Journal of the American College of Nutrition, Vol. 17, No. 2, 105-108 (1998)
Published by the American College of Nutrition
The Glucose/Insulin System and Vitamin C: Implications in Insulin-Dependent Diabetes Mellitus
John J. Cunningham, PhD, FACN
Department of Nutrition, University of Massachusetts, Amherst
Address reprint requests to: John J. Cunningham, PhD, FACN, Department of Nutrition, Chenoweth Lab, Box 31420, University of Massachusetts, Amherst, MA 01003-1420
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ABSTRACT
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The cellular uptake of vitamin C (ascorbic acid, ASC) is promoted by insulin and inhibited by hyperglycemia. If a rise in plasma ASC is uncoupled from insulin replacement in insulin-dependent diabetes mellitus (IDDM) then the degree of hyperglycemia could account for "tissue scurvy" in IDDM. Leukocyte ASC is lower in IDDMs compared with nondiabetics when vitamin C consumption is adequate and our data suggest that this is a variable component of the pathophysiology of IDDM.
The complications of diabetes mellitus are believed to result from either the intracellular accumulation of sorbitol or the nonenzymatic glycoxidation of proteins or both. With respect to the abnormal cellular accumulation of sorbitol, vitamin C supplementation has been shown to be effective in several studies of adults with diabetes; the situation regarding the prevention of protein glycoxidations by supplementation is presently unclear. The roles of ASC as an aldose reductase inhibitor and a water soluble antioxidant in body fluids are potentially very important as adjuncts to tight glycemic control in the management of diabetes. Tissue saturation and maximal physiologic function in IDDM may require supplemental vitamin C intake.
Key words: vitamin C, insulin, insulin-dependent diabetes mellitus
Key teaching points:
• Tissue uptake of ascorbic acid is influenced by glycemia and insulin concentrations.
• Leukocyte ascorbic acid concentrations are often significantly decreased in IDDM despite adequate dietary vitamin C consumption.
• Supplementation with vitamin C is effective in normalizing erythrocyte sorbitol concentrations in IDDM.
• ASC as a water soluble antioxidant could be important in preventing glycoxidations of body proteins in IDDM, however, experimental evidence is presently insufficient.
• Vitamin C consumption above the RDA to saturate plasma ASC may provide important health benefits for individuals with IDDM.
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INTRODUCTION
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In most species, the hepatic metabolism of glucose (C6H12O6; MW 180) includes the synthesis of ascorbic acid [(ASC): C6H6O8; MW 176] [1]. In man, however, the absence of one enzyme in that pathway [2] necessitates the dietary intake of a micronutrient, termed vitamin C, to prevent scurvy. The presence of this "antiscorbutic chemical" in citrus fruits was well appreciated long before Szent-Gyorgi’s isolation of ASC itself in 1928 [3].
Although the biosynthetic relationship between glucose and ASC is absent in man, the glucose/insulin system does influence ASC metabolism. In particular, the cellular uptake of vitamin C is regulated by both glucose and insulin and the renal reabsorption of ASC is impaired by hyperglycemia [4]. Evidence also suggests that vitamin C supplementation may be beneficial in countering the pathophysiologies resulting from the chronic hyperglycemia of insulin-dependent diabetes mellitus (IDDM).
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REGULATION OF VITAMIN C UPTAKE BY GLUCOSE AND INSULIN
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The body pool of ASC in healthy adults is estimated to be between 900 and 1500 mg [5,6]. That pool must be depleted by two-thirds or more before scurvy is manifested. Virtually all tissues concentrate ASC at levels well above the plasma ASC concentration [1,7,8]. One exception is erythrocytes which can only equilibrate with the plasma ASC concentration [5,9].
The cellular uptake of ASC from plasma can occur by two mechanisms. An active transport of ASC is documented [4,8]. With regard to this active transport, insulin has been shown to accelerate ASC clearance from plasma, and presumably into cells since there is no increase in urinary excretion [10]. An hypothesis of "tissue scurvy" in IDDM as a consequence of a defective cellular uptake of ASC from plasma was advanced by Mann [11] on the basis of evidence accumulated prior to 1974. The recent observation of a clear late-phase insulin release following an intravenous infusion of ASC [12] could explain the variability seen in tissue ASC stores in IDDM (Fig. 1) if an insulin release is important for cellular ASC uptake. That is, since the exogenous replacement of insulin for IDDM occurs in discrete episodes that may or may not be closely coupled to dietary vitamin C intake, some individuals with IDDM may be disadvantaged by the absence of insulin-stimulated transport in response to an increase in plasma ASC.
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Fig. 1. Concentrations of ascorbic acid (milligrams ASC per total protein) in mononuclear leukocytes from individuals with insulin-dependent diabetes mellitus and from nondiabetic individuals. Bar graphs show mean and SEM for these groups (p<0.02 by t-test) with individual concentrations depicted as circles (from reference 31) or triangles (unpublished data for subjects detailed in reference 22).
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Hyperglycemia has been shown to inhibit ASC transport. This inhibition seems somewhat paradoxical given the evidence suggesting that insulin promotes both ASC and dehydroascorbic acid (DHA) uptake by cells. The inhibition of ASC uptake by hyperglycemia was demonstrated in vitro in the absence of insulin and may not, therefore, be important in normal physiology. But, if a high plasma ASC in IDDM is uncoupled from insulin replacement then the hyperglycemic inhibition could have substantial implications for uptake. Hyperglycemia is also known to enhance renal ASC losses [4].
The glucose transport system (GTS) also transports the minor oxidized and uncharged species, DHA with a presumed subsequent intracellular reduction to ASC. Stankova et al [13] showed that DHA competes for GTS transport on an equimolar basis with the transport surrogates 2-deoxy-glucose and 3-O-methyl-glucose. Earlier studies [14] clearly show an enhancement of leukocyte DHA uptake by insulin, consistent with the recruitment of GTS transporters from the cytosol to membrane surfaces. Much emphasis has been placed on this potential uptake mechanism. However, since plasma glucose exceeds plasma DHA by three orders of magnitude [14] there is some question about the physiologic significance of the GTS for cellular uptake of DHA.
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COMPLICATIONS OF DIABETES AND RESPONSIVENESS TO VITAMIN C SUPPLEMENTATION
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Given the structural similarity between glucose and ASC and the knowledge that ASC is synthesized from glucose, it is not surprising to find an early focus on vitamin C status in individuals with IDDM. Two such early reports of patient populations [15,16] found no evidence for an altered metabolism of ASC or an increased dietary requirement for vitamin C among IDDMs. Subsequent work suggested a need to more closely examine tissue ASC stores in the face of hyperglycemia as reviewed elsewhere [17]. Since that review, Lysy and Zimmerman [18] reported that leukocyte ASC was low, on average, in IDDMs compared with nondiabetic controls when all subjects were consuming a diet estimated to provide 100 to 180 mg of vitamin C daily. Our data from two separate studies (Fig. 1) agree with this and, furthermore, suggest that a diminished tissue pool of ASC is a variable component of the pathophysiology IDDM. While the mean mononuclear ASC concentration is significantly (p<0.02) lower in IDDMs as a group, approximately one-quarter of the individuals with IDDM maintain normal stores. As noted, the timing of insulin injections and hyperglycemic excursions may contribute to this variability. The clinical correlates to and the metabolic cause of the diminished ASC stores in the majority of subjects with IDDM are areas of ongoing research interest.
The complications of diabetes mellitus are believed to result from hyperglycemia either via the intracellular accumulation of sorbitol or via the nonenzymatic glycoxidation of proteins or through both of these mechanisms operating in tandem [19,20]. The Diabetes Control and Complications Trial [21] demonstrated that substantial clinical benefits can be expected from an adherence to "tight" glycemic control. These benefits are countered, to some degree, by an intrusion on the normalcy and quality of life that is inherent the practice of tight control. In addition, intensive or "tight" glycemic control generally establishes plasma glucose at approximately 6 to 8 mM and glycosylated hemoglobin at approximately 6 to 7% rather than the 5 mM and 5% levels, respectively, normally expected in nondiabetics. There is, therefore, room for adjunct therapies that can augment tight control. Among those therapies, strong evidence supports the likely efficacy of vitamin C supplementation.
With respect to the abnormal cellular accumulation of sorbitol, ASC has been shown to be effective in several studies of adults with diabetes [9,22,23]. A variety of molecules have been shown to function as aldose reductase inhibitors (ARIs), and these range from customized pharmaceutical agents through analgesics [24]. The supplemental dose of ASC required to achieve sorbitol normalization in IDDM appears to be on the order of 100 to 500 mg daily beyond typical dietary intakes of the vitamin. The choice of food or tablet source may be influenced by considerations of the impact of fruit or juice exchanges on the insulin regimen. In vitro data using a crude enzyme preparation [22] suggest that ASC functions as an ARI. In another set of experiments performed with the same assay system and semi-purified aldose reductase from brain, ASC inhibited the enzyme in a dose responsive manner (Table 1). The bioflavonoid quercitin provides an in vitro "gold standard" and is clearly a more potent inhibitor, however, it is poorly soluble in water and is much less abundant than vitamin C in the diets of most people.
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Table 1. In vitro Inhibition of Glycerealdehyde Reduction Requiring NADPH as a Cofactor in a Preparation Containing Semi-Purified Aldose Reductase from Brain*
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The irreversible glycations of proteins under oxidative conditions forms advanced glycosylation end products (AGEs) [25]. A straightforward antioxidant function makes vitamin C supplementation attractive for minimizing AGEs, analogous to the use of ASC to minimize the "browning" reaction in foods. Nevertheless, experimental evidence regarding the prevention of protein glycoxidations by ASC is presently unclear. Glycated albumin and glycated total protein have been studied as biomarkers and do show substantial positive responses to ASC supplementation, but questions about the value of those markers and the sensitivity and specificity of the methods remain. The glycation of hemoglobin (Hb) is more often recognized as a useful marker of hyperglycemic damage and this reversible glycation process correlates highly with Hb-AGE formation. The glycated species termed HbA1c predominates in erythrocytes and is readily detected due to a change difference using ion exchange chromatography [26]. However, HbA1c results soley from the glycation of N-terminal valine residues in the B chain of Hb that may, or may not, be functionally relevant to AGE formation. In contrast, the glycations of lysine residues in Hb are not directly measurable without customized antibody methods, but these glycations are likely to be very relevant in the AGE process. The total glycated hemoglobin (glycHb), when measured by affinity chromatography, includes molecules that are glycated at either the N-terminal valine or at internal lysine residues. In nondiabetics the effect of ASC supplementation is reported to be either significant [27] or nonsignificant [28]. Studies on diabetics similarly report significant [18,29] or nonsignificant [30] results.
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CONCLUSION
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ASC status depends on the interactions of dietary vitamin C intake, plasma insulin concentrations and glycemia. Insulin promotes the active cellular uptake of ASC whereas hyperglycemia inhibits renal ASC reabsorption. In IDDM, an adequate dietary vitamin C intake is often associated with an unexpectedly low ASC status [4,31] (Fig. 1). The roles of ASC as an aldose reductase inhibitor and a water soluble antioxidant in body fluids are potentially very important as adjuncts to tight glycemic control in the management of diabetes. Tissue saturation and maximal physiologic function in IDDM may require supplemental vitamin C intake above the amount recommended for healthy individuals.
Received April 1, 1997.
Accepted August 1, 1997.
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ABSTRACT
INTRODUCTION
