July 2014 Issue

Diabetes and Cardiovascular Damage — Can Antioxidants Reduce the Risk?
By Densie Webb, PhD, RD
Today’s Dietitian
Vol. 16 No. 7 P. 24
 
Diabetes and its cardiovascular complications are an epidemic in the making. An estimated 8.3% of the US population has diabetes (90% to 95% of those have type 2 diabetes), while 35% of adults older than age 20 have prediabetes, and most don’t know they have it.1 Fifty percent of adults aged 65 and older have diabetes, and according to a recent report, if the current pattern continues, by 2020, more than one-half of the people in the United States either will have prediabetes or diabetes.2

These statistics are more sobering when considering that diabetes increases the risk of cardiovascular disease (CVD) three- to eightfold.3,4 Diabetes makes the heart more vulnerable to injury and more susceptible to heart failure.5 It isn’t surprising then that nearly 25 million adults in the United States have been diagnosed with diabetes and coronary artery atherosclerosis.5

Oxidative stress, in large part, contributes to cardiovascular complications associated with diabetes,4 caused by an imbalance between damaging free radicals and the body’s antioxidant defenses, which is linked to cellular dysfunctions that lead to various diseases such as CVD.6

What Is Oxidative Stress?
“Diabetes is associated with a state of increased oxidative stress,” says Angela Ginn, RDN, LDN, CDE, a spokesperson for the Academy of Nutrition and Dietetics. Studies have shown that the metabolism of excessive glucose and free fatty acids that occurs with diabetes and insulin resistance increases oxidative stress and may accelerate the development of complications.7

Oxidative stress results from the production of oxidizing compounds (free radicals) in cells that exceeds the body’s natural antioxidant defense system and can destroy cardiac tissue and promote atherosclerosis. Chemically, free radicals are highly reactive and form when oxygen interacts with certain molecules in the body. They also result from exposure to cigarette smoke, ultraviolet rays, pollutants and chemicals, alcohol, and saturated fat and are found in disproportionate levels in those with diabetes.8

The initial trigger by which high blood glucose levels impair vascular function is an imbalance between nitric oxide availability and reactive free radicals.9 Nitric oxide, an anti-inflammatory and antiatherosclerotic molecule, can relax blood vessels and increase blood flow to tissues, but the nitric oxide system is compromised in the presence of excessive free radicals, resulting in hypertension and insulin resistance and further impairing the nitric oxide system, creating a downward spiral of cardiovascular damage.

Once formed, these free radicals set off a chain reaction of creating even more free radicals. Hyperglycemia, hyperlipidemia, and insulin resistance, which are hallmarks of diabetes, enhance oxidative stress. The production of the oxidant superoxide is the major cause of diabetes tissue damage and responsible for inactivating antiatherosclerotic enzymes.4

Not only does oxidative stress cause damage, it impairs the heart’s ability to respond to stressors, such as a lack of blood flow and oxygen, and can cause inflammation that lingers even after blood sugar is normalized.4 The downward spiral of free radical formation and damage to the systems designed to neutralize them can result in disease.10

How to Treat Oxidative Stress
Vitamin E is one of the most common antioxidant compounds suggested to reduce oxidative damage in patients with and without diabetes. Several observational, epidemiological studies have suggested that both dietary vitamin E and vitamin E supplements may decrease CVD risk.11,12 While only one looked specifically at diabetes patients, approximately 30% of patients with CVD have diabetes.11

Some population studies also have suggested that vitamin C may offer similar protection. However, several prospective clinical trials have found that antioxidant supplements provide no consistent cardiovascular benefits.12

Vitamin E
Arguably, vitamin E is the most widely studied and consumed antioxidant compound in the hope of reducing CVD risk in populations with and without diabetes. Although antioxidant treatments, including vitamin E, show benefits in animals with diabetes, research has failed to show that supplements consistently provide any heart health benefits in clinical trials.13

In the Physicians Health Study II, men taking 400 IU of vitamin E every other day for eight years obtained no cardiovascular benefits. In fact, an increased risk of hemorrhagic stroke occurred.14

A meta-analysis of more than 135,000 individuals treated with vitamin E concluded that high-dose vitamin E (more than 400 IU/day) slightly increased the risk of death.15

The contradictory results of vitamin E protecting against cardiovascular complications has prevented researchers from recommending high-dose supplemental vitamin E. Moreover, further study has revealed that it may be only a subgroup of diabetes patients with a certain genotype called Hp2-2 who are likely to benefit from vitamin E supplementation, and that supplementation in diabetes patients without the Hp2-2 genotype may be harmful.11

In most Western populations, about 36% of diabetes patients have the Hp2-2 genotype. However, in Southeast Asia, approximately 90% of the diabetes population has the genotype, suggesting that the study findings of one population may not apply to others.11 “Pharmacogenetic testing allows the health care provider to tailor treatment to a patient’s unique genetic makeup,” Ginn says, “but the jury is still out.”

While there appears to be no difference in the distribution of the genotype among diabetes patients, studies have established that the Hp genotype can predict CVD risk. The specific Hp2-2 genotype appears to predict who among diabetes patients will benefit from vitamin E supplementation. Among those with the vitamin-E–responsive genotype, adding statins to the mix reduces risk even further.16 Both the Heart Outcomes Prevention Evaluation (HOPE) study and the ICARE study found diabetes patients with the Hp2-2 genotype who took vitamin E supplements at 400 IU/day experienced a 50% reduction in myocardial infarction, cardiovascular death, and overall incidences of cardiovascular events, respectively.17,18

Vitamin C
While population studies suggest that vitamin C in supplemental or dietary form may improve inflammatory markers (indicators of oxidation in the body), it’s unclear whether vitamin C intake reduces CVD risk among diabetes patients.19 It does appear to decrease fasting insulin levels and improve insulin action, though.20

Two large-scale, long-term trials that tested 500 mg/day of supplemental vitamin C found it had no effect in women at high risk of CVD or in men for preventing CVD.14,21

In a study of 315 patients, among those taking a combination of vitamin C (average intake of 500 mg/day) and vitamin E (average intake of 400 IU/day) supplements for three months, there were no improvements in body weight, hemoglobin A1c, LDL, or triglycerides in those with either metabolic syndrome or type 2 diabetes.22

Studies in which people took 800 to 3,000 mg/day of vitamin C have found no significant differences in fasting glucose or fasting insulin levels or specific inflammation markers.23-25 However, one study showed improved levels of free radicals in patients who took 1,000 mg/day of vitamin C for four months.26

While the effectiveness of antioxidant supplements appears to be determined by genetic predisposition so is the extent to which tissue damage likely is to occur.4 Furthermore, it seems as though oxidative stress is only one factor contributing to diabetes complications; thus, antioxidant treatment most likely would be more effective if it were coupled with other treatments for diabetes complications.7

Glutathione
Sometimes referred to as the “master antioxidant,” glutathione, a tripeptide, is the most abundant antioxidant in animal tissues and one of the most powerful. It’s responsible for several metabolic functions, including intracellular defense against oxidative stress such as from toxins, drugs, and carcinogens.27 “Gluathione is an important defense mechanism against damage to the heart,” Ginn says.

Glutathione depletion can occur from diabetes and aging,28 and levels also are affected by genotypes.29 Freshly prepared meats are relatively high in glutathione, while fruits and vegetables have moderate to high amounts and dairy products, cereals, and breads generally are low in the antioxidant. Frozen foods have similar amounts as fresh foods, but other forms of processing and preservation usually result in extensive loss of the antioxidant.30

When consumed, glutathione is broken down into its constituent amino acids, including cysteine. Available cysteine primarily determines glutathione concentrations in cells. N-acetyl cysteine (NAC) supplements sometimes are used to provide cysteine and increase glutathione levels.31 However, studies haven’t consistently found that NAC supplementation increases glutathione levels.27

Can Oxidative Damage Be Prevented?
While researchers continue to study antioxidant compounds and the medical community waits for genetic phenotypes to be identified and genetic testing to be perfected, the only proven way to prevent the oxidative damage associated with type 2 diabetes is to prevent the disease from occurring through diet and lifestyle changes, which include regular exercise and maintaining a healthy weight. Eating a diet rich in fruits and vegetables provides antioxidants shown to reduce oxidative damage and may provide protection against free radical damage.

“Healthy eating, physical activity, and blood glucose control are the pillars of prevention of diabetes and diabetes-related complications,” Ginn says.

— Densie Webb, PhD, RD, is a freelance writer, editor, and industry consultant based in Austin, Texas.

References
1. Fast facts: data and statistics about diabetes. American Diabetes Association website. http://professional.diabetes.org/admin/UserFiles/0 - Sean/FastFacts March 2013.pdf. Revised March 2013.

2. The United States of diabetes: new report shows half the country could have diabetes or prediabetes at a cost of $3.35 trillion by 2020. UnitedHealthcare website. http://www.uhccommunityandstate.com/newsroom/half-the-country-could-have-diabetes.html. November 23, 2010.

3. Brown JR, Edwards FH, O’Connor GT, Ross CS, Furnary AP. The diabetic disadvantage: historical outcomes measures in diabetic patients undergoing cardiac surgery — the preintravenous insulin era. Semin Thorac Cardiovasc Surg. 2006;18(4):281-288.

4. Giacco F, Michael B. Oxidative stress and diabetic complications. Circ Res. 2010;107(9):1058-1070.

5. Ansley DM, Wang B. Oxidative stress and myocardial injury in the diabetic heart. J Pathol. 2013;229(2):232-241.

6. Raprasath T, Selvam GS. Potential impact of genetic variants in Nrf2 regulated antioxidant genes and risk prediction of diabetes and associated cardiac complications. Curr Med Chem. 2013;20(37):4680-4693.

7. Scott JA, King GL. Oxidative stress and antioxidant treatment in diabetes. Ann N Y Acad Sci. 2004;1031:204-213.

8. Maritim AC, Sanders RA, Watkins JB 3rd. Diabetes, oxidative stress, and antioxidants: a review. J Biochem Mol Toxicol. 2003;17(1):24-38.

9. Paneni F, Beckman JA, Creager MA, Cosentino F. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part 1. Eur Heart J. 2013;34(31):2436-2443.

10. Botker HE, Moller N. ON NO — the continuing story of nitric oxide, diabetes, and cardiovascular disease. Diabetes. 2013;62(8):2645-2647.

11. Goldenstein H, Levy NS, Lipener YT, Levy AP. Patient selection and vitamin E treatment in diabetes mellitus. Expert Rev Cardiovasc Ther. 2013;11(3):319-326.

12. Wang Y, Chun OK, Song WO. Plasma and dietary antioxidant status as cardiovascular disease risk factors: a review of human studies. Nutrients. 2013;5(8):2969-3004.

13. Selvaraju V, Joshi M, Suresh S, Sanchez J, Maulik N, Maulik G. Diabetes, oxidative stress, molecular mechanism, and cardiovascular disease–an overview. Toxicol Mech Methods. 2012;22(5):330-335.

14. Sesso HD, Buring JE, Christen WG, et al. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2008;300(18):2123-2133.

15. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Inter Med. 2005;142(1):37-46.

16. Blum S, Milman U, Shapira C, et al. Dual therapy with statins and antioxidants is superior to statins alone in decreasing the risk of cardiovascular disease in a subgroup of middle-aged individuals with both diabetes mellitus and the haptogolobin 2-2 genotype. Arterioscler Thromb Vasc Biol. 2008;28(3):e18-e20.

17. Levy AP, Gerstein HC, Miller-Lotan R, et al. The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes. Diabetes Care. 2004;27(11):2767.

18. Milman U, Blum S, Shapira C, et al. Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptogolobin 2-2 genotype: a prospective double-blinded clinical trial. Arterioscler Thromb Vasc Biol. 2008;28(2):341-347.

19. Barcia-Bailo B, El-Sohemy A, Haddad PS, et al. Vitamins D, C, and E in the prevention of type 2 diabetes mellitus: modulation of inflammation and oxidative stress. Biologics. 2011:5:7-19.

20. Zatalia SR, Sanusi H. The role of antioxidants in the pathophysiology, complications, and management of diabetes mellitus. Acta Med Indones. 2013;45(2):141-147.

21. Cook NR, Albert CM, Gaziano JM, et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women’s Antioxidant Cardiovascular Study. Arch Intern Med. 2007;167(15):1610-1618.

22. Lavie CJ, Milani JN. Do antioxidant vitamins ameliorate the beneficial effects of exercise training on insulin sensitivity? J Cardiopulm Rehabil Prev. 2011;31(4):211-216.

23. Lu Q, Bjorkhem I, Wretlind B, Diczfalusy U, Henriksson P, Freyschuss A. Effect of ascorbic acid on microcirculation in patients with type II diabetes: a randomized placebo-controlled crossover study. Clin Sci (Lond). 2005;108(6):507-513.

24. Chen H, Karne RJ, Hall G, et al. High-dose oral vitamin C partially replenishes vitamin C levels in patients with type 2 diabetes and low vitamin C levels but does not improve endothelial dysfunction or insulin resistance. Am J Physiol Heart Circ Physiol. 2006;290(1):H137-H145.

25. Tousoulis D, Antoniades C, Vasiliadou C, et al. Effects of atorvastatin and vitamin C on forearm hyperaemic blood flow, asymmentrical dimethylarginine levels and the inflammatory process in patients with type 2 diabetes mellitus. Heart. 2007;93(2):244-246.

26. Paolisso G, Balbi V, Volpe C, et al. Metabolic benefits deriving from chronic vitamin C supplementation in aged non-insulin dependent diabetics. J Am Coll Nutr. 1995;14(4):387-392.
27. De Rosa SC, Zaretsky MD, Dubs JG, et al. N-acetylcysteine replenishes glutathione in HIV infection. Euro J Clin Invest. 2000;30(10):915-929.

28. van Lieshout EM, Peters WH. Age and gender dependent levels of glutathione and glutathione S-transferases in human lymphocytes. Carcinogenesis. 1998;19(10):1873-1875.

29. Nichenametla SN, Ellison I, Calcagnotto A, Lazarus P, Muscat JE, Richie JP Jr. Functional significance of the GAG trinucleotide-repeat polymorphism in the gene for the catalytic subunit of gamma-glutamylcysteine ligase. Free Radic Biol Med. 2008;45(5):645-650.

30. Jones DP, Coates RJ, Flagg EW, et al. Glutathione in foods listed in the National Cancer Institute’s Health Habits and History food frequency questionnaire. Nutr Cancer. 1992;17(1):57-75.

31. Potential health benefits of two dietary antioxidants, glutathione and N-acetylcysteine, among adults with CVD risk. Stanford Medicine website. http://nutrition.stanford.edu/projects/Glutathione-NACStudy.html.

 

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