Hypothesis: The Role of Vitamin C in Diabetic Angiopathy

HYPOTHESIS: THE ROLE OF VITAMIN C IN DIABETIC ANGIOPATHY* GEORGE V. MANN, ScD., M.D.t The optimal daily intake of vitamin C for human beings is uncertain. Pauling's contention that human beings have high requirements for vitamin C is based upon inconclusive trials and inferences from evolutionary evidence [I]. His argument has been discounted by many nutritionists because they have not seen signs of classical scurvy among persons taking 10-100-mg quantities of ascorbic acid (AA) daily, nor are they persuaded that clinical trials have shown any health advantages for subjects taking 10-50 times larger quantities [2]. There is another possible explanation for high and variable requirements of AA which can -be derived from the known facts about its metabolism and the nature of diabetes mellitus. The primates and a variety of other organisms require dietary AA because they lack gulonolactone oxidase, which most other organisms use to make AA from hexoses in liver cells [3]. This circumstance puts the dietary-dependent species in a kind of metabolic double jeopardy. They must have a dietary source, and they must be able to transport vitamin C across cell membranes. The transport of many different sugars is facilitated by insulin [4]. These include D-glucose, D-mannose, D-galactose, D-xylose, Larabinose , and D-lyxose. Both pyranose and furanose structures are included in this group of insulin-facilitated sugars. Attempts have been made to generalize the molecular structure required by this insulinsensitive transport system [5]. Crane, Field, and Cori [6] found that the Goldstein-Levine [7] structural hypothesis for transport ofsugars according to their configuration at carbons 1, 2, and 3 cannot be true. This admits the possibility of insulin facilitation ofsuch a 2-3 diketose as dehydroascorbic acid (DHA), the transportable form of AA. *Paper submitted to Perspectives June 25, 1973. tNutrition Division, Vanderbilt University School of Medicine, Nashville, Tennessee 37232. Career Investigator, National Heart Institute, Bethesda. 5K06 HL-08288-12. 210 I George V. Mann · Diabetic Angiopathy Another suggestive feature of sugar transport is it phylogenetic peculiarity . Widdas [8] found that the erythrocytes of fetal pigs, rabbits, guinea pigs, sheep, and deer are all hexose permeable at birth, but this sensitivity soon begins to disappear so that by the eighth day of life only the primates, of all the species examined, retain facilitated transport. There are thus three unusual features of facilitated transport of sugars: it is structurally selective for certain molecules; it is tissue specific, the dependency on insulin tending to be prominent in the eye, in muscle cells, and in adipocytes; and it is phylogenetically specific, tending to persist into adult life in the red blood cells of primates, which happen also to require dietary AA. Facilitated transport of sugars also shows competitive inhibition by structurally related molecules. This is interpreted to mean that these molecules are competing for a common carrier. Thus impairment of AA utilization could have two possible mechanisms. Insulin lack may impair transport of AA if the latter is an insulin-dependent process, or hyperglycemia, of whatever cause, might impair transport of AA if the two sugars compete for a common carrier. The prevalence of carbohydrate intolerance and diabetes mellitus varies among ethnic groups, being common among people in technically advanced countries [9]. The prevalence of carbohydrate intolerance increases strikingly with age, coming to affect 40 percent of persons past the age of 50 years [10, H]. The disorder is often associated with accelerated vascular disease [12]. This diabetic angiopathy consists of thickening ofbasement membranes and fragility ofcapillary vessel walls. These changes impair transport and tissue nutrition and lead to aneurysmal dilatation and hemorrhage. In some patients with overt diabetes, the angiopathy is manifested as retinopathy causing blindness or as a nephropathy with uremia. The hallmark of chronic diabetes is accelerated vascular disease, and conventional therapy with insulin has had only limited preventive success. These vascular complications of diabetes are not well correlated with elevation of levels of cholesterol and triglycerides in the blood, with age at diagnosis, with severity, or even with degree of control, although there is argument about the last point [13]. They are correlated with resistance to the action of insulin and with duration of diabetes...