Ascorbic acid and diabetes mellitus

ASCORBIC ACID AND DIABETES MELLITUS C. ALAN B. CLEMETSON.

The Methodist Hospital, 506 Sixth Street, Brooklyn, New York 11215, USA.

SUMMARY Dehydroascorbic acid, the oxidized form of vitamin C, causes diabetes when injected into animals and has been reported to be present in increased amounts in the blood of patients with diabetes mellitus and even in prediabetics. One of the earliest changes in diabetes mellitus is electron-microscopic evidence of damage to the inner endothelial lining of the blood -vessels. Certain bioflavonoids, which are natural non-toxic food substances from plants, like rutin from buckwheat, prevent the oxidation of ascorbic acid and seem to protect the endothelium when given with vitamin C; it is therefore suggested that all vitamin C tablets should be combined with these flavonoids.

diabetes mellitus have markedly elevated levels of DHAA in their blood and that even prediabetics show an elevated level of DHAA (4). Certain “capillary active” bioflavonoids, such as rutin and quercetin, which are potent anti-oxidants for ascorbic acid (5) and presumably act by preventing oxidation of this vitamin in the lumen of the jejunum, have been reported to protect against retinal hemorrhage, radiation injury and various disorders of the capillary endothelium, when given in combination with ascorbic acid (6,7). Since electron microscopic evidence of damage to the vascular endothelium is one of the earliest detectable changes in diabetes mellitus, we can at last perhaps understand why certain bioflavonoids have a beneficial action on the capillary endothelium and its extension, the endothelium of the larger blood vessels, which needs AA and is damaged by DHAA. Chatterjee et al (4) have shown that the rate of hydrolysis of DHAA to 2, 3-diketogulonic acid is markedly low in blood cells from diabetics, so there is good reason to avoid DHAA in diabetics and prediabetics. Too much ascorbic acid or too little ascorbic acid can both be harmful in this respect. However, I have shown that proteins and certain flavonoids, such as rutin or quercetin, prevent the oxidation of AA by chelating heavy metal catalysts, such as Cu++ in tap water (5,8,9). It is therefore interesting to note that Chatterjee et al (4) found that the increase in the blood sugar level, following the feeding of large doses of ascorbic acid (100 mg AA per 1OOgbody weight) to guinea pigs on high cereal diets, is dependent on the increase in the blood DHAA level. When the same dose of ascorbic acid was fed to guinea pigs on the same diet with a casein supplement, the blood DHAA level did not increase and there was no increase in the blood sugar level (4). It is the purpose of this communication to point out that “capillary active” flavonoids, such as rutin or quercetin, should be added to all ascorbic acid tablets to prevent oxidation to DHAA in the alkaline medium of the jejunum. so as to avoid the possibility of hastening the development

It has been known for many years that dehydroascorbic acid (DHAA), the oxidized form of ascorbic acid (AA), has a chemical structure closely related to that of alloxan (Figure 1). When injected intravenously into rats, it causes hypertension in doses as low as 5 mg/kilo and temporary or permanent diabetes mellitus with atrophy of the islets of Langerhans in higher doses (1,2). It has also been known for many years that small amounts of DHAA are found alone in the blood and tissues without AA in scurvy and that both the glucose tolerance and the plasma insulin levels are decreased in scurvy (3). It has now been shown that large doses of ascorbic acid by mouth can also cause a rise in the DHAA level in the blood of both guinea pigs and human subjects, and associated elevations of the blood sugar levels have been observed (4). Moreover, it is now reported that patients with

H

I HO-C-H

I

H-C-OH O-C-H

FIGURE

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Chemical similarity between dehydroascorbic acid (DHAA) and alloxan. Both substances cause diabetes mellitus by damaging the islets of Langerhans and both contain three adjacent carbonyl groups. Since DHAA is a triketone or trione and is not itself an acid, some authors have proposed the name ascorbone for this substance.

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of diabetes mellitus. It may be that only diabetics and prediabetics are at risk, but who knows which individuals are prediabetics? With the addition of rutin, the ascorbic acid requirement will be reduced because of reduced losses by oxidation and hydrolysis and the danger of increasing the blood DHAA level will be obviated, so all will benefit. Pure rutin and its aglycone, quercetin, are entirely nontoxic natural food substances; commercial rutin obtained from buckwheat or from Sophoru juponica is completely safe and harmless (6). However, some specimens of quercetin from ecualyptus have been found to be contaminated (IO), so the government authorities should insist that only pure bio-flavonoids be allowed on the market. The amount of flavonoids needed will be related to the amount of heavy metals in the drinking water. The first water drawn from copper pipes in the morning in soft water areas may contain as much as two parts per million of copper; this could well explain the high mortality from degenerative vascular disease in soft water areas (1 l), for subendothelial cholesterol deposition and atherosclerosis are also closely related to ascorbic acid status and metabolism (12,13,14). In hard water areas, the water pipes are coated with fur and will not present such a problem. Before we all start having the copper pipes removed from our homes, further studies will be needed to confirm the presence of increased amounts of DHAA and/or a decrease in the AA/DHAA ratio in the blood plasma of diabetics and prediabetics. For this purpose it will be necessary to arrest oxidation at the time the blood is drawn. Other factors influencing the Eh or oxidation-reduction potential of the blood and tissues, such as the ratio of

reduced to oxidized glutathione and other SH-SS equilibria may be of great importance. The Eh of the blood plasma may be found to be as important as the pH in the homeostasis of the milieu interieur.

REFERENCES 1. Patterson JW. The diabetogenic effect of dehydroascorbic acid and dehydroisoascorbic acids. J Biol Chem. 183, 81, 1950 2. Patterson JW, Mastin DW. Some effects of dehydroascorbic acid on the central nervous system. Am J Physiol. 167, 119, 195 1 3. Banerjee S, Ghosh NC. Relation of scurvy to glucose tolerance test, liver glycogen, and insulin content of pancreas of guinea pigs. J Biol Chem. 168, 207, 1947 4. Chatterjee IB, Majumdec AK, Nandi BK, Subramanian N. Synthesis and some major functions of vitamin C in animals. Ann N Y Acad Sci. 258, 24, 1975 5. Clemetson CAB, Anderson L. Plant polyphenols as antioxidants for ascorbic acid. Ann N Y Acad Sci. 136, 339, 1966 6. Griffiths JQ, Krewson CF, Naghski J. Ruth and Related Fluvonoids. Mack Publishing Company, Easton, Pennsylvania, 1955 1. Vitamin P. Its Properties and Uses. Translated from the Russian. Israel Program for Scientific Translations, Jerusalem, 1963 (Published for the National Science Foundation, Washmgton, DC.). Available from the Office of Technical Services, U.S. Department of Commerce, Washington 25, D.C. 8. Clemetson CAB. I bioflavonoidi quali antiossidanti per l’acido ascorbico. BioJavonoidi, 584, Ed. V. Zambotti, Scuole Grsflche Artigianelli, Pavoniani, Milano? 1967 9. Clemetson CAB. Menorrhagla rheumatica. La Vie Medicale, Numero Hors Serie, 8, December 1969 10. Dunlap WJ, Nakagawa Y, Wender SH. Preparation of highly purified flavonoid aglycones for biological studies. Anal Biochem. 3, 350, 1962 11. Schroeder HA. Municipal drinking water and cardiovascular death rates. JAMA. 195, 125, 1966 12. Willis GC. An experimental study of the intimal ground substance in atherosclerosis. Can Med Assoc J. 69, 17, 1953 13. Willis GC, Fishman S. Ascorbic acid content of human arterial tissue. Can Med Assoc J. 72, 500, 1955 14. Shalfer CF. Ascorbic acid and atherosclerosis. Amer J Clin Nutr. 23, 27, 1970

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