Abstract
Background:
Omega 3 and vitamin E are two critical nutrients which include beneficial effects in coronary artery disease (CAD). The aim of this study was to assess the effects of omega 3 alone supplementation or in combination with vitamin E on serum glucose and lipid levels and insulin resistance in CAD patients.
Methods:
Participants of this clinical trial included 60 male patients with CAD who selected from Tehran Heart Center in Tehran, Iran in 2014. They received 4 g/day omega 3 plus 400 IU/day vitamin E (OE), 4 g/day omega 3 with vitamin E placebo (OP), or omega 3 and vitamin E placebo (PP) for two months. Serum glucose, lipids and insulin were assessed and HOMA-IR was calculated before and after the trial and effects of these nutrients on the highlighted parameters were compared within the study groups.
Results:
Serum glucose level increased significantly in OP group (P=0.004), but not in OE group. OE and OP groups showed a significant decrease in fasting serum TG (P=0.020 and P=0.001, respectively). Serum insulin and HOMA-IR decreased significantly in OE group (P=0.044 and P=0.039, respectively) but did not change significantly in OP group.
Conclusion:
Although, omega 3 supplementation may include adverse effects on serum glucose level, co-administration of omega 3 and vitamin E can beneficially decrease serum insulin and insulin resistance in CAD patients.
Keywords: CAD, Omega 3, Vitamin E, Glucose homeostasis, Insulin resistance
Introduction
Cardiovascular disease (CVD) is the most common disease in developing countries. Nearly 23.6 million people will die from CVDs and coronary artery disease (CAD) will become the leading cause of death by 2030 (1, 2).
Hyperinsulinemia resulted from insulin resistance is a valuable prediction factor in CAD disease (3, 4). Insulin resistance can increase blood fibrinogen (5) and is closely associated with salt-sensitive type of hypertension in obese and non-obese patients; and therefore, can increase individual vulnerability to cardiovascular diseases (6).
Changes in lifestyle and also consumption of some dietary supplements have a critical role in managing of many chronic diseases (7). For example, diets reduced in total fat can prevent CVD (8) and high levels of monounsaturated fatty acids (MUFA) and some polyunsaturated fatty acids (PUFA) can reduce the risk of CVD (9). Relatively, Mediterranean diets rich in fish oil and other marine sources of omega 3 fatty acids can decrease the risk of CHD mortality (10).
Omega 3 supplementation can improve endothelial function and decrease serum endothelial dysfunction markers such as E-selectin, I-CAM and V-CAM (11, 12). In some studies, consumption of omega 3 fatty acids was associated to increased risk of type 2 diabetes (13, 14); however, other studies did not show such an association (15, 16). Omega 3 supplementation has resulted in a significant decrease in insulin resistance in several studies (17). This decrease seems to be linked to changes in adiponectin (18) and also activation of AMPK pathway (19).
Vitamin E is an important nutrient and can develop beneficial effects in patients with heart diseases. This vitamin is an antioxidant and can possibly decrease oxidative stress. Vitamin E also is an anti-inflammatory agent and can decrease inflammatory factors such as IL-1β and IL-6 (20, 21).
Effects of omega 3 and vitamin E co-administration on insulin resistance and glucose homeostasis have been less described in previous studies. Therefore, the current study was carried out to assess possible effects of omega 3 alone and combined omega 3 and vitamin E supplementations on serum lipid profile and glucose homeostasis in CAD patients.
Methods
Sixty-five non-smoker male patients with CAD were participated in this randomized double-blind placebo-controlled clinical trial. All participants had at least 50% stenosis in one coronary artery and were selected from the Heart Medical Center of Tehran, Tehran, Iran. Participants signed an informed consent before the study. Furthermore, this study was registered in www.clinicaltrial.org under the registry number of NCT02011906 and approved by the Ethical Committee of Tehran University of Medical Sciences (ID: 23605).
All patients had BMI ≤ 30 and none of them had history of kidney and liver disorders, diabetes and thyroid malfunction. Patients were divided randomly into three groups including OP group received 4 g/day of omega-3 fatty acids and vitamin E placebo, OE group received 4 g/day of omega-3 fatty acid soft gels and 400 IU of vitamin E, and PP group received omega-3 fatty acids and vitamin E placebos. The contents of DHA and EPA in each gram of omega 3 soft gels were respectively 120 and 180 mg. Supplementation continued for eight months. Supplements and placebos used in this study were supplied by Minoo Pharmaceutical, Cosmetic and Hygienic Company, Iran.
Anthropometric measurements were carried out before and after the intervention. Weight was measured closely to the nearest 0.1 kg with minimal clothing and no shoes. Height, hip and waist circumferences were measured to the nearest 0.1 cm. BMI was calculated as the weight in kg divided by the square of height in meter. Waist to hip ratio (WHR) was calculated by dividing the circumference of waist to the circumference of hip.
Dietary information of the patients was obtained using a 2-day food recall filled before the beginning and after finishing off the intervention. Ten milliliters of blood were collected from the patients after 12 to14 h of overnight fasting. Then, serum samples were separated and stored at −80 °C until use. Fasting serum glucose, total cholesterol, HDL-C, LDLC and triglyceride concentrations were assessed using commercial kits (Pars Azmoon, Iran). Serum insulin was assessed using ELISA method (Diametra, Italy) with the sensitivity of 0.25 mcIU/ml and HOMA-IR was calculated by fasting glucose (mg/dl) multiplied by fasting insulin (μIU/ml)/405 (22).
Dietary data were analyzed using Nutritionist IV Software and statistical analysis was carried out using SPSS Software v18. All data were shown as mean ±SE (standard error) of the parameter. Normality of the parameter distribution was checked using Kolmogorov-Smirnoff test. Oneway analysis-of-variance (ANOVA) test and paired t-test were used respectively to compare the mean of variables between and within the groups before and after the intervention. Significance was considered when P-values ≤ 0.05.
Results
At the beginning of the study, 65 male CAD patients were participated in the clinical trial. However, three patients were hospitalized for heart surgery during the intervention and two patients consumed less than 90% of the total supplements and hence, were excluded from the study. Therefore, the study was carried out with 60 patients, as 20, 21 and 19 patients were included in OE, OP and PP groups, respectively. Patients in these groups were not statistically different from each other in mean ages and disease duration at the baseline of the study (P= 0.079 and P= 0.299, respectively).
Table 1 describes the baseline anthropometric measurements of the three groups at the beginning of intervention. No significant differences were seen between the means of weight, BMI and other anthropometric parameters of the study groups at the baseline. Dietary intakes of the three groups are shown in Table 2. Food recall analysis of the patients revealed that no significant differences existed between energy and macronutrient intakes in OP, OE and PP groups at the baseline and at the end of the intervention. Furthermore, the intakes of vitamin E and different fatty acids were not different between study groups and they were not changed their routine dietary patterns during the intervention.
Table 1:
Basic anthropometric parameters of the study groups before the intervention
| Variable | OE (n = 21) | OP (n = 20) | PP (n = 19) | P-value* |
|---|---|---|---|---|
| Height (cm) | 170.32 ±1.19 | 169.04 ±1.36 | 170.92 ±1.58 | 0.623 |
| Weight (kg) | 78.54 ±2.17 | 79.95 ±2.68 | 78.35 ±1.87 | 0.864 |
| BMI (kg/cm2) | 27.08 ±0.70 | 27.95 ±0.83 | 26.85 ±0.61 | 0.530 |
| Waist circumference (cm) | 95.76 ±1.58 | 98.72 ±2.11 | 96.18 ±1.88 | 0.479 |
| Hip circumference (cm) | 100.33 ±1.15 | 101.12 ±1.59 | 99.63 ±0.80 | 0.701 |
| WHR | 0.95 ±0.01 | 0.97 ±0.01 | 0.96 ±0.01 | 0.463 |
OP, omega-3 fatty acid and placebo; OE, omega-3 fatty acid and vitamin E; PP, placebo and placebo; BMI, body mass index; WHR; waist to hip ratio;
ANOVA analysis
Table 2:
Dietary intakes of the study groups before and after the intervention
| Treatment group | OE (n = 21) | OP (n = 20) | PP (n = 19) | P-value* | |
|---|---|---|---|---|---|
| Energy (Kcal) | Baseline | 1469.10 ±93.33 | 1450.74 ± 114.37 | 1528.49 ±111.25 | 0.867 |
| Post-intervention | 1649.48 ±122.47 | 1684.55 ±131.39 | 1508.20 ±130.59 | 0.596 | |
| difference | 180.38 ±162.53 | 233.81 ±169.99 | 32.36 ±173.82 | 0.688 | |
| P-value# | 0.281 | 0.185 | 0.854 | ||
| Carbohydrate (g) | Baseline | 228.44 ±16.93 | 231.47 ±22.93 | 246.01 ±18.52 | 0.800 |
| Post-intervention | 259.51 ±21.96 | 271.56 ±25.45 | 238.00 ±21.37 | 0588 | |
| difference | 31.06 ±25.68 | 40.09 ±26.02 | −8.01 ±30.04 | 0.426 | |
| P-value# | 0.241 | 0.140 | 0.793 | ||
| Protein (g) | Baseline | 69.64 ±8.76 | 62.25 ±7.75 | 62.27 ±7.71 | 0.770 |
| Post-intervention | 66.16 ±6.98 | 60.44 ±5.74 | 59.30 ±6.49 | 0.722 | |
| difference | −3.48 ±11.49 | −1.81 ±10.58 | 3.42 ±10.64 | 0.992 | |
| P-value# | 0.765 | 0.866 | 0.751 | ||
| Fat (g) | Baseline | 33.45 ±2.96 | 33.05 ±2.79 | 35.08 ±3.82 | 0.895 |
| Post-intervention | 41.80 ±4.10 | 42.88 ±3.75 | 37.01 ±3.86 | 0.538 | |
| difference | 8.34 ±5.28 | 9.82 ±4.97 | 1.93 ±5.53 | 0.538 | |
| P-value# | 0.131 | 0.063 | |||
| Vitamin E (mg) | Baseline | 2.72 ±0.74 | 2.70 ±0.55 | 2.29 ±0.65 | 0.427 |
| Post-intervention | 4.04 ±0.97 | 4.19 ±1.04 | 2.77 ±0.45 | 0.311 | |
| difference | 1.33 ±1.35 | 1.48 ±1.29 | 0.48 ±0.78 | 0.971 | |
| P-value# | 0.338 | 0.265 | 0.456 | ||
| Omega-3 fatty acids (g) | Baseline | 0.13 ±0.04 | 0.12 ±0.03 | 0.11 ±0.04 | 0.963 |
| Post-intervention | 0.11±0.05 | 0.21 ±0.10 | 0.10 ±0.03 | 0.464 | |
| difference | −0.01±0.06 | 0.09 ±0.11 | −0.01 ±0.05 | 0.570 | |
| P-value# | 0.821 | 0.428 | 0.781 | ||
| Omega 6 fatty acids (g) | Baseline | 10.80 ±1.17 | 11.47 ±0.93 | 10.89 ±1.76 | 0.926 |
| Post-intervention | 13.58 ±2.15 | 13.76 ±1.95 | 12.87 ±2.19 | 0.148 | |
| difference | 2.78 ±2.59 | 2.29 ±2.21 | 1.98 ±2.91 | 0.534 | |
| P. value# | 0.380 | 0.273 | 0.506 | ||
| Saturated fatty acids (g) | Baseline | 9.73 ±1.05 | 8.17 ±6.28 | 10.33 ±1.19 | 0.333 |
| Post-intervention | 8.98 ±0.77 | 9.16 ±0.80 | 10.11 ±1.13 | 0.649 | |
| difference | −0.75 ±1.28 | 0.99 ±1.07 | −0.22 ±1.65 | 0.643 | |
| P-value# | 0.566 | 0.367 | 0.897 |
OE, omega-3 fatty acid and vitamin E; OP, omega-3 fatty acid and placebo; PP, placebo and placebo;
ANOVA analysis;
paired T test
Table 3 demonstrates fasting serum levels and HOMA-IR index in the study groups at the baseline and at the end of the supplementation. Serum levels of FBS increased significantly in patients receiving omega supplement (P=0.004). The patients were not statistically different in mean FBS at the end of the intervention. OE and OP groups showed a significant decrease in fasting serum TG (P=0.020 and P=0.001, respectively). Serum TG did not change significantly in PP group. Serum level of insulin and HOMA-IR decreased significantly in OE group (P=0.044 and P=0.039, respectively), but not in OP or PP group. Furthermore, the means of serum insulin level and HOMA-IR were significantly different between the study groups at the end of the intervention (P=0.032 and P=0.023, respectively). Post-hoc analysis (Tukey Test) showed no significant differences between the mean of serum insulin level and HOMA-IR in OE and OP groups (P=0.029 and P=0.019, respectively). Serum levels of LDL, HDL and TC did not change significantly within or between the study groups. However, differences were not significant statistically after adjusting BMI and disease duration.
Table 3:
Serum biochemical characteristics in the study groups before and after the intervention
| Treatment group | OE (n = 21) | OP (n = 20) | PP (n = 19) | P-value* | |
|---|---|---|---|---|---|
| FBS (mg/dl) | Baseline | 92.19 ±3.27 | 87.75 ±3.25 | 89.32 ±4.78 | 0.697 |
| Post-intervention | 89.38 ±2.32 | 99.13 ±3.78 | 94.5 ±3.53 | 0.108 | |
| difference | 2.81 ±3.79 | 11.37 ±3.46 | 4.74 ±4.13 | 0.034 | |
| P-value# | 0.264 | 0.004 | 0.267 | ||
| TG (mg/dl) | Baseline | 185.48 ±17.39 | 180.38 ±18.02 | 174.53 ±19.41 | 0.914 |
| Post-intervention | 145.38 ±9.44 | 131.28 ±14.53 | 154.58 ±19.87 | 0.458 | |
| difference | −40.10 ±15.92 | −49.10 ±12.25 | −19.95 ±12.25 | 0.325 | |
| P-value# | 0.020 | 0.001 | 0.121 | ||
| TC (mg/dl) | Baseline | 186.57 ±8.71 | 157.95 ±7.79 | 170.47 ±15.85 | 0.190 |
| Post-intervention | 165.00 ±12.35 | 154.55 ±6.16 | 169.76 ±10.87 | 0.568 | |
| difference | −21.57 ±16.04 | −3.40 ±9.09 | −0.71 ±13.69 | 0.484 | |
| P-value# | 0.194 | 0.713 | 0.959 | ||
| LDL (mg/dl) | Baseline | 109.90 ±4.38 | 100.10 ±3.77 | 105.21 ±5.26 | 0.302 |
| Post-intervention | 107.14 ±6.60 | 95.40 ±4.05 | 109.21 ±5.93 | 0.189 | |
| difference | −2.76 ±7.43 | −4.70 ±3.94 | 4.00 ±3.836 | 0.512 | |
| P-value# | 0.311 | 0.248 | 0.714 | ||
| HDL (mg/dl) | Baseline | 34.35 ±1.92 | 31.30 ±1.66 | 34.42 ±1.89 | 0.394 |
| Post-intervention | 37.14 ±2.38 | 35.55 ±1.62 | 37.95 ±1.95 | 0.702 | |
| difference | 2.73 ±2.03 | 4.25 ±2.21 | 3.52 ±0.97 | 0.854 | |
| P-value# | 0.120 | 0.065 | 0.182 | ||
| Insulin (μIU/ml) | Baseline | 9.96 ±0.88 | 13.64 ±1.79 | 10.74 ±1.21 | 0.129 |
| Post-intervention | 9.09 ±0.71 | 13.83 ±1.92 | 10.38 ±0.90 | 0.032 | |
| difference | −0.86 ±0.40 | 0.185 ±1.35 | −0.36 ±0.86 | 0.729 | |
| P-value# | 0.044 | 0.893 | 0.678 | ||
| HOMA-IR | Baseline | 2.28 ±0.24 | 2.97 ±0.39 | 2.48 ±0.36 | 0.339 |
| Post-intervention | 2.02 ±0.20 | 3.45 ±0.54 | 2.46 ±0.27 | 0.023 | |
| difference | 0.48 ±0.37 | −0.25 ±0.12 | 0.02 ±0.25 | 0.142 | |
| P-value# | 0.039 | 0212 | 0.931 |
OE, omega-3 fatty acid and vitamin E; OP, omega-3 fatty acid and placebo; PP, placebo and placebo; hsCRP, high-sensitivity C-reactive protein;
ANOVA analysis;
paired T test
Discussion
In the current study, omega 3 supplementation alone or in combination with vitamin E significantly decreased serum TG levels in OE and OP groups. Supplementation with omega 3 fatty acids can include a dose-dependent effect on serum triglycerides and reduce its concentration up to 30% (23, 24). These fatty acids seem to be able to inhibit the production of TG and apolipoprotein B by the liver (25). Furthermore, these fatty acids can increase fatty acid oxidation by mitochondria (23). Serum glucose levels have increased significantly in patients receiving omega 3 supplements alone; however, the level was in normal range. This increase was not seen in OE group.
Therefore, the question was if omega 3 fatty acid supplements could include adverse effects on glucose homeostasis. Effects of omega 3 fatty acids on serum glucose level have been conflicting in various studies. While, omega 3 supplementation was previously shown to adversely influence glucose homeostasis (26, 27), these fatty acids can increase glucose uptake and improve insulin sensitivity (28, 29). An experimental study on rats has demonstrated that consumption of fish oil can prevent insulin resistance induced by high-fat feeding (30). In contrast, results of the current study revealed that serum insulin level and HOMA-IR index did not change significantly in patients receiving omega 3 supplements only. Interestingly, these parameters decreased significantly in OE group. However, the mechanism for this is not clearly explained, it is possibly associated to use of vitamin E.
Vitamin E can improve glucose homeostasis because it can influence insulin sensitivity (31, 32). Indeed, oxidative stress is a key factor in development of insulin resistance and vitamin E with its ROS scavenger ability can positively affect insulin action and glycemic control (33). Another mechanism, which links vitamin E to insulin resistance, is the anti-inflammatory property of this vitamin. Inflammatory cytokines such as TNF-α and IL-1β have been shown to induce insulin resistance. TNF-α can increase adipocyte lipolysis and serine/threonine phosphorylation of IRS-1 and IL-1β can increase CRP level via elevating IL-6 and impair signaling of insulin in peripheral tissues which can result in reduced insulin sensitivity and impair insulin secretion (34, 35). Both α and γ-tocopherol forms of vitamin E include anti-inflammatory effects and can reduce serum level of CRP (36).
Conclusion
Supplementation with combined omega 3 fatty acids and vitamin E includes beneficial effects on serum insulin level and HOMA-IR and co-administration of these supplements can be a good strategy against development of insulin resistance seen in CAD patients.
Ethical considerations
Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.
Acknowledgments
This study was supported by Health Services grants from the School of Nutritional Science and Dietetics of Tehran University of Medical Sciences (ID: 23605). The authors declare that there is no conflict of interests.
References
- 1.Mathers CD, Loncar D. (2006). Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med, 3:e442. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Gaziano TA. (2005). Cardiovascular disease in the developing world and its cost-effective management. Circulation, 112:3547–53. [DOI] [PubMed] [Google Scholar]
- 3.Ginsberg HN. (2000). Insulin resistance and cardiovascular disease. J Clin Invest, 106:453–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Pyörälä M, Miettinen H, Laakso M, Pyörälä K. (1998). Hyperinsulinemia Predicts Coronary Heart Disease Risk in Healthy Middle-aged Men The 22-Year Follow-up Results of the Helsinki Policemen Study. Circulation, 98:398–404. [DOI] [PubMed] [Google Scholar]
- 5.Chen J, Wildman RP, Hamm LL, Muntner P, Reynolds K, Whelton PK, He J. (2004). Association Between Inflammation and Insulin Resistance in US Nondiabetic Adults Results from the Third National Health and Nutrition Examination Survey. Diabetes Care, 27:2960–2965. [DOI] [PubMed] [Google Scholar]
- 6.Giner V, Coca A, de La Sierra A. (2001). Increased insulin resistance in salt sensitive essential hypertension. J Hum Hypertens, 15:481–485. [DOI] [PubMed] [Google Scholar]
- 7.Yousefi Rad E, Djalali M, Koohdani F, Saboor-Yaraghi AA, Eshraghian MR, Javanbakht MH, et al. (2014). The Effects of Vitamin D Supplementation on Glucose Control and Insulin Resistance in Patients with Diabetes Type 2: A Randomized Clinical Trial Study. Iran J Public Health, 43(12): 1651–56. [PMC free article] [PubMed] [Google Scholar]
- 8.Zyriax BC, Windler E. (2000). Dietary fat in the prevention of cardiovascular disease—a review. Eur J Lipid Sci Technol, 102:355–365. [Google Scholar]
- 9.Lichtenstein AH, Appel LJ, Brands M, et al. (2006). Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Circulation, 114:82–96. [DOI] [PubMed] [Google Scholar]
- 10.Sofi F, Abbate R, Gensini GF, Casini A. (2010). Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis. Am J Clin Nutr, 92:1189–96. [DOI] [PubMed] [Google Scholar]
- 11.de Roos B, Mavrommatis Y, Brouwer IA. (2009). Long-chain n-3 polyunsaturated fatty acids: new insights into mechanisms relating to inflammation and coronary heart disease. Br J Pharmacol, 158:413–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Robinson JG, Stone NJ. (2006). Antiatherosclerotic and antithrombotic effects of omega-3 fatty acids. Am J Cardiol, 98(4A):39i–49i. [DOI] [PubMed] [Google Scholar]
- 13.Djoussé L, Gaziano JM, Buring JE, Lee IM. (2011). Dietary omega-3 fatty acids and fish consumption and risk of type 2 diabetes. Am J Clin Nutr, 93:143–150. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Kaushik M, Mozaffarian D, Spiegelman D, Manson JE, Willett WC, Hu FB. (2009). Long-chain omega-3 fatty acids, fish intake, and the risk of type 2 diabetes mellitus. Am J Clin Nutr, 90:613–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Laaksonen DE, Lakka TA, Lakka HM, Nyyssonen K, Rissanen T, Niskanen LK, Salonen JT. (2002). Serum fatty acid composition predicts development of impaired fasting glycaemia and diabetes in middle-aged men. Diabet Med, 19:456–64. [DOI] [PubMed] [Google Scholar]
- 16.Villegas R, Xiang YB, Elasy T, et al. (2011). Fish, shellfish, and long-chain n-3 fatty acid consumption and risk of incident type 2 diabetes in middle-aged Chinese men and women. Am J Clin Nutr, 94:543–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Navas-Carretero S, Pérez-Granados AM, Schoppen S, Vaquero MP. (2009). An oily fish diet increases insulin sensitivity compared to a red meat diet in young iron-deficient women. Br J Nutr, 102:546–553. [DOI] [PubMed] [Google Scholar]
- 18.Kondo K, Morino K, Nishio Y, Kondo M, Fuke T, Ugi S, Iwakawa H, Kashiwagi A, Maegawa H. (2010). Effects of a fish-based diet on the serum adiponectin concentration in young, non-obese, healthy Japanese subjects. J Atheroscler Thromb, 17:628–37. [DOI] [PubMed] [Google Scholar]
- 19.Flachs P, Rossmeisl M, Bryhn M, Kopecky J. (2009). Cellular and molecular effects of n-3 polyunsaturated fatty acids on adipose tissue biology and metabolism. Clin Sci (Lond), 116:1–16. [DOI] [PubMed] [Google Scholar]
- 20.Jialal I, Devaraj S. (2005). Scientific evidence to support a vitamin E and heart disease health claim: research needs. J Nutr, 135:348–353. [DOI] [PubMed] [Google Scholar]
- 21.Singh U, Devaraj S, Jialal I. (2005). Vitamin E, oxidative stress, and inflammation. Annu Rev Nutr, 25:151–174. [DOI] [PubMed] [Google Scholar]
- 22.Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. (1985). Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 28:412–9. [DOI] [PubMed] [Google Scholar]
- 23.Kris-Etherton PM, Harris WS, Appel LJ. (2002). Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation, 106:2747–2757. [DOI] [PubMed] [Google Scholar]
- 24.Skulas-Ray AC, Kris-Etherton PM, Harris WS, Heuvel JPV, Wagner PR, West SG. (2011). Dose-response effects of omega-3 fatty acids on triglycerides, inflammation, and endothelial function in healthy persons with moderate hypertriglyceridemia. Am J Clin Nutr, 93:243–252. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Skulas-Ray AC, Alaupovic P, Kris-Etherton PM, West SG. (2015). Dose-response effects of marine omega-3 fatty acids on apolipoproteins, apolipoprotein-defined lipoprotein subclasses, and Lp-PLA 2 in individuals with moderate hypertriglyceridemia. J Clin Lipidol, 9: 360–7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Glauber H, Wallace P, Griver K, Brechtel G. (1988). Adverse metabolic effect of omega-3 fatty acids in non-insulin-dependent diabetes mellitus. Ann Intern Med, 108:663–8. [DOI] [PubMed] [Google Scholar]
- 27.Heine RJ. (1993). Dietary fish oil and insulin action in humans. Ann N Y Acad Sci, 683:110–21. [DOI] [PubMed] [Google Scholar]
- 28.Carpentier YA, Portois L, Malaisse WJ. (2006). n-3 fatty acids and the metabolic syndrome. Am J Clin Nutr, 83 (Supple 6):1499s–1504s. [DOI] [PubMed] [Google Scholar]
- 29.Dangardt F, Chen Y, Gronowitz E, Dahlgren J, Friberg P, Strandvik B. (2012). High physiological omega-3 Fatty Acid supplementation affects muscle Fatty Acid composition and glucose and insulin homeostasis in obese adolescents. J Nutr Metab, 2012:395757. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Storlien LH, Kraegen EW, Chisholm DJ, Ford GL, Bruce DG, Pascoe WS. (1987). Fish oil prevents insulin resistance induced by high-fat feeding in rats. Science, 237:885–8. [DOI] [PubMed] [Google Scholar]
- 31.Manzella D, Barbieri M, Ragno E, Paolisso G. (2001). Chronic administration of pharmacologic doses of vitamin E improves the cardiac autonomic nervous system in patients with type 2 diabetes. Am J Clin Nutr, 73:1052–7. [DOI] [PubMed] [Google Scholar]
- 32.Park S, Choi SB. (2002). Effects of alpha-tocopherol supplementation and continuous subcutaneous insulin infusion on oxidative stress in Korean patients with type 2 diabetes. Am J Clin Nutr, 75:728–33. [DOI] [PubMed] [Google Scholar]
- 33.Farvid MS, Jalali M, Siassi F, Hosseini M. (2005). Comparison of the effects of vitamins and/or mineral supplementation on glomerular and tubular dysfunction in type 2 diabetes. Diabetes care, 28:2458–2464. [DOI] [PubMed] [Google Scholar]
- 34.Böni-Schnetzler M, Donath MY. (2013). How biologics targeting the IL-1 system are being considered for the treatment of type 2 diabetes. Br J Clin Pharmacol, 76:263–268. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Su D, Coudriet GM, Kim DH, Lu Y, Perdomo G, Qu S, Slusher S, Hubert MT, Piganelli J, Giannoukakis N. (2009). FoxO1 links insulin resistance to proinflammatory cytokine IL-1β production in macrophages. Diabetes, 58:2624–2633. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Saboori S, Shab-Bidar S, Speakman JR, Yousefi Rad E, Djafarian K. (2015). Effect of vitamin E supplementation on serum C-reactive protein level: a meta-analysis of randomized controlled trials. Eur J Clin Nutr, 69: 867–73. [DOI] [PubMed] [Google Scholar]