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recommended COLLAGEN, ASCORBATE (vitamin C)

ascorbate deficiency reduced collagen polyol pathway

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‐productionUnder‐hydroxylation‐of‐proline‐leadsto‐increased‐intracellular degradation.pdf    FULL


Ascorbate deficiency results in decreased collagen production: Under‐

hydroxylation of proline leads to increased intracellular degradation





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 myoinositol is also effective in this regard is further evidence that the polyol pathway is involved in the abnormal metabolism of AA in diabetes (14). myolnositol supplementation can reverse some of the polyolrelated 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+‐gradientdependent 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 myoinositol, 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 myoinositol 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 myoinositol is depleted in diabetes (14). The contrasting response of myoinositol 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 myoinositol 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 myoinositol 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 myoinositol 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.






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).



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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.





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