inositol
is depleted in diabetes (14).
The contrasting response of myo‐inositol concentration in the renal
cortex and medulla to the
development of diabetes is not
surprising. More and more, tissues are reported to
have different patterns of change
reflection of the unique biochemical features of each tissue (16). This interpretation of the action of aldose reductase inhibitor
and myo‐inositol
in raising plasma and decreasing urinary AA
is not necessarily the only possibility. Because there was no AA
in the rat chow used in this study,
the increased urinary AA in
untreated
diabetic animals
clearly reflects
increased synthesis, perhaps a
compensatory attempt to normalize plasma AA
concentration. The primary action
of aldose reductase inhibitor and myo‐inositol may therefore be
to normalize plasma AA and thereby
reduce the stimulus for increased
AA production, which in turn leads to
a reduction in urinary
output of AA. The amelioration of glomerular hyper‐filtration in experimental diabetes by dietary
myo‐inositol and aldose reductase inhibitor may also have contributed to
the reduced excretion of AA
(17). These studies also confirm
the close relationship between
the polyol pathway
and AA metabolism in diabetes. The interaction is not a
simple one: the disturbance of AA metabolism
in
galactose‐fed rats was much
less severe than in diabetes, and we found normal plasma
AA concentration and only modestly increased urinary
AA, which again was normalized by aldose
reductase inhibition. Although galactose
feeding has been used extensively as a
model to simulate the polyol disturbance in diabetes,
increasing differences of
this model from diabetes have been reported (18). The aldose
reductase inhibitors are being investigated extensively for their
possible role in the treatment and prevention of diabetic
complications. Initially, interest
was
focused on their action
in preventing sorbitol accumulation. Subsequently, attention was turned to their
ability to normalize tissue
myo‐inositol level. Their action on AA
metabolism can now be added to this
list and may turn out to be
important as a
result of the ubiquitous
nature and the great biological
significance of AA. The
relevance
of these findings
to the situation in human diabetes
remains to be explored. Because
rats synthesize AA and do not rely
on dietary AA intake, their metabolism
of this vitamin may be
quite different from humans. However, diabetic
patients also have lower plasma AA
concentrations. Our unpublished observations have shown that diabetic patients excrete
AA in amounts inversely proportional
to their glycosylated hemoglobin level,
suggesting tissue depletion of
this vitamin with increasing hyperglycemia. Because humans
cannot synthesize AA, a
change in production rate cannot be a
factor but other disturbances in
the metabolism of AA are possible. These may include a shift
in its equilibrium with
dehydroascorbate, alteration of renal excretion, change in half‐life,
and competition for cellular uptake
during high glucose
level. Further
studies to characterize the nature of AA disturbance and
its functional significance in humans would be of great interest. ACKNOWLEDGMENTS This study was supported by
the National Health and
Medical Research Council
of Australia, the Kellion
Foundation, and
the Hoechst Foundation of Australia. Tolrestat was a gift of
Ayerst (Princeton, NJ). REFERENCES 1. Som
S,
Basu D, Deb S, Choudhury PR,
Mukherjee S, Chatterjee SN, Chatterjee IB: Ascorbic acid metabolism
in diabetes mellitus. Metabolism 30:572-77, 1981 2. Yew MS:
Effect of streptozotocin diabetes on tissue
ascorbic acid and dehydroascorbic acid. Horm
Metab
Res 15:158,
1983 3. Chen
MS, Hutchinson ML, Pecoraro RE, Lee WYL,
Labbe RF: Hypergly- cemia-induced intracellular depletion of ascorbic acid in human mono- nuclear leukocytes. Diabetes 32:1078-81, 1983 4. McLennan S, Yue
DK, Fisher E, Capogreco C,
Heffeman S, Ross GR, Turtle JR: Deficiency of ascorbic
acid in experimental diabetes:
relation- ship with collagen and
polyol
pathway abnormalities. Diabetes 37:359- 61, 1988 5. Levine M: New
concepts in
the biology
and biochemistry of ascorbic acid. N Engl
J
Med 314:892-902,
1986 6. Barnes
MJ: Function of ascorbic acid
in collagen metabolism.
Ann NY Acad
Sci 258:264-75,
1976 7. Myllyla
R, Kuutti-Savolainen
ER, Kivirikko Kl: The
role of ascorbate in the prolyl hydroxylase
reaction. Biochem
Biophys Res Commun 83:441-48, 1978 8. Freeman
BA, Crapo JD: Biology
of disease: free radicals
and tissue injury.
Lab Invest 47:412-26,
1982 9. Bergmeyer HU,
Gruber W, Gutmann I: o-Sorbitol. In
Methods of Enzymatic
Analysis.
Vol. 3. Bergmeyer
HU,
Ed. New York,
Academic, 1974, p. 1323—
26
10.
Weissbach
A: myo-lnositol.
In
Methods
of
Enzymatic
Analysis. Vol. 3.
Bergmeyer
HU, Ed. New York, Academic, 1974,
p. 1333-36
11.
Yue DK, McLennan
S, Marsh M, Mai YW, Spaliviero J, Delbridge, Reeve T, Turtle JR: Effects of
experimental diabetes,
uremia, and malnutrition on wound
healing.
Diabetes
36:295-99, 1987
12.
Yue DK, Swanson S, McLennan S, Marsh M, Spaliviero
J, Delbridge
L, Reeve T, Turtle JR: Abnormalities of granulation tissue and collagen
for- mation in experimental
diabetes, uraemia and malnutrition.
Diabetic Med
3:221-25,
1986
260
DIABETES,
VOL.
38, FEBRUARY 1989
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