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Poursoleiman F, Mozaffari-Khosravi H, Naghdipour Biregani A. Does Omega-3 Fatty Acid Supplementation Have Beneficial Effects on Plasma Homocysteine, Insulin Resistance and Lipid Profile of Type 2 Diabetic Patients? A Randomized Clinical Trial. JNFS. 2018; 3 (1) :40-50
URL: http://jnfs.ssu.ac.ir/article-1-127-en.html
PhD Does Omega-3 Fatty Acid Supplementation Have Beneficial Effects on Plasma Homocysteine, Insulin Resistance and Lipid Profile of Type 2 Diabetic Patients? A Randomized Clinical Trial
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Does Omega-3 Fatty Acid Supplementation Have Beneficial Effects on Plasma Homocysteine, Insulin Resistance and Lipid Profile of Type 2 Diabetic Patients? A Randomized Clinical Trial
 
Faezeh Poursoleiman; MSc1, Hassan Mozaffari-Khosravi; PhD *1,2  & Akram Naghdipour Biregani; MSc1
 
1 Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
2 Yazd Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
 
ARTICLE INFO   ABSTRACT
ORIGINAL ARTICLE Background: This study was conducted to determine the effects of n-3 PUFAs supplementation on plasma homocysteine (Hcy) level, lipid profile and insulin resistance in patients with type 2 diabetes (T2D). Methods: This study is a double-blind controlled trial involving 70 patients with T2D selected from Yazd Diabetes Research Center in 2013. Patients were randomly assigned to receive either 2 g/day omega-3 soft gels (OG) or 2 g/day placebo (PG) for 6 weeks. At the beginning and end of the study, Hcy concentration, fasting plasma glucose (FBG), fasting plasma insulin, total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c), HDL-c/LDL-c ratio, insulin resistance (HOMA-IR), insulin sensitivity (IS) and beta-cell function were measured and compared. Results: Sixty five participants completed the study. The results of this study showed that
omega-3 fatty acid supplementation caused significant increase in Hcy
(P = 0.007) and LDLc (P = 0.02), while HDLc and HDLc/LDLc ratio were significantly decreased (P = 0.001 and 0.006, respectively). In both groups, insulin and HOMA-IR were increased, while IS decreased significantly. Βeta-cell function was increased only in OG (P = 0.005). There was no significant difference in mean change of any factors. Conclusion: The present study found no beneficial effects of 2 g/day omega-3 supplement for 6 weeks on biomarkers of Hcy, FBG, insulin and lipid profile in th T2D patients.
Key words: Type 2 diabetes; Homocysteine; Omega-3; Lipid profiles;
HOMA-IR
.
Article history:
Received: 15 Apr 2017
Revised: 18 Jun 2017
Accepted: 13 Sep 2017
IRCT code:
2013011312122N1
*Corresponding author:
mozaffari.kh@gmail.com
Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Shohaday Gomname BLV, Yazd, Iran.
 
Postal code: 8915173160
Tel: +98 35 38209143
 
Introduction
 
T
ype 2 diabetes (T2D) has been declared
“the epidemic of the 21st century” affecting approximately 347 million people worldwide (Danaei et al., 2011).  Its rapidly increasing global prevalence is a primary cause of concern (Huang et al., 2012) as it is anticipated to be the 7th  leading cause of death in 2030 (WHO, 2011). Diabetes and hyperglycemia cause vascular damage and impaired lipid profile, particularly increased susceptibility to peroxidation. These factors result in atherosclerosis, which can lead to decreased blood flow to the heart muscle or brain (Buse et al., 2007).
Homocysteine (Hcy) is a sulfur containing amino acid [COOHCH (CH2CH2SH) NH3] that is produced by the metabolism of methionine in the body and does not participate in the building of proteins (McDowell and Lang, 2000). It is known as an independent risk factor for cardiovascular disease (CVD) (Huang et al., 2012). Recent evidence suggests that high levels of fasting Hcy may be a direct participant of different diseases, including brain atrophy, cognitive impairment and possibly Alzheimer's disease (Sachdev, 2004), diabetic nephropathy (House et al., 2010), stroke and vascular-heart disease (Elias and Eng, 2005, Smulders and Blom, 2011). Hcy has been considered to play an important role in vascular injury, resulting in the development of peripheral and coronary arterial disease (Elias and Eng, 2005). Mild homocysteinemia is an independent risk factor for atherosclerosis, atherothrombosis and may even increase the risk of CVD in people with T2D (Smulders and Blom, 2011, Zeman et al., 2006). On the other hand, in patients with T2D, serum Hcy levels are higher than normal, which is associated with endothelial dysfunction, insulin resistance, diabetic nephropathy and prothrombosis (Huang et al., 2012). High Hcy levels may independently play a direct causative role in the pathogenesis of T2D obesity and metabolic syndrome by promoting oxidative stress, systematic inflammation and endothelial dysfunction (Hofmann et al., 2001, Stamler et al., 1993, Weiss et al., 2003). In human studies, plasma Hcy levels were strongly associated with insulin concentration. As such, this association may also help to explain the discrepancy between
plasma Hcy levels in diabetic patients and in healthy ones (Elias and Eng, 2005).
N-3 polyunsaturated fatty acids (n-3 PUFAs), particularly eicosapentaenoic acid (EPA, C 20:5 n-3) and docosahexaenoic acid (DHA, C 20:6 n-3), found in fish oil are known to have potential anti-atherosclerotic effects and anti-inflammatory properties and also reduce deaths due to CVD (D’Alessandro et al., 2002, Grundt et al., 2003). In addition, a high intake of marine n-3 PUFAs is associated with lower risk of CVD (Yokoyama
et al., 2007
). In non- diabetic people, supplementation with n- 3 PUFAs have potential protective effects on cardiovascular system, such as anti-inflammatory effects, fixing atherosclerotic plaques, increasing fibrinolysis, anti-thrombotic effects and lowering of blood pressure (Hartweg et al., 2007). There is a low prevalence of diabetes in Greenland and Alaskan Eskimos; populations known for a very high intake of n-3 PUFAs (De Caterina et al., 2007). Based on previous researches, supplementation with n-3 PUFAs have been suggested as one of the methods of reducing Hcy levels (Grundt et al., 2003, Huang et al., 2012). In recent years, several studies regarding n-3 fatty acids have been conducted, but none of them have been able to completely show its effects on diabetes patients. However, the results of n-3 PUFAs effects on Hey are still contradictory  (De Caterina et al., 2007, Huang et al., 2012). Several clinical trials with small sample size and short duration of the effect of n-3 PUFAs on plasma Hcy have been performed (De Caterina et al., 2007, Selhub, 1999, Zeman et al., 2006). While few studies have been conducted on T2D (De Caterina et al., 2007).
The mechanism of action of n-3 PUFAs on blood Hcy is yet to be well understood. N-3 PUFAs effects on vascular endothelial function can neutralize the effect of Hcy (Grundt et al., 2003). But on the other hand, some studies asserted that supplementation with n-3 PUFAs may lead to increase in oxidative stress (Saedisomeolia et al., 2009). Therefore, the present study was carried
out to determine the effect of n-3 PUFAs supplementation on Hcy, lipid and glycemic profile in T2D patients.
Materials and Methods
Patients and study design: This study is a double-blind controlled trial involving 70 patients with T2D selected from Yazd Diabetes Research Center in 2013. Inclusion criteria included: (1) less than 60 years, (2) diagnosed diabetes, (3) a minimum of 5 years’ experience in diabetes, (4) without any kidney, liver, heart, thyroid or bleeding disorders and malignancies, (5) not taking omega-3 supplementation during recent month, (6) without insulin therapy and (7) not pregnant or lactating. Exclusion criteria included: (1) taking less than 80% of the capsules, (2) changing the type and dose of routine medicines and (3) consumption of B vitamins supplementations during the study. Patients were randomly assigned into 2 groups, and they received either omega-3 soft gels (OG) or placebo (PG).
In previous studies, supplementation dose ranged from 200 to 6 g/day (Huang et al., 2011), but based on similar studies, an effective dose at 2 g/day was intended for this study. The OG received was 2 g/day omega-3 soft gels (Zahravi Pharmaceutical Co, Tabriz, Iran, consists of 240 mg of DHA, 360 mg EPA) and the PG received was 2 g/day placebo (Zahravi Pharmaceutical Co, Tabriz, Iran). The duration of our intervention was 6 weeks. Participants were asked not to change their lifestyle, diet, dietary patterns, physical activity and medication within the intervention. During this study, each person compulsorily took 84 capsules. At the beginning of the study, half of the capsules (42 capsules) were given to participants. After 3 weeks, they were invited to receive the second package of soft gels (another 42 soft gels). During the second session, residual capsules were counted. After completion of intervention, the remaining capsules were counted again.
Measurements: General information questionnaire including age, height, weight, sex, occupation, duration of disease, blood pressure, type and dose of medication etc., was completed. To evaluate anthropometric indices, weight was measured using digital scale (Seca, Germany) with minimal clothing and accuracy of 100 g, and height was measured with a stadiometer with an accuracy of 0.5 cm without shoes. At the beginning and end of the study, 24-h dietary recall questionnaire was used to estimate the intake of energy, macro and micronutrients, and also to check whether the  person's eating habits have changed during the study or not.
Biochemical measurements recorded were plasma fasting glucose (FBG), plasma fasting insulin, lipid profile (triglycerides (TG), HDL-c, LDL-c and total cholesterol (TC)) and serum Hcy. At the baseline and after 6-week, 10 ml of blood samples were taken after 12 h of fasting. For serum separation, samples were centrifuged at 3000 rpm for 10 min at room temperature.
Serum Hcy was measured using enzymatic cycling method (REAGENT kit by Axis-shield of England) and Alfa classic autoanalyzer (Iran). The normal range of Hcy based on the kits is 5-15 µm/L. Serum insulin was measured by ELISA method using monobind kits (made by USA) and with autoanalyzer having a sensitivity of 2 µIU per ml. Serum glucose, TG, TC and HDLc were assessed using enzymatic-colorimetric method with autoanalyzer, and the serum LDLc was calculated with FriedWald formula. In order to calculate the insulin resistance (IR), insulin sensitivity (IS) and β-cell function (B%), HOMA Calculator Software (version 2.2.2, Diabetes trials Unit University of oxford) was used.
Data analysis: In this study, to analyze the 24-h dietary recall data, Nutritionist4 was used.  Data were analyzed using SPSS software v.16. Descriptive statistics were used to explain the general characteristics of the participants. Student’s t-test was used to compare the mean of variables before and after the intervention between the groups and paired t-test for within group caparison. A P-value < 0.05 was considered to be statistically significant.
Ethical considerations: Written consent was obtained from the participants before beginning the study. Entering and leaving of the study was completely voluntary, and all experiments were performed free of charge.  This study was approved by the Shahid Sadoughi University of Medical Sciences Research Ethic Committee. In addition, it was registered with the Iranian Clinical Trial Registration Center (www.irct.ir) under the code of IRCT2013011312122N1.
Results
Sixty five out of 70 participants completed the study and 5 patients were excluded (Figure 1). From the 65 participants, 21 were men (52% in OG and 48% in the PG) and 44 were female (54.5% in the OG and 45.5% in the PG). Before the intervention, 71.4% and 73.3% of subjects received OG and PG, respectively and had normal serum Hcyconcentration (> 15 µm/L). But at the end of the study, it was 41.2% and 57.1% that received OG and PG, respectively.
The baseline characteristics, such as age, height, weight, body mass index (BMI), and sex at the beginning of the study are shown in Table 1. There were no significant differences in baseline variables between the two groups. The dietary energy and the other nutrients intakes are shown in Table 2. No significant differences were observed in dietary intakes between the two groups.
The mean Hcy level was compared in
between and within groups in Table 3. Omega-3 supplementation caused a significant increase in Hcy level as compared with placebo (P = 0.007). But there was not any significant difference in mean change between the groups. Table 4
shows the mean of TC, TG, LDLc, HDLc concentration and HDLc/LDLc. According to these findings, we observed no significant differences in TG and TC before and after the intervention between groups. But LDLc and HDLc/LDLc ratio were significantly increased, while HDLc concentration was significantly decreased in OG (P < 0.05). No significant differences were observed in mean changes of TG, TC, LDLc, HDLc concentration and HDLc/LDLc between groups.
Table 5 shows the changes of insulin, IR, IS, β-cell function and FBG before and after the study. Insulin and IR significantly increased, IS significantly decreased in both groups and β-cell function was significantly increased only in OG, while there were no differences in mean changes of fasting insulin, IR, IS, β-cell function.
 
 
 
6 weeks Follow-up
N = 35
N= 30
Omega-3 group 
(N=35)
 
Patients with diagnosed type 2 diabetes (N=70)
Excluded (n = 5):
Did not receive 80% of capsules (n = 3)
Changed their routine medicines (n = 2)
Data Analysis
Placebo group 
(N=35)
Random Allocation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. The Intervention framework
 
 
Table 1. Baseline characteristics of participants
 
Characteristics Omega-3 Group (N = 35) Placebo Group (N = 30) P-value
Age (y) 48.51±  6.80 a 50.66 ±   6.62 0.1 b
Height (cm) 162.12 ± 7.75 161.97 ± 8.83 0.4 b
Weight (kg) 73.97 ± 13.46 72.27 ± 12.31 0.9 b
BMI (kg/m2) 28.16 ± 4.96 27.50 ±  4.63 0.8 b
Sex
Male
Female
N (%)
11 (31.4)
24 (68.6)
N (%)
10 (33.3)
20 (66.7)
0.6 c
a: Mean±SD, b: Student t-test, c: Chi square test
Table 2. Daily dietary energy and nutrients intake
 
Variables Before After P-value c
Energy(Kcal)      
Omega-3 Group 1450.44 ± 400.45 a 1450.76 ± 521.11 0.43
Placebo Group 1532.65 ± 634.12 1427.32 ± 534.36 0.72
P-value b 0.70 0.83  
Carbohydrate(g/day)      
Omega-3 Group 143.43 ± 48.65 44.65 ± 145.65 0.24
Placebo Group 165.48 ± 85.34 72.54 ± 153.65 0.52
P-value 0.45 0.65  
Protein (g/day)      
Omega-3 Group 53.21 ± 27.43 55.12 ± 37.87 0.33
Placebo Group 53.23 ± 54.23 56.61 ± 26.92 0.76
P-value 0.45 0.92  
Fat (g/day)      
Omega-3 Group 60.42 ± 22.14 61.31 ± 21.34 0.94
Placebo Group 65.15 ± 34.55 61.76 ±  26.83 0.85
P-value 0.28 0.66  
Omega-3 (g/day)      
Omega-3 Group 6.43 ± 6.51 6.72 ± 5.43 0.23
Placebo Group 5.98 ± 5.83 5.13 ± 4.96 0.47
P-value 0.64 0.86  
B6 (mg/day)      
Omega-3 Group 1.21 ± 0.57 1.60 ± 0.43 0.54
Placebo Group 1.36 ± 0.37 1.45 ± 0.76 0.34
P-value 0.12 0.29  
B12 (µg /day)      
Omega-3 Group 2.23 ± 0.98 2.45 ± 0.92 0.54
Placebo Group 3.02 ± 1.45 2.61 ± 1.76 0.34
P-value 0.12 0.29  
Folate (µg/day)      
Omega-3 Group 210.34 ± 54.12 213.54 ± 60.43 0.94
Placebo Group 189.12 ± 43.23 184.28 ± 42.96 0.12
P-value 0.54 0.8  
a: Mean±SD, b: Student t-test, c: Paired t-test
 
Table 3. Means of Homocysteine concentration (µm/L) before and after the study.
 
Groups Before After Change P-valuea
Omega-3 Group 13.21 ± 4.97 15.24 ± 5.53 2.02 ± 3.80 0.007
Placebo Group 13.19 ± 4.89 14.40 ± 5.68 1.20 ± 4.82 0.21
P-valueb 0.98 0.57 0.47  
a: Paired t-test, b: Student t-test
 
Table 4. Means of total cholesterol, TG, LDLc, HDLc, HDLc/LDLc concentration before and after the study.
 
Variables Before After Change P-valuea
Total cholesterol (mg/dL)        
Omega-3 Group 163.8 ± 29.77 163.88 ± 35.45 0.07± 31.68 0.98
Placebo Group 184.07 ± 46.06 177.14 ± 45.29 - 6.92 ± 46.43 0.43
P-valueb 0.10 0.20 0.48  
Triglyceride (mg/dL)        
Omega-3 Group 168.58 ± 105.37 156.51 ± 105.25 12.07± 72 0.33
Placebo Group 155.16 ± 60.90 165.22 ± 97.66 10.05 ± 70.03 0.46
P-value 0.36 0.75 0.48  
LDLc (mg/dL)        
Omega-3 Group 84.26 ± 22.93 96.40 ± 32.36 12.14 ± 28.09 0.02
Placebo Group 105.27 ± 44.78 96.24 ± 37.39 - 9.02 ± 36.71 0.21
P-value 0.07 0.97 0.16  
HDLc (mg/dL)        
Omega-3 Group 47.63 ± 11.63 40.50 ± 11.45 7.13 ± 10.89 0.001
Placebo Group 47.67 ± 10.49 44.55 ± 8.61 3.12 ± 10.31 0.12
P-value 0.89 0.12 0.14  
HDLc/LDLc        
Omega-3 Group 0.59 ± 0.18 0.48 ± 0.26 - 0.11 ± 0.21 0.006
Placebo Group 0.54 ± 0.27 0.51 ± 0.18 - 0.02±  0.25 0.59
P-value 0.36 0.49 0.16  
a: Paired t-test, b: Student t-test
 
 
Discussion
In this study, which involved 65 T2D patients, after 6 weeks of n-3 PUFAs supplementation, the overall results showed that a daily intake of 2 g n-3 PUFAs capsules caused a significant decrease in HDLc, HDLc/ LDLc and IS; a significant increase in LDLc, Hcy, fasting insulin, IR and β-cell function; a reduction in TG; and an increase in FBG level. But based on mean changes, n-3 PUFAs supplementation had no positive effects on Hcy, lipid and insulin profile.
The results of the present study on Hcy are in line with some previous studies (Piolot et al., 2003) and inconsistent with some others (Grundt et al., 2003, Zeman et al., 2006). Zeman
et al. (Zeman et al., 2006) recommended
that 3.6 g PUFA n-3 supplementation for
3 months decreased Hcy levels in diabetic dyslipidemia. But in the present study, omega-3 supplementation was accompanied by statin-fibrate treatment. Several studies have shown that supplementation with omega-3 can reduce Hcy concentration in T2D (Benito et al., 2006, Tayebi-Khosroshahi et al., 2013).  Fiedler et al.
 
Table 5. Means of insulin, insulin resistance, insulin sensitivity, beta cell function and fasting glucose before and after the study.
 
Variables Before After Change P-valuea
Insulin (mU/L)        
Omega-3 Group 7.04 ± 4.72 10.04 ± 4.53 2.99 ± 3.66 <0.001
Placebo Group 7.73 ± 4.98 11.07 ± 7.49 3.34 ± 4.56 0.001
P-valueb 0.73 0.50 0.74  
Fasting blood  glucose (mg/dL)        
Omega-3 Group 137.01 ± 40.48 142.53 ± 48.34 5.07 ± 27.19 0.28
Placebo Group 150.98 ± 48.57 159.11 ± 48.08 5.09 ± 26.15 0.25
P-value 0.21 0.18 0.9  
Insulin resistance        
Omega-3 Group 1.06 ± 0.66 1.52 ± 0.67 0.45 ± 0.49 <0.001
Placebo Group 1.21 ± 0.66 1.74 ± 0.98 0.52 ± 0.62 <0.001
P-value 0.76 0.28 0.64  
Insulin sensitivity (%)        
Omega-3 Group 124.03 ± 63.47 78.86 ± 37.42 - 45.16 ± 57.59 <0.001
Placebo Group 110.66 ± 73.72 84.05± 60.14 - 26.60 ± 56.13 0.02
P-value 0.99 0.66 0.23  
Beta cell function (%)        
Omega-3 Group 46.89 ± 23.13 62.07± 34.67 15.18 ±  28.40 0.005
Placebo Group 46.01 ± 31.38 51.84± 34.52 15.83 ± 25.92 0.29
P-value 0.86 0.32 0.21  
a: Paired t-test, b: Student t-test
 
 
(Fiedler et al., 2005) administered 1.2 g of omega-3 with 11.2 g of pectin for 12 weeks to 11 hemodialysis patients. They conducted a short-term intervention and found no reduction in Hcy level. Piolot et al. (Piolot et al., 2003) observed a progressive and significant increase in Hcy concentration in 16 normolipidemic subjects, which is in line with our study. However, certain effect of omega-3 fatty acids on Hcy is equivocal. This inconsistency may be due to different target groups, supplementation doses, intervention duration, sample size, type of medications and disease progression in different studies. Fiedler (2005) suggested that high doses of omega-3 for a long time may have anti-inflammatory effects (Fiedler et al., 2005). In addition, the initial Hcy concentration in subjects may also be effective in results.
Some proposed mechanisms of the association between omega-3 and Hcy: Omega-3 PUFAs
in cell membranes can cause modulation of
the expression of enzymes involved in
Hcy metabolism (Li et al., 2007), such as Cystathionine beta synthase. Dietary fatty acids may interact with methylene tetrahydrofolate reductase (MTHFR) and methionine adenosyl transferase I, alpha (MAT1A) genetic variants in determining the Hcy level (Huang et al., 2012). Omega-3 fatty acids may counteract the adverse effects of Hcy on endothelial function (Grundt et al., 2003), they may increase nitric oxide (NO) production and subsequently inhibit methionine synthase (Haglund et al., 1993, Zeman et al., 2006). The increased Hcy concentrations during supplementation with n-3 fatty acids may be explained by the last mechanism, but other studies are needed to identify more precise mechanisms.
According to results of the present study, there was unfavorable effect on LDLc and HDLc. Thus there was no change in total cholesterol, and non-significant reduction in TG concentration in OG was observed. As such, n-3 PUFAs did not ameliorate lipid profiles in diabetic patients. N-3 PUFAs have been shown to improve plasma lipid profile in normal and hypertriglyceridemic subjects in some studies (Friday et al., 1989, Haglund et al., 1993) but in contrast, some others did not show the same (García-Alonso et al., 2012). The result obtained in a study by West et al. (West et al., 2005) on diabetic patients is in line with the finding of the present study in terms of LDLc. Piolot (Piolot et al., 2003), Schiano (Schiano et al., 2008) and Garci (García-Alonso et al., 2012) in different studies showed that supplementation with n-3 PUFAs had not significant effects on HDLc and total cholesterol. But another study on patients with hyperlipidemia proved increasing HDLc (Haglund et al., 1993). Crochemore suggested that the reduction effects of omega-3 PUFAs on total cholesterol and TG are dose dependent (Crochemore et al., 2012).
The hypotriglyceridemic effect of n-3 PUFAs have been proven, but this effect is dose dependent (Kris-Etherton et al., 2003). Based on previous studies, n-3 PUFAs reduced TG, mainly by declining the production and secretion of hepatic VLDL and also increasing the catabolism of VLDL (Grimsgaard et al., 1997). After n-3 PUFA supplementation, PPARα increased which resulted in an increase in lipoprotein lipase (LPL), thereby reducing VLDL production (Schmidt et al., 2012). In addition, it has been observed that the lowering effects of omega-3 fatty acids consumption on postprandial TG (PPTG) is significant (Kris-Etherton et al., 2003). That ≤ 2 g of omega-3 consumption can significantly reduce PPTG(Roche and Gibney, 1996).
In the present study, fasting insulin level and IR were significantly increased in both groups after the intervention, while IS was significantly reduced. β -cell function and fasting glucose level had increasing trend in both groups, which was statistically significant in the intervention group. Several studies have shown the useful effects of omega-3 fatty acids on insulin function in animals (Chicco et al., 1996, D’Alessandro et al., 2002, Vessby, 2000). However, limited and conflicting results on humans, especially on diabetic patients are available.  It has been shown that Greenland Eskimos, with diets rich in fish, have a low prevalence of diabetes. Giacco et al. (Giacco et al., 2007) observed in their study that 3.6 g/day omega-3 PUFAs supplementation on 162
healthy subjects had no effect on IS, insulin secretion, beta-cell function and glucose tolerance. In another study, omega-3 fatty acids supplementation did not cause detrimental glycemic effects (Holness MJ, 2003).
Similar to our study, In overall, n-3 PUFAs may lead to higher glucose concentrations. Possible mechanism may: (1) lower glucose utilization and increase glucagon-stimulated C-peptide (2) increase gluconeogenesis in liver, and (3) increase glucose circulation (Kaushik et al., 2009). Several mechanisms have been suggested for n-3 PUFAs mediated effects on insulin
action: (1) the prevention of  decrease by phosphatidylinositol 3’ kinase (PI3 kinase) activity; (2) prevention of the depletion of glucose transporter protein GLUT4 in muscles; (3) the prevention of decrease in expression of GLUT4 in adipose tissue; and (4) inhibition of both the activity and expression of liver glucose-6-phosphatase (Delarue et al., 2004, Taouis et al., 2002). With regard to the adverse effect of omega-3 supplementation on insulin function, some studies suggested that dioxins or methyl mercury can disrupt insulin signaling pathways (Kaushik et al., 2009, Lee et al., 2006).
Omega-3 fatty acids can cause oxidative stress by increasing the production of reactive oxygen species and intracellular antioxidant defense reduction. Experimental studies have shown that oxidative stress can disrupt insulin signaling and insulin secretion. Endothelial dysfunction, due to Omega-3 fatty acids, lowers insulin delivery to insulin sensitive tissues, which in turn impairs the insulin-dependent glucose metabolism, leading to insulin resistance. Dietary intake of n-3 PUFAs s may have favorable effects on T2D prevention, but supplementation in people diagnosed with T2D seems not to be suitable.
The limitations of our study were short duration of intervention and low DHA concentration in omega-3 soft gels. To determine the pure effect and mechanisms of omega-3 fatty acids in T2D, future studies with longer periods are needed.
Conclusions
The present study found no beneficial effects of 2 g/day omega-3 supplement for 6 weeks on biomarkers of Hcy, FBG, insulin and lipid profile in patients with T2D.
Acknowledgements
The authors are grateful to Dana Pharmaceutical



Company for placebo preparation and also to the Yazd Diabetes Research Center staff and all the patients involved. There is no conflict of interest regarding the publication of the study.
Authors’ contribution
Mozaffari-Khosravi H participated to conception and design of study, managing the project and drafting the manuscript. Naghdipour Biregani A and Poursoleiman  F participated to acquisition of data, data analysis and drafting the manuscript. All authors read manuscript and they finally verified it.
Conflict of interest
The authors declare that there is no any conflict of interests.
 
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García-Alonso F, Jorge-Vidal V, Ros G & Periago M 2012. Effect of consumption of tomato juice enriched with n-3 polyunsaturated fatty acids on the lipid profile, antioxidant biomarker status, and cardiovascular disease risk in healthy women. European journal of nutrition. 51 (4): 415-424.
Giacco R, et al. 2007. Fish oil, insulin sensitivity, insulin secretion and glucose tolerance in healthy people: Is there any effect of fish oil supplementation in relation to the type of background diet and habitual dietary intake of omega-6 and omega-3 fatty acids? Nutrition, metabolism and cardiovascular diseases. 17 (8): 572-580.
Grimsgaard S, Bonaa KH, Hansen J-B & Nordøy A 1997. Highly purified eicosapentaenoic acid and docosahexaenoic acid in humans have similar triacylglycerol-lowering effects but divergent effects on serum fatty acids. The American journal of clinical nutrition. 66 (3): 649-659.
Grundt H, Nilsen DW, Mansoor MA, Hetland Ø & Nordøy A 2003. Reduction in homocysteine by n–3 polyunsaturated fatty acids after 1 year in a randomised double-blind study following an acute myocardial infarction: no effect on endothelial adhesion properties. Pathophysiology of haemostasis and thrombosis. 33 (2): 88-95.
Haglund O, Hamfelt A, Hambraeus L & Saldeen T 1993. Effects of fish oil supplemented with pyridoxine and folic acid on homocysteine, atherogenic index, fibrinogen and plasminogen activator inhibitor-1 in man. Nutrition research. 13 (12): 1351-1365.
Hartweg J, Farmer A, Holman R & Neil H 2007. Meta-analysis of the effects of n-3 polyunsaturated fatty acids on haematological and thrombogenic factors in type 2 diabetes. Diabetologia. 50 (2): 250-258.
Hofmann MA, et al. 2001. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. The journal of clinical investigation. 107 (6): 675-683.
Holness MJ GG, Smith ND, Sugden MC 2003. Diabetogenic Impact of Long-Chain ω-3 Fatty Acids on Pancreatic β-Cell Function and the Regulation of Endogenous Glucose Production. Endocrinology. 144 (9): 3958-3968.
House AA, et al. 2010. Effect of B-vitamin therapy on progression of diabetic nephropathy. The journal of the American medical asociation. 303 (16): 1603-1609.
Huang T, Asimi S, Lou D & Li D 2012. Plasma phospholipid polyunsaturated fatty acids and homocysteine in Chinese type 2 diabetes patients. Asia Pacific journal of clinical nutrition. 21 (3): 394.
Huang T, et al. 2011. High consumption of Ω-3 polyunsaturated fatty acids decrease plasma homocysteine: a meta-analysis of randomized, placebo-controlled trials. Nutrition. 27 (9): 863-867.
Kaushik M, et al. 2009. Long-chain omega-3 fatty acids, fish intake, and the risk of type 2 diabetes mellitus. The American journal of clinical nutrition. 90: 613-620.
Kris-Etherton PM, Harris WS & Appel
LJ
2003. Fish consumption, fish oil,
omega-3 fatty acids, and cardiovascular
disease. Arteriosclerosis, thrombosis, and vascular biology. 23 (2): e20-e30.
Lee D-H, et al. 2006. A strong dose-response relation between serum concentrations of persistent organic pollutants and diabetes results from the National Health and Examination Survey 1999–2002. Diabetes care. 29 (7): 1638-1644.
Li D, et al. 2007. Platelet phospholipid omega−3 PUFA negatively associated with plasma homocysteine in middle-aged and geriatric hyperlipaemia patients. Prostaglandins, leukotrienes and essential fatty acids. 76 (5): 293-297.
McDowell IF & Lang D 2000. Homocysteine and endothelial dysfunction: a link with cardiovascular disease. The journal of nutrition. 130 (2): 369S-372S.
Piolot A, et al. 2003. Effect of fish oil on LDL oxidation and plasma homocysteine concentrations in health. Journal of laboratory and clinical medicine. 141 (1): 41-49.
Roche H & Gibney M 1996. Postprandial triacylglycerolaemia: the effect of low-fat dietary treatment with and without fish oil supplementation. European journal of clinical nutrition. 50 (9): 617-624.
Sachdev P 2004. Homocysteine, cerebrovascular disease and brain atrophy. Journal of the neurological sciences. 226 (1): 25-29.
Saedisomeolia A, Wood LG, Garg ML, Gibson PG & Wark PA 2009. Lycopene enrichment of cultured airway epithelial cells decreases the inflammation induced by rhinovirus infection and lipopolysaccharide. The Journal of nutritional biochemistry. 20 (8): 577-585.
Schiano V, et al. 2008. Omega-3 polyunsaturated fatty acid in peripheral arterial disease: effect on lipid pattern, disease severity, inflammation profile, and endothelial function. Clinical nutrition. 27 (2): 241-247.
Schmidt S, et al. 2012. Regulation of lipid metabolism-related gene expression in whole blood cells of normo-and dyslipidemic men after fish oil supplementation. Lipids health Disease. 11: 172.
Selhub J 1999. Homocysteine metabolism. Annual review of nutrition. 19 (1): 217-246.
Smulders YM & Blom HJ 2011. The homocysteine controversy. Journal of inherited metabolic disease. 34 (1): 93-99.
Stamler JS, et al. 1993. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. Journal of clinical investigation. 91 (1): 308.
Taouis M, et al. 2002. N-3 polyunsaturated fatty acids prevent the defect of insulin receptor signaling in muscle. American journal of physiology-endocrinology and metabolism. 282 (3): E664-E671.
Tayebi-Khosroshahi H, et al. 2013. Effect of omega-3 supplementation on serum level of homocysteine in hemodialysis patients. Iranian journal of kidney diseases. 7 (6): 479-484.
Vessby B 2000. Dietary fat and insulin action in humans. British journal of nutrition. 83 (S1): S91-S96.
Weiss N, et al. 2003. Influence of hyperhomocysteinemia on the cellular redox state–impact on homocysteine-induced endothelial dysfunction. Clinical chemistry and laboratory medicine. 41 (11): 1455-1461.
West S, et al. 2005. Acute effects of monounsaturated fatty acids with and without omega-3 fatty acids on vascular reactivity in individuals with type 2 diabetes. Diabetologia. 48 (1): 113-122.
WHO 2011. Global status report on noncommunicable diseases 2010. WHO: Geneva.
Yokoyama M, et al. 2007. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. The lancet. 369 (9567): 1090-1098.
Zeman M, et al. 2006. N-3 fatty acid supplementation decreases plasma homocysteine in diabetic dyslipidemia treated with statin–fibrate combination. The journal
of nutritional biochemistry.
17 (6): 379-384.
 

 
 
Type of article: orginal article | Subject: public specific
Received: 2017/04/15 | Accepted: 2017/09/30 | Published: 2018/01/30

References
1. Benito P, et al. 2006. Effects of milk enriched with omega-3 fatty acid, oleic acid and folic acid in patients with metabolic syndrome. Clinical nutrition. 25 (4): 581-587.
2. Buse JB, et al. 2007. Primary prevention of cardiovascular diseases in people with diabetes mellitus a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes care. 30 (1): 162-172.
3. Chicco A, D’Alessandro M, Karabatas L, Gutman R & Lombardo Y 1996. Effect of moderate levels of dietary fish oil on insulin secretion and sensitivity, and pancreas insulin content in normal rats. Annals of nutrition and metabolism. 40 (2): 61-70.
4. Crochemore ICC, Souza AF, de Souza AC & Rosado EL 2012. ω-3 Polyunsaturated fatty acid supplementation does not influence body composition, insulin resistance, and lipemia in women with type 2 diabetes and obesity. Nutrition in clinical practice. 27 (4): 553-560.
5. D’Alessandro M, Lombardo Y & Chicco A 2002. Effect of dietary fish oil on insulin sensitivity and metabolic fate of glucose in the skeletal muscle of normal rats. Annals of nutrition and metabolism. 46 (3-4): 114-120.
6. Danaei G, et al. 2011. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2• 7 million participants. The lancet. 378 (9785): 31-40.
7. De Caterina R, Madonna R, Bertolotto A & Schmidt EB 2007. n-3 Fatty Acids in the Treatment of Diabetic Patients Biological rationale and clinical data. Diabetes care. 30 (4): 1012-1026.
8. Delarue J, LeFoll C, Corporeau C & Lucas D 2004. N-3 long chain polyunsaturated fatty acids: a nutritional tool to prevent insulin resistance associated to type 2 diabetes and obesity? Reproduction nutrition development. 44 (3): 289-299.
9. Elias AN & Eng S 2005. Homocysteine concentrations in patients with diabetes mellitus–relationship to microvascular and macrovascular. Diabetes, obesity and metabolism. 7: 117-121.
10. Fiedler R, Mall M, Wand C & Osten B 2005. Short-term administration of omega-3 fatty acids in hemodialysis patients with balanced lipid metabolism. Journal of renal nutrition. 15 (2): 253-256.
11. Friday KE, et al. 1989. Elevated plasma glucose and lowered triglyceride levels from omega-3 fatty acid supplementation in type II diabetes. Diabetes care. 12 (4): 276-281.
12. García-Alonso F, Jorge-Vidal V, Ros G & Periago M 2012. Effect of consumption of tomato juice enriched with n-3 polyunsaturated fatty acids on the lipid profile, antioxidant biomarker status, and cardiovascular disease risk in healthy women. European journal of nutrition. 51 (4): 415-424.
13. Giacco R, et al. 2007. Fish oil, insulin sensitivity, insulin secretion and glucose tolerance in healthy people: Is there any effect of fish oil supplementation in relation to the type of background diet and habitual dietary intake of omega-6 and omega-3 fatty acids? Nutrition, metabolism and cardiovascular diseases. 17 (8): 572-580.
14. Grimsgaard S, Bonaa KH, Hansen J-B & Nordøy A 1997. Highly purified eicosapentaenoic acid and docosahexaenoic acid in humans have similar triacylglycerol-lowering effects but divergent effects on serum fatty acids. The American journal of clinical nutrition. 66 (3): 649-659.
15. Grundt H, Nilsen DW, Mansoor MA, Hetland Ø & Nordøy A 2003. Reduction in homocysteine by n–3 polyunsaturated fatty acids after 1 year in a randomised double-blind study following an acute myocardial infarction: no effect on endothelial adhesion properties. Pathophysiology of haemostasis and thrombosis. 33 (2): 88-95.
16. Haglund O, Hamfelt A, Hambraeus L & Saldeen T 1993. Effects of fish oil supplemented with pyridoxine and folic acid on homocysteine, atherogenic index, fibrinogen and plasminogen activator inhibitor-1 in man. Nutrition research. 13 (12): 1351-1365.
17. Hartweg J, Farmer A, Holman R & Neil H 2007. Meta-analysis of the effects of n-3 polyunsaturated fatty acids on haematological and thrombogenic factors in type 2 diabetes. Diabetologia. 50 (2): 250-258.
18. Hofmann MA, et al. 2001. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. The journal of clinical investigation. 107 (6): 675-683.
19. Holness MJ GG, Smith ND, Sugden MC 2003. Diabetogenic Impact of Long-Chain ω-3 Fatty Acids on Pancreatic β-Cell Function and the Regulation of Endogenous Glucose Production. Endocrinology. 144 (9): 3958-3968.
20. House AA, et al. 2010. Effect of B-vitamin therapy on progression of diabetic nephropathy. The journal of the American medical asociation. 303 (16): 1603-1609.
21. Huang T, Asimi S, Lou D & Li D 2012. Plasma phospholipid polyunsaturated fatty acids and homocysteine in Chinese type 2 diabetes patients. Asia Pacific journal of clinical nutrition. 21 (3): 394.
22. Huang T, et al. 2011. High consumption of Ω-3 polyunsaturated fatty acids decrease plasma homocysteine: a meta-analysis of randomized, placebo-controlled trials. Nutrition. 27 (9): 863-867.
23. Kaushik M, et al. 2009. Long-chain omega-3 fatty acids, fish intake, and the risk of type 2 diabetes mellitus. The American journal of clinical nutrition. 90: 613-620.
24. Kris-Etherton PM, Harris WS & Appel LJ 2003. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Arteriosclerosis, thrombosis, and vascular biology. 23 (2): e20-e30.
25. Lee D-H, et al. 2006. A strong dose-response relation between serum concentrations of persistent organic pollutants and diabetes results from the National Health and Examination Survey 1999–2002. Diabetes care. 29 (7): 1638-1644.
26. Li D, et al. 2007. Platelet phospholipid omega−3 PUFA negatively associated with plasma homocysteine in middle-aged and geriatric hyperlipaemia patients. Prostaglandins, leukotrienes and essential fatty acids. 76 (5): 293-297.
27. Benito P, et al. 2006. Effects of milk enriched with omega-3 fatty acid, oleic acid and folic acid in patients with metabolic syndrome. Clinical nutrition. 25 (4): 581-587.
28. Buse JB, et al. 2007. Primary prevention of cardiovascular diseases in people with diabetes mellitus a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes care. 30 (1): 162-172.
29. Chicco A, D’Alessandro M, Karabatas L, Gutman R & Lombardo Y 1996. Effect of moderate levels of dietary fish oil on insulin secretion and sensitivity, and pancreas insulin content in normal rats. Annals of nutrition and metabolism. 40 (2): 61-70.
30. Crochemore ICC, Souza AF, de Souza AC & Rosado EL 2012. ω-3 Polyunsaturated fatty acid supplementation does not influence body composition, insulin resistance, and lipemia in women with type 2 diabetes and obesity. Nutrition in clinical practice. 27 (4): 553-560.
31. D’Alessandro M, Lombardo Y & Chicco A 2002. Effect of dietary fish oil on insulin sensitivity and metabolic fate of glucose in the skeletal muscle of normal rats. Annals of nutrition and metabolism. 46 (3-4): 114-120.
32. Danaei G, et al. 2011. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2• 7 million participants. The lancet. 378 (9785): 31-40.
33. De Caterina R, Madonna R, Bertolotto A & Schmidt EB 2007. n-3 Fatty Acids in the Treatment of Diabetic Patients Biological rationale and clinical data. Diabetes care. 30 (4): 1012-1026.
34. Delarue J, LeFoll C, Corporeau C & Lucas D 2004. N-3 long chain polyunsaturated fatty acids: a nutritional tool to prevent insulin resistance associated to type 2 diabetes and obesity? Reproduction nutrition development. 44 (3): 289-299.
35. Elias AN & Eng S 2005. Homocysteine concentrations in patients with diabetes mellitus–relationship to microvascular and macrovascular. Diabetes, obesity and metabolism. 7: 117-121.
36. Fiedler R, Mall M, Wand C & Osten B 2005. Short-term administration of omega-3 fatty acids in hemodialysis patients with balanced lipid metabolism. Journal of renal nutrition. 15 (2): 253-256.
37. Friday KE, et al. 1989. Elevated plasma glucose and lowered triglyceride levels from omega-3 fatty acid supplementation in type II diabetes. Diabetes care. 12 (4): 276-281.
38. García-Alonso F, Jorge-Vidal V, Ros G & Periago M 2012. Effect of consumption of tomato juice enriched with n-3 polyunsaturated fatty acids on the lipid profile, antioxidant biomarker status, and cardiovascular disease risk in healthy women. European journal of nutrition. 51 (4): 415-424.
39. Giacco R, et al. 2007. Fish oil, insulin sensitivity, insulin secretion and glucose tolerance in healthy people: Is there any effect of fish oil supplementation in relation to the type of background diet and habitual dietary intake of omega-6 and omega-3 fatty acids? Nutrition, metabolism and cardiovascular diseases. 17 (8): 572-580.
40. Grimsgaard S, Bonaa KH, Hansen J-B & Nordøy A 1997. Highly purified eicosapentaenoic acid and docosahexaenoic acid in humans have similar triacylglycerol-lowering effects but divergent effects on serum fatty acids. The American journal of clinical nutrition. 66 (3): 649-659.
41. Grundt H, Nilsen DW, Mansoor MA, Hetland Ø & Nordøy A 2003. Reduction in homocysteine by n–3 polyunsaturated fatty acids after 1 year in a randomised double-blind study following an acute myocardial infarction: no effect on endothelial adhesion properties. Pathophysiology of haemostasis and thrombosis. 33 (2): 88-95.
42. Haglund O, Hamfelt A, Hambraeus L & Saldeen T 1993. Effects of fish oil supplemented with pyridoxine and folic acid on homocysteine, atherogenic index, fibrinogen and plasminogen activator inhibitor-1 in man. Nutrition research. 13 (12): 1351-1365.
43. Hartweg J, Farmer A, Holman R & Neil H 2007. Meta-analysis of the effects of n-3 polyunsaturated fatty acids on haematological and thrombogenic factors in type 2 diabetes. Diabetologia. 50 (2): 250-258.
44. Hofmann MA, et al. 2001. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. The journal of clinical investigation. 107 (6): 675-683.
45. Holness MJ GG, Smith ND, Sugden MC 2003. Diabetogenic Impact of Long-Chain ω-3 Fatty Acids on Pancreatic β-Cell Function and the Regulation of Endogenous Glucose Production. Endocrinology. 144 (9): 3958-3968.
46. House AA, et al. 2010. Effect of B-vitamin therapy on progression of diabetic nephropathy. The journal of the American medical asociation. 303 (16): 1603-1609.
47. Huang T, Asimi S, Lou D & Li D 2012. Plasma phospholipid polyunsaturated fatty acids and homocysteine in Chinese type 2 diabetes patients. Asia Pacific journal of clinical nutrition. 21 (3): 394.
48. Huang T, et al. 2011. High consumption of Ω-3 polyunsaturated fatty acids decrease plasma homocysteine: a meta-analysis of randomized, placebo-controlled trials. Nutrition. 27 (9): 863-867.
49. Kaushik M, et al. 2009. Long-chain omega-3 fatty acids, fish intake, and the risk of type 2 diabetes mellitus. The American journal of clinical nutrition. 90: 613-620.
50. Kris-Etherton PM, Harris WS & AppelLJ 2003. Fish consumption, fish oil,omega-3 fatty acids, and cardiovascular disease. Arteriosclerosis, thrombosis, and vascular biology. 23 (2): e20-e30.
51. Lee D-H, et al. 2006. A strong dose-response relation between serum concentrations of persistent organic pollutants and diabetes results from the National Health and Examination Survey 1999–2002. Diabetes care. 29 (7): 1638-1644.
52. Li D, et al. 2007. Platelet phospholipid omega−3 PUFA negatively associated with plasma homocysteine in middle-aged and geriatric hyperlipaemia patients. Prostaglandins, leukotrienes and essential fatty acids. 76 (5): 293-297.
53. McDowell IF & Lang D 2000. Homocysteine and endothelial dysfunction: a link with cardiovascular disease. The journal of nutrition. 130 (2): 369S-372S.
54. Piolot A, et al. 2003. Effect of fish oil on LDL oxidation and plasma homocysteine concentrations in health. Journal of laboratory and clinical medicine. 141 (1): 41-49.
55. Roche H & Gibney M 1996. Postprandial triacylglycerolaemia: the effect of low-fat dietary treatment with and without fish oil supplementation. European journal of clinical nutrition. 50 (9): 617-624.
56. Sachdev P 2004. Homocysteine, cerebrovascular disease and brain atrophy. Journal of the neurological sciences. 226 (1): 25-29.
57. Saedisomeolia A, Wood LG, Garg ML, Gibson PG & Wark PA 2009. Lycopene enrichment of cultured airway epithelial cells decreases the inflammation induced by rhinovirus infection and lipopolysaccharide. The Journal of nutritional biochemistry. 20 (8): 577-585.
58. Schiano V, et al. 2008. Omega-3 polyunsaturated fatty acid in peripheral arterial disease: effect on lipid pattern, disease severity, inflammation profile, and endothelial function. Clinical nutrition. 27 (2): 241-247.
59. Schmidt S, et al. 2012. Regulation of lipid metabolism-related gene expression in whole blood cells of normo-and dyslipidemic men after fish oil supplementation. Lipids health Disease. 11: 172.
60. Selhub J 1999. Homocysteine metabolism. Annual review of nutrition. 19 (1): 217-246.
61. Smulders YM & Blom HJ 2011. The homocysteine controversy. Journal of inherited metabolic disease. 34 (1): 93-99.
62. Stamler JS, et al. 1993. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. Journal of clinical investigation. 91 (1): 308.
63. Taouis M, et al. 2002. N-3 polyunsaturated fatty acids prevent the defect of insulin receptor signaling in muscle. American journal of physiology-endocrinology and metabolism. 282 (3): E664-E671.
64. Tayebi-Khosroshahi H, et al. 2013. Effect of omega-3 supplementation on serum level of homocysteine in hemodialysis patients. Iranian journal of kidney diseases. 7 (6): 479-484.
65. Vessby B 2000. Dietary fat and insulin action in humans. British journal of nutrition. 83 (S1): S91-S96.
66. Weiss N, et al. 2003. Influence of hyperhomocysteinemia on the cellular redox state–impact on homocysteine-induced endothelial dysfunction. Clinical chemistry and laboratory medicine. 41 (11): 1455-1461.
67. West S, et al. 2005. Acute effects of monounsaturated fatty acids with and without omega-3 fatty acids on vascular reactivity in individuals with type 2 diabetes. Diabetologia. 48 (1): 113-122.
68. WHO 2011. Global status report on noncommunicable diseases 2010. WHO: Geneva.
69. Yokoyama M, et al. 2007. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. The lancet. 369 (9567): 1090-1098.
70. Zeman M, et al. 2006. N-3 fatty acid supplementation decreases plasma homocysteine in diabetic dyslipidemia treated with statin–fibrate combination. The journal of nutritional biochemistry. 17 (6): 379-384.

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