Archives of Medical Research 50 (2019) 11e14
Vitamin C for Type 2 Diabetes Mellitus and Hypertension Undurti N. Das UND Life Sciences, Battle Ground, WA, USA Department of Medicine, GVP Hospital and Medical College, Visakhapatnam, India BioScience Research Centre, GVP College of Engineering Campus, Visakhapatnam, India Received for publication April 20, 2019; accepted May 13, 2019 (ARCMED_2019_338). Available online xxx
It is suggested that supplementation of vitamin C reduces hyperglycemia and lowers blood pressure in hypertensives by enhacing the formation of prostaglandin E1 (PGE1), PGI2 (prostacyclin), endothelial nitric oxide (eNO), and restore essential fatty acid (EFA) metabolism to normal and enhance the formation of lipoxin A4 (LXA4), a potent anti-inflammatory, vasodilator and antioxidant. These actions are in addition to the ability of vitamin C to function as an antioxidant. In vitro and in vivo studies revealed that PGE1, PGI2 and NO have cytoprotective and genoprotective actions and thus, protect pancreatic b and vascular endotheilial cells from the cytotoxic actions of endogenous and exogenous toxins. AA, the precursor of LXA4 and LXA4 have potent anti-diabetic actions and their plasma tissue concentrations are decreased in those with diabetes mellitus and hypertension. Thus, vitamin C by augmenting the formation of PGE1, PGI2, eNO, LXA4 and restoring AA content to normal may function as a cytoprotective, anti-mutagenic, vasodilator and platelet anti-agregator actions that explains its benefical action in type 2 diabetes mellitus and hypertension. Ó 2019 IMSS. Published by Elsevier Inc. Key Words: Ascorbic acid (vitamin C), Diabetes mellitus, Hypertension, Prostaglandin, Prostacyclin, Sepsis.
Nutrients and nutritional factors are known to play a significant role in the pathobiology of type 2 diabetes mellitus (T2DM) and hypertension (HTN). But little attention is paid to this issue in the prevention and management of T2DM and HTN. In 1981, we were the first to show that vitamin C (1000 mg per day) when administered for 15 d can produce a significant decrease in plasma fasting, 1 h and 2 h glucose levels after glucose load in those with T2DM (drug na€ıve patients) compared to T2DM control who did not receive vitamin C (1). In this study, we measured plasma vitamin C levels using 2-4 dinitrophenylhydrozone method and noted that there was a small but insignificant increase in the plasma levels of vitamin C. It is known that vitamin C enhances the formation of prostaglandin E1 (PGE1), a metabolite of dihomogamma-linolenic acid (DGLA, 20:3 n-6), which imitates
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and enhances the actions of insulin (2). Studies showed that vitamin C augments the production of PGE1 and prostacyclin (PGI2) that have potent platelet antiaggregator and vasodilator actions (3e6). It is noteworthy that both PGE1 and PGI2 enhance endothelial nitric oxide (eNO) generation by endothelial cells and vitamin C by itself seems to augment eNO production in a tetrahydrobiopterin (BH4) dependent manner (7e13). It is likely that increase in eNO generation is, in part, due to the ability of vitamin C to enhance PGE1 and PGI2 production (8e12). In addition to their vasodilator and platelet antiaggregator actions, we showed that PGE1 and PGI2 prevent alloxan-induced cytotoxicity to pancreatic b cells in vitro and diabetes in experimental animals (14,15). Both PGE1 and PGI2 were found to be capable of preventing genotoxicity by various chemicals and radiation in vitro and in vivo (16e20). Thus, vitamin C, by virtue of its ability to enhance PGE1, PGI2 and eNO synthesis, has cytoprotective, anti-mutagenic, vasodilator and platelet anti-aggregator actions that may explain its (vitamin C) beneficial action in T2DM and HTN (1,14,15). These beneficial actions may be in addition to
0188-4409/$ - see front matter. Copyright Ó 2019 IMSS. Published by Elsevier Inc. https://doi.org/10.1016/j.arcmed.2019.05.004
Das/ Archives of Medical Research 50 (2019) 11e14
Figure 1. Scheme showing the role of folic acid, B6, B12 and vitamin C in the metabolism of essential fatty acids, and the interaction among EFAs and their metabolites and eNO and cytokines and their role in hypertension and type 2 DM. (þ) indicates increase in synthesis/action; (‒) indicates decrease in the synthesis/action.
its known anti-oxidant action. Since endothelial dysfunction due to eNO deficiency is known to occur in obesity, insulin resistance, T2DM, hypertension and cardiovascular diseases and all these diseases are characterized by oxidative stress, it is likely that vitamin C could be of benefit in them (8,10). Furthermore, PGE1, PGI2 and NO have anti-inflammatory actions by suppressing the production of pro-inflammatory interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) (reviewed in 8,10). Since AA forms the precursor to PGI2 and enhances eNO generation and suppresses IL-6 and TNF-a production by its direct action and partly, by enhancing the formation of lipoxin A4 (LXA4), a potent anti-inflammatory molecule (21), it is likely that vitamin C may enhance the formation of LXA4. Thus, vitamin C may function as an antiinflammatory molecule (22,23). This implies that similar to folic acid, B6 and B12, vitamin C may also serve as a
co-factor to augment the activities of desaturases and enhance the formation of PGE1, PGI2, LXA4 and eNO (8,10) (Figure 1). Since PGE1 is derived from DGLA and PGI2 and LXA4 from AA, studies performed with DGLA and AA and other polyunsaturated fatty acids (PUFAs) on chemical-induced type 1 and type 2 DM, showed that LA, GLA, DGLA, AA, ALA, EPA and DHA but not oleic acid, the monounsaturated fatty acid, and stearic acid, a saturated fatty acid, protect pancreatic b cells against both alloxan and streptozotocin (STZ)-induced cytotoxicity in vitro (21,24e27). Of all the PUFAs tested, AA is the most effective against both alloxan-induced type 1 DM and STZ-induced type 1 and type 2 DM in experimental animals. Subsequent studies showed that lipoxin A4 (LXA4) is the mediator of the beneficial actions of AA (21,24,25). Both AA and LXA4 showed significant anti-inflammatory and anti-diabetic
Vitamin C for Type 2 Diabetes Mellitus and Hypertension
actions (21,26e29). It is noteworthy that these unsaturated fatty acids, especially AA, promote glucose-stimulated insulin secretion from pancreatic b cells by activating on GPR40 (30). Since unsaturated fatty acids DGLA, AA, EPA and DHA enhance eNO generation (8,10,31e34), it is worth investigating whether a combination of vitamin C and unsaturated fatty acids function as potential antidiabetic and anti-hypertensive molecules. In addition, we observed that patients with type 2 DM and essential hypertension have decreased plasma phospholipid content of especially AA and circulating LXA4 (35,36). It is interesting to note that L-arginine-nitric oxide system interacts with the essential fatty acid (EFA) metabolism. Administration of L-arginine, the precursor of NO, and sodium nitroprusside, a nitric oxide donor, was found to enhance the activities of delta-6- and delta-5 desaturases, which are depressed in diabetes, and restored plasma and tissue levels of PUFAs to normal suggesting that L-arginine-nitric oxide system and EFA metabolism are interconnected (37). The usefulness of vitamin C in the management of type 2 DM and hypertension is supported by a recent study (38) that showed that oral vitamin C (1000 mg per day) may be of benefit in reducing hyperglycemia and blood pressure in those with T2DM. This beneficial action of vitamin C has been attributed to the anti-oxidant action of vitamin C due to a decrease in the plasma F2-isoprostanes in these subjects. These evidences indicate that the beneficial action(s) of vitamin C is not only due to its anti-oxidant property but also as a result of its ability to enhance PGE1, PGI2, LXA4 and eNO generation (1,3e7,31e34,38e40). Despite the fact that vitamin C behaves as an anti-oxidant, it is noteworthy that it may possess pro-oxidant action at very high doses especially when administered intravenously that may explain its anti-cancer action both in vitro and in vivo (41). At pharmacological doses, vitamin C shows antioxidant capacity that underlies its benefit in sepsis (42,43). Thus, the beneficial actions of vitamin C in T2DM, HTN, sepsis and cancer suggest its pleiotropic actions on unsaturated fatty acid metabolism, pro- and anti-oxidant actions and ability to enhance PGE1, PGI2, LXA4 and eNO generation. This implies that to derive its beneficial actions vitamin C may need to be co-administered with unsaturated fatty acids and other nutrients. Dietary essential fatty acids (EFAs) linoleic acid (LA) and alpha-linolenic acid (ALA) are converted to their respective long-chain metabolites gamma-linolenic acid (GLA), dihomo-gamma-linolenic acid (DGLA) and arachidonic acid (AA) and eicosapentaenoic acid (EPA) and docosahexaenoic acid respectively by the action of delta-6- and adelta-5-desaturases. Conversion of GLA to DGLA is due to the action of an elongase enzyme. EPA can be converted to DHA and DHA, in turn, can be retroconverted to EPA. GLA, DGLA, AA, EPA and DHA enhance eNO formation especially, by vascular endothelial cells. Folic acid, vitamins B6, B12 and C are co-factors for
the normal activity of desaturases and for conversion of DGLA to PGE1. AA is the precursor of PGI2 and LXA4. GLA, DGLA, AA, EPA and DHA and PGE1, PGI2 and LXA4 have anti-inflammatory action and suppress IL-6 and TNF-a formation and enhance the formation of antiinflammatory cytokines (IL-4, IL-10, IL-12). Under normal physiological conditions, a balance is maintained between pro- and anti-inflammatory cytokines. NO quenches ROS and thus, reduces oxidative stress. On the other hand, high levels of ROS (generated by pro-inflammatory cytokines) can inactive eNO leading to an increase in vascular tone and hypertension. Similar to the formation of LXA4 from AA, EPA and DHA are precursors to resolvins, protectins and maresins that also have anti-inflammatory action. It is likely that B6, B12, folic acid and vitamin C may also enhance the formation of resolvins, protectins and maresins from EPA and DHA. Though not shown in the figure, high doses of vitamin C can enhance ROS generation specifically, in tumor cells and induce their apoptosis. Paradoxically, when patients with sepsis are administered pharmacological doses of vitamin C oxidative stress is decreased. Thus, actions of vitamin C depends on the dose, duration of administration (from few hours to days and weeks) and context. Vitamin C may show both pro- and anti-oxidant actions. Since vitamin C is a co-factor of EFA metabolism and PGE1, PGI2 and LXA4 mediate some, if not all, of the actions of vitamin C, it is likely that in EFA deficiency states, it (vitamin C) alone may not produce the desired beneficial action. Both type 2 DM and hypertension are low-grade systemic inflammatory conditions in which plasma IL-6 and TNF-a levels are high, lipid peroxides are increased, AA and LXA4 deficiency is seen. IL-6 and TNF-a are known to induce EFA deficiency state. Hence, it is prudent to give vitamin C along with other co-factors (folic acid, B6, B12) and PUFAs. Thus, in all inflammatory conditions, it is desirable to administer PUFAs, B6, B12, folic acid and vitamin C together to obtain their optimal action.
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