Diabetes
(See Table 2 for a summary of the following diabetes related studies.)
In type 1 diabetes, the pancreas does not produce enough insulin for the body to properly absorb glucose from the blood. The fundamental cause of type 1 diabetes is the autoimmune destruction of the insulin producing beta cells in the pancreas. Studies have shown free radical oxidation enhances beta cell destruction. Thus, some researchers believe antioxidant defenses such as adequate vitamin E levels help prevent the development of diabetes.
In this study from the National Public Health Institute, Helsinki, Finland, 7,526 men (average age 28) who did not have any form of diabetes were given general medical exams during which blood samples were taken, frozen, and stored. After 21 years, 19 men developed type 1 diabetes, the first which developed 4 years and the last 14 years after the study's beginning. Blood samples from these men were thawed along with 57 controls from subjects who did not develop diabetes, and the concentrations of insulin, alpha-tocopherol, retinol (vitamin A), and selenium were determined. Those who developed diabetes were found to have significantly lower alpha-tocopherol concentrations than those who did not. The relative risk of developing diabetes was 88% less for those with the highest vitamin E concentrations.
The authors caution that the results do not conclusively show a causal connection between low vitamin E and development of diabetes. Many aspects complicate the findings, including the small number of samples, the adverse effects of blood storage on the accuracy of the results, the possibility vitamin E is acting as a marker for some other substance which is actually more directly involved in the process, and the rather short time of the study. Moreover, the lower vitamin E levels may be the result of (and not the cause of) the diabetes, which may have been slowly developing in the subjects for a period of time longer than the study duration. Nevertheless, the study does support the possibility antioxidant status is inversely associated with development of diabetes, and warrants larger scale investigations.
Knekt, P., Reunanen, A., Marniemi, J., Leino, A., Aromaa, A. Low Vitamin E Status is a Potential Risk Factor for Insulin-Dependent Diabetes Mellitus. Journal of Internal Medicine. Vol. 245, pp.99-102, 1999.
One of the complications in diabetes is vascular disease, including atherosclerosis, heart disease, nephropathy (kidney disease), and retinopathy (eye disease). A measurement of vascular health is the flexibility of blood vessels, medically termed "endothelial function". Researchers can relatively easily access endothelial function using non-invasive ultrasound technology.
In this study from Monash Medical Center and University, Melbourne, Australia, 41 type 1 diabetics (average age 26, average duration of disease 9 years) were given either 1,000 IU vitamin E (synthetic "all-rac-alpha-tocopherol") daily or placebo in a double-blind, random fashion. LDL oxidation rate and endothelial function were tested before and after 3 months of supplementation. After supplementation, the vitamin E levels in LDL of subjects taking the vitamin increased 12%, and LDL oxidation rates significantly decreased. No such benefits were seen in the placebo group. Also, the endothelial function was measured using ultrasound of the brachial artery and vessels in the forearm. Those taking vitamin E showed significant improvement in endothelial function, and the improvement was directly correlated to the reduction in LDL oxidation rate. However, systemic arterial compliance, a multi-variable parameter measuring aortic flow volume and driving pressure, did not change.
The authors conclude, "These findings suggest that vitamin E may have a role in the management of early vascular disease in subjects with type 1 diabetes mellitus."
Skyrme-Jones, R., O'Brien, R., Berry, K., Meredith, I. Vitamin E Supplement Improves Endothelial Function in Type 1 Diabetes Mellitus: A Randomized, Placebo-Controlled Study. Journal of the American College of Cardiology. Vol. 36, pp.94-102, 2000.
Patients suffering from diabetes mellitus may also experience greater oxidative (free radical) damage. As a result, diabetics tend to develop diseases more commonly associated with aging, such as heart disease and atherosclerosis. Certain biochemical by-products of oxidation can be measured as indicators of free radical activity. Two such biochemicals are 8-isoPGF and 11-dehydro-thromboxane B2 (TXM). Increased levels of these substances signify excessive free radical damage and platelet activity, which may initiate and worsen vascular disease.
In this study from the University of Chieti, Italy, 85 diabetic patients (both insulin and non-insulin dependent) and 85 healthy controls were tested for 8-isoPGF and TXM in urine samples. Diabetic patients had significantly higher levels than controls. Then, 10 diabetic patients were given 600 IU vitamin E (synthetic "dl-alpha-tocopherol acetate") per day for 14 days. In these patients, 8-isoPGF levels dropped by 37% and TXM dropped by 43%. These significant reductions brought the values within the range of the healthy controls. Another group of diabetic patients were given the medication aspirin and indobufen, which greatly reduced TXM, but not 8-isoPGF.
The researchers conclude their study demonstrates diabetes is associated with increased free radical activity, some of which can be effectively controlled with vitamin E supplementation.
Davi, G., Ciabattoni, G., Consoli, A. In vivo Formation of 8-Iso-Prostaglandin F2-alpha and Platelet Activation in Diabetes Mellitus. Circulation. Vol. 99, pp.224-9, 1999.
One of the diseases which diabetics often develop is kidney failure. Dialysis, the filtering of body's fluids via external devices, is a common treatment for the condition. The two major types of dialysis are hemodialysis (filtering the blood) and peritoneal dialysis (filtering the peritoneal fluid). However, complications often result, such as accelerated development of atherosclerosis, which is the most common killer of diabetics on prolonged dialysis. Some researchers believe that increased oxidative damage may occur in dialysis patients in part because many key antioxidants are filtered away during the dialysis procedure.
To test whether vitamin E supplementation helps reduce oxidation in dialysis patients, researchers at the University of Texas Southwestern Medical Center in Dallas, Texas, measured the rate of formation of two oxidative substances, conjugated dienes and lipid peroxides, in vitro from blood samples of 16 hemodialysis patients, 17 peritoneal dialysis patients, and 17 healthy controls. Then, all subjects were given 800 IU/day vitamin E (natural-source "RRR-alpha-tocopherol") for 12 weeks. After the trial period, blood samples were taken again and tested for the oxidative activity. Vitamin E levels of plasma and LDL substantially increased in all subjects, but did not alter plasma lipid or lipoprotein profiles. Compared to baseline values, conjugated diene formation was significantly slower after supplementation for all subjects, signifying decreased oxidative activity. Also, lipid peroxide formation was slower for the control and peritoneal dialysis subjects. Overall, the study successfully demonstrated that oxidative stress of dialysis patients can be significantly reduced with vitamin E supplementation.
Islam, K., O'Byrne, D., Devaraj, S., et al. Alpha-Tocopherol Supplementation Decreases the Oxidative Susceptibility of LDL in Renal Failure Patients on Dialysis Therapy. Atherosclerosis. Vol. 150, pp. 217-24, 2000.
Most studies of vitamin E and diabetes use rather large amounts, from 800 IU to 1,800 IU per day. In this study from Norfolk and Norwich Hospital, Norwich, United Kingdom, 400 IU vitamin E (natural-source "alpha-tocopherol") per day or placebo was given to 42 type 1 diabetics and 31 healthy controls in a double-blind, random fashion. After 8 weeks, blood samples were taken from all subjects and in vitro tests measured LDL oxidation rate and DNA damage. While the LDL oxidation rates were lower in the healthy controls after supplementation, the same benefit was not observed in diabetic subjects. Moreover, there was no evidence that diabetic patients had higher oxidative damage than normal. The researchers conclude their results do not support the hypothesis that oxidative damage is greater in type 1 diabetics, and 400 IU per day for 8 weeks does not reduce LDL oxidation for them. Possibly, the relatively smaller amount and shorter duration of supplementation contributed to these results.
Astley, S., Langrish-Smith, A., Southon, S., Sampson, M., Vitamin E Supplementation and Oxidative Damage to DNA and Plasma LDL in Type 1 Diabetes. Diabetes Care. Vol. 22, Issue 10, p.1626-, 1999.
Diabetics often suffer from cardiovascular conditions, such as atherosclerosis, although why they are more susceptible is still not well understood. One possibility is the elevated production of inflammatory agents, such as C-reactive protein (CRP), excessively high in nearly 40% of diabetics. Another substance, interleukin-6 (IL-6), stimulates CRP synthesis, as well as making cells sticky and stimulating smooth muscle cell growth, processes which contribute to the development of atherosclerosis. In the present study, vitamin E supplementation was found to effectively decrease both CRP and IL-6 in both type 2 (adult-onset) diabetic and healthy controls.
Twenty-three type 2 diabetics with vascular disease, 24 type 2 diabetics without vascular disease, and 25 healthy controls were involved in this study at the Southwestern Medical Center in Dallas, Texas. Blood samples were taken from all subjects and levels of CRP and IL-6 were measured to establish baseline values. Then, everyone was given 1200 IU/day vitamin E (natural source "RRR-alpha-tocopherol") for 3 months. After the 3 months of supplementation, blood tests were again administered to measure CRP and IL-6 levels. After another 2 months of no supplementation, the same measurements were taken again.
Before supplementation, levels of CRP and IL-6 were significantly higher in diabetic patients than healthy controls. At this time, the diabetics with vascular disease had higher CRP than diabetics without vascular disease. After the 3 month supplementation period, both CRP and IL-6 levels dropped in all subjects. Notably, IL-6 levels in diabetics dropped to the same values as found in healthy subjects. After 2 months of no supplementation, all levels returned to nearly baseline values.
The amount of vitamin E used in this study is much greater than most vitamin E trials. The researchers believe these amounts are necessary to effectively treat existing conditions such as atherosclerosis in diabetics.
Devaraj, S., Jialal, I. Alpha-Tocopherol Supplementation Decreases Serum C-Reactive Protein and Monocyte Interleukin-6 Levels in Normal Volunteers and Type 2 Diabetic Patients. Free Radical Biology and Medicine. Vol. 29, No.8, pp.790-2, 2000.
C-reactive protein (CRP) is an inflammatory agent which is a better indicator of future cardiovascular disease in some people than the traditionally monitored cholesterol (Ridker, New England Journal of Medicine, Vol. 342, pp.836-43, 2000).
In this study from the University of Otago, Dunedin, New Zealand, 57 type 2 diabetics (less than age 75) were given tomato juice (500 ml/day), vitamin E (800 IU/day, "D-alpha-tocopherol from a natural source"), vitamin C (500 mg/day) or placebo for 4 weeks. CRP and oxidizability of LDL were then measured from blood samples in vitro. Vitamin E helped reduce CRP levels by 49%, but the tomato juice and vitamin C did not significantly lower CRP levels. Another interesting finding was that tomato juice, a rich source of the natural antioxidant lycopene, was as effective as vitamin E in reducing LDL oxidation rates. Plasma glucose levels and circulating levels of cell adhesion molecules did not change during the study.
Upritchard, J., Sutherland, W., Mann, J. Effect of Supplementation with Tomato Juice, Vitamin E, and Vitamin C on LDL Oxidation and Products of Inflammatory Activity in Type 2 Diabetes. Diabetes Care. Vol. 23, Issue 6, p.733-, 2000.
Two disorders which complicate diabetes is the reduced blood flow to the retina in the eye and impaired kidney function. Untreated, these complications may result in blindness and kidney failure. Animal studies suggest vitamin E effectively corrects these disorders, and a double-blind clinical trial was conducted to test its effectiveness in human type 1 diabetes.
In this study from the Beetham Eye Institute, Harvard Medical School, Boston, Massachusetts, 36 type 1 diabetic patients and 9 healthy controls were randomly assigned to two groups: Group 1) 1,800 IU/ day vitamin E (natural-souce "D-alpha-tocopherol acetate") for the first 4 months followed by placebo for another 4 months; or, Group 2) placebo for the first 4 months, followed by 1,800 IU/ day vitamin E for another 4 months. Retinal blood flow was measured using video fluorescein angiography, and kidney function was determined using normalized creatinine (a metabolic waste product which normal kidneys filter out from the blood) levels from urine. At baseline, diabetics had significantly less (17.3%) retinal blood flow than healthy controls. After supplementation, retinal blood flow increased to 88% of normal values. The greatest improvements were found in diabetics with the poorest retinal blood flow at the beginning of the study. Moreover, in those who received the vitamin E in the first 4 months and placebo for the next 4 months, retinal blood flow remained high during the last half of the study. The prolonged benefits may be due to the release of stored vitamin E during periods of non-supplementation. Creatinine levels in diabetic patients taking vitamin E decreased 11% to normal levels. Again, the most benefit was seen in diabetics with the worst starting values. However, the effect did not persist when supplementation ceased. Also, vitamin E did not have an effect on blood sugar levels.
The researchers are very optimistic about the results and state, "Thus, vitamin E may potentially provide additional risk reductions for the development of retinopathy or nephropathy in addition to those achievable through intensive insulin therapy alone. Vitamin E is a low-cost and readily available compound associated with few known side effects; thus its use could have a dramatic socioeconomic impact if found to be efficacious in delaying the onset of diabetic retinopathy and/or nephropathy."
Bursell, S., Clermont, A., Aiello, L., et al. High-Dose Vitamin E Supplementation Normalizes Retinal Blood Flow and Creatine Clearance in Patients with Type 1 Diabetes. Diabetes Care. Vol. 22, pp. 1245-51, 1999.
As clinical studies increasingly demonstrate vitamin E supplementation to be an effective part of diabetic therapy, such practical details concerning dosage, frequency, and length of supplementation need to be clarified. This study from the University of Antwerp, Belgium, suggests that to sustain vitamin E's antioxidant benefits in reducing lipoprotein peroxidation in type 1 diabetics, vitamin E needs to be supplemented indefinitely.
Forty-four subjects were divided into two groups in a double-blind, random fashion: Group 1) 250 IU vitamin E (natural source "RRR-alpha-tocopherol"), three times a day (total of 750 IU/day) for 12 months; or, Group 2) placebo for 6 months, followed by 250 IU vitamin E, three times a day for the next 6 months. Every 3 months, blood samples were taken from all subjects and tested in vitro for the rate of LDL and VLDL oxidation, and production of oxidative substances. The supplementation regiment doubled serum vitamin E levels after 3 months. Moreover, LDL and VLDL oxidation rates significantly decreased, as did production of oxidative substances. Continued supplementation for the additional 3 to 9 months of the study did not further change serum vitamin E levels or oxidative parameters. After supplementation stopped, all values returned to baseline.
Thus, the researchers found that vitamin E supplementation causes saturable and reversible benefits, and recommend life-long supplementation for patients with type 1 diabetes. Based on other studies, they also suggest other antioxidants such as vitamin C be included in the supplementation.
Engelen, W., Keenoy, B., Verommen, J., De Leeuw, I. Effects of Long-Term Supplementation with Moderate Pharmacologic Doses of Vitamin E are Saturable and Reversible in Patients with Type 1 Diabetes. American Journal of Clinical Nutrition. Vol. 72, pp. 1142-9, 2000.
Glutathione is a sulfur containing compound that is an essential co-factor for many powerful antioxidant enzymes in the body, including glutathione peroxidase. Higher levels of glutathione is desirable, indicating a larger supply for the body to incorporate into antioxidant enzymes. Studies in animals suggest that vitamin E supplementation helps increase glutathione levels, possibly by assisting in the neutralization of free radicals and thus decreasing the oxidative stress on the body.
In one study from the Louisiana State University Health Sciences Center (Jain, et al), 29 type 1 diabetic children (average age 12) and 21 healthy siblings (average age 10) were given 100 IU vitamin E (synthetic "DL-alpha-tocopherol") daily for 3 months in a double-blind, randomized manner. Concentrations of glutathione and malondialdehyde (a product of oxidation) were measured in red blood cells. At the beginning of the study, diabetic subjects had 15% lower glutathione and 21% higher malondialdehyde concentrations, suggesting they were subject to greater oxidative stress. Vitamin E supplementation raised glutathione levels by 9% and decreased malondialdehyde by 23% to normal values. The researchers conclude such antioxidant benefits due to daily vitamin E supplementation may help lower the risk of vascular disease in type 1 diabetic patients.
In a similar study from India (Sharma, et al), 30 diabetic patients were given 400 IU for 4 weeks. The levels of glutathione increased, while free radical by-products decreased substantially. However, total oxidative stress could not be reduced to levels measured in healthy controls, indicating continued free radical damage was occurring in diabetics.
Jain, S., McVie, R., Smith, T. Vitamin E Supplementation Restores Glutathione and Malondialdehyde to Normal Concentrations in Erythrocytes of Type 1 Diabetic Children. Diabetes Care, Vol. 23, Issue 9, p.1389-, 2000.
Sharma, A., Kharb S, Chugh SN, Kakkar R, Singh GP. Evaluation of Oxidative Stress Before and After Control of Glycemia and After Vitamin E Supplementation in Diabetic patients. Metabolism. Vol. 49, pp.160-2, 2000.
With increasing evidence that free radical activity may cause diabetic complications, some researchers are considering whether reducing free radical damage can help the body better metabolize glucose, the main sugar it uses for fuel. If it does, then antioxidant supplementation would help diabetics not only avoid complications but also help treat the central problem in diabetes. In type 2 diabetes, patients produce enough insulin, but the insulin somehow does not do what it is suppose to, that is, allow cells to absorb glucose to use it for energy. Then, glucose levels in the blood remain high and may enhance free radical activity.
In this study from the University of Naples and the University of Udine, Italy, researchers accessed how well glucose was tolerated by 15 type 2 diabetic and 10 healthy controls before and after taking 900 mg vitamin E (synthetic "dl-alpha-tocopherol) per day for 4 months. For the form of vitamin E used, the supplement amount is equivalent to about 500 IU alpha-tocopherol. The vitamin E significantly improved glucose handling of both diabetics and healthy controls. In healthy subjects, glucose removal from the blood increased 17%. In diabetics, total glucose removal increased 47% and non-oxidative glucose metabolism increased by 63%. The authors conclude their results support using large amounts of vitamin E in type 2 diabetics to help improve insulin action and reduce free radical activity.
Paolisso, G., Amore, A., Giugliano, D. Pharmacologic Doses of Vitamin E Improve Insulin Action in Healthy Subjects and Non-Insulin-Dependent Diabetic Patients. American Journal of Clinical Nutrition. Vol. 57, pp.650-6, 1993.
One problem elderly people face is impaired insulin function, and along with it, increased free radical stress. Thus, even though they are not clinically diagnosed with diabetes, many elderly suffer from lowered ability to utilize glucose for energy and the related problems which result. Moreover, increased free radical activity due to the higher glucose levels in the blood may accelerate cellular destruction and lead to more serious conditions. Since vitamin E effectively improved insulin action in diabetics, it may benefit the elderly.
The same Italian research group which conducted the previous study (Paolisso, 1993) next tested vitamin E's insulin improving action in 20 elderly subjects (average age 77) who were not obese or had diabetes. In this study, the subjects were given either 900 mg vitamin E (natural-source "d-alpha-tocopherol") or placebo in a double-blind, randomized manner. Glucose tests similar to the previous study were performed before and after the 4 month trial period. Vitamin E supplementation improved the clearance of total glucose from the blood by 30%. Moreover, vitamin E concentrations in the plasma were directly related with the improvement. No similar benefits were found in those taking placebo.
The authors conclude, "Plasma vitamin E concentrations seem to play an important role in the modulation of insulin action in elderly people."
Paolisso, G., Maro, G., Galzerano, D. et al. Pharmacological Doses of Vitamin E and Insulin Action in Elderly Subjects. American Journal of Clinical Nutrition. Vol. 59, pp.1291-6, 1994.