Fish oil supplementation improves endothelial function in normoglycemic offspring of patients with type 2 diabetes

doi:10.1016/j.atherosclerosis.2009.03.006

Atherosclerosis

Volume 206, Issue 2, October 2009, Pages 569-574

https://doi.org/10.1016/j.atherosclerosis.2009.03.006 Get rights and content

Abstract

Objective

Offspring of patients with type 2 diabetes (OPDs) exhibits endothelial dysfunction (ED) associated with a chronic inflammatory state. N-3 polyunsaturated fatty acids (n-3 PUFA) may have antioxidant and anti-inflammatory properties that are beneficial for cardiovascular and metabolic health. Therefore, in the present study, we tested the hypothesis that dietary supplementation with fish oil rich in n-3 PUFA may improve ED in otherwise healthy OPDs.

Methods and design

A double-blind, placebo-controlled trial was conducted with 50 OPDs. Participants were randomized to treatment with either placebo or n-3 PUFA (2 g/day) for 12 weeks. Before and after treatment we evaluated endothelial function (using flow-mediated dilation (FMD) of the brachial artery), circulating inflammatory markers (adiponectin, TNF-α, and high sensitivity-CRP), and insulin resistance (QUICKI).

Results

No significant changes were observed in study outcomes in subjects treated with placebo. By contrast, when compared with baseline values, subjects treated with n-3 PUFA had significant improvement in FMD (9.1 ± 5.8% vs. 11.7 ± 4.4%, p = 0.02) that was accompanied by decreased plasma triglycerides (117 ± 73 mg/dl vs. 86 ± 44 mg/dl, p = 0.001) and TNF-α levels (8.9 ± 2.3 pg/ml vs. 6.8 ± 2.7 pg/ml, p = 0.001), and a trend towards increased plasma adiponectin levels (7.8 ± 4.5 μg/ml vs. 9.5 ± 5.1 μg/ml, p = 0.09). When data were analyzed by multiple regression analysis, decreased TNF-α after treatment with n-3 PUFA predicted increased FMD.

Conclusion

Dietary supplementation with n-3 PUFA significantly improved endothelial function and reduced pro-inflammatory markers in OPDs. Thus, fish oil consumption may have beneficial cardiovascular and metabolic health effects in otherwise healthy subjects predisposed to diabetes and its vascular complications.

Introduction

Endothelial dysfunction (ED) is a major contributor to the pathogenesis of cardiovascular disease (CVD) [1], [2]. ED is frequently observed in normoglycemic offspring of patients with type 2 diabetes (OPDs) [3]. Indeed, several clinical studies demonstrate that OPDs have impaired endothelium-mediated vasodilation that may be linked to underlying cardiovascular risk factors including insulin resistance and increased circulating pro-inflammatory markers [4]. We previously reported that OPDs, characterized by cardiometabolic abnormalities, have concomitant ED [5], [6], [7]. Moreover, several clinical trials demonstrate that therapy with antioxidant or antidiabetic agents ameliorates insulin resistance and the pro-inflammatory state in OPDs [8], [9], [10]. However, only few studies have tested effects of pharmacological interventions to improve impaired endothelial vascular reactivity of OPDs [11].

Evidence from both animal and human studies suggests that n-3 polyunsaturated fatty acids (n-3 PUFA) including eicosapentaenoic (EPA) and docosahexaenoic (DHA) acid have anti-inflammatory properties [12]. Moreover, dietary supplementation with fish oil rich in n-3 PUFA positively impacts vascular function and reduces CVD in the setting of atherosclerosis [13]. Therefore, in the present study, we tested the hypothesis that dietary supplementation with fish oil rich in n-3 PUFA may improve ED by normalizing lipid abnormalities and decreasing the pro-inflammatory state in OPDs that is suggested by elevated levels of circulating pro-inflammatory cytokines and other biomarkers [4]. To investigate this hypothesis we carried out a randomized double-blind, placebo-controlled clinical trial in 50 OPDs for 12 weeks.

Section snippets

Subjects

We studied 50 healthy subjects (age 29.9 ± 6.2 years, 25 men and 25 women) with ≥1 parent with a diagnosis of type 2 diabetes (DM2). Subjects were recruited and completed all phases of the study at the Clinical Centre for Atherosclerosis at the University of Rome “Tor Vergata”.

All of the participating women reported regular menstrual cycles without oral contraceptives therapy. In female subjects, all experiments were performed during the first week of the menstrual cycle. None of the study's

Experimental results

Results from OGTT identified 33 subjects with normal glucose tolerance (NGT; 2-h post-load glucose level <7.8 mmol/L), and 17 subjects with impaired glucose tolerance (IGT; 2-h post-load glucose level between 7.8 and 11.1 mmol/L). After participants were randomized to placebo or n-3 PUFA treatment, the subject distributions according to OGTT results were as follows: PUFA–NGT (n = 16), PUFA–IGT (n = 10) and placebo–NGT (n = 17), placebo–IGT (n = 7).

Discussion

We demonstrate that oral supplementation with fish oil rich in n-3 PUFA improves endothelial function in OPDs with or without IGT. N-3 PUFA treatment of OPDs is also associated with a significant lowering of elevated circulating TNF-α levels consistent with improvement in a chronic pro-inflammatory state. Chronic metabolic diseases such as obesity and diabetes are often associated with persistent elevations in circulating levels of pro-inflammatory cytokines such as TNF-α and other biomarkers

Conflict of interest

No conflict of interest, potentially prejudicing the impartiality of the research reported, concerns this manuscript.

Acknowledgements

We thank Miss Leela Thaiparambil for technical assistance.

Funding: This manuscript was funded in part by research grants: Italian Ministero della Salute RS 2003 (to Drs. Tremoli and D. Lauro) and Italian Ministero dell’Università e della Ricerca Scientifica/Tecnologica (to Drs. Mannarino and D. Lauro).

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Diabetes mellitus (DM)-induced endothelial dysfunction (DED) contributes to macrovascular complications of DM, resulting in high mortality. Fish oil (FO) is a dietary source of omega-3 polyunsaturated fatty acids, with little known for its action on DED. Thus, the objective of the current study was to investigate the effect of FO on aortic DED using a mouse model of DM. To this end, C57BL/6 J male mice (n = 8/each group) were intraperitoneally injected with streptozotocin (50 mg/kg/day, 5 days), following feeding with a high-fat diet containing FO for 24 weeks, with fasting blood glucose levels and glucose tolerance monitored. At the end of the procedure, aortic rings were harvested and evaluated for the contraction and relaxation in response to phenylephrine and acetylcholine respectively. Aortic pathological injuries were assessed by hematoxylin and eosin, and Masson's trichrome staining. Aortic expression of proinflammatory, oxidative stress and profibrotic markers were determined by qRT-PCR and immunohistochemical staining. The diabetic mice developed impaired glucose tolerance, abnormal endothelial dependent aortic contraction and relaxation, thickened tunica media, and increased accumulation of fibrosis in the aortas. These effects were remarkably reversed by FO supplementation. Further investigation revealed that FO inhibited aortic mRNA expression of Tnf-α, Il-6, Il-1β and Vcam-1 as markers for inflammation, Nox1, Nox2, Nox4 and Nos2 as markers for oxidative stress, as well as Acta 2, Col1a1, Col3 and Ccn2 as markers for fibrosis. Moreover, FO decreased the aortic protein expression of TNF-α, 4-HNE and COL1, all of which were increased under the diabetic condition. The present study may provide a molecular basis for the application of FO in prevention of macrovascular complications of DM.
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Long-chain n–3 poly unsaturated fatty acids have anti-inflammatory effects but their effects on serum levels of adhesion molecules are inconsistent and contradictory. In this updated systematic review and meta-analysis, marine sources of omega-3 fatty acids were pooled up to determine the effects of omega-3 supplementation on adhesion molecules. PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases (from inception to April 2023) were searched and all RCTs investigating the effects of marine sources of omega-3, on blood concentrations of adhesion molecules were included and a meta-analysis undertaken. Forty-two RCTs were included involving 3555 participants aged from 18 to 75 years. Meta-analysis of 38 arms from 30 RCTs reporting serum concentrations of vascular cell adhesion molecule-1 (VCAM-1) showed a significant reduction after omega-3 supplementation (WMD: −1.26, 95% CI: −1.88 to −0.64 ng/mL, P < 0.001). Meta-analysis of 40 arms from 30 RCTs reporting serum concentrations of intercellular adhesion molecule-1 (ICAM-1) revealed a reduction following omega-3 supplementation, although it was not significant (WMD: −1.76, 95%CI: −3.68 to 0.16 ng/mL, P = 0.07). Meta-analysis of 27 arms from 21 trials showed no effect on E-selectin (WMD: 0.01, 95%CI: −0.02 to 0.04 ng/mL, P = 0.62). Pooling 15 arms from 11 RCTs showed a marginally significant reducing effect on P-selectin concentrations (WMD: −2.67, 95%CI: −5.53 to 0.19 ng/mL, P = 0.06). A considerable decrease in VCAM concentration was observed after omega-3 supplementation in this meta-analysis with a trend to decreases in both ICAM and P-selectin levels, with effects that may be significant depending on study design, and there was no effect on E-selectin.
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The 2 studies that found statistically significant differences at study endpoints both used combined EPA+DHA supplements and were conducted over 10 and 24 weeks, respectively. Fifteen of the 31 studies included in this review included adiponectin as a primary outcome variable and reported that adiponectin levels in peripheral circulation were higher in the EPA or EPA+DHA supplementation group by study end point [50-54,58,61,64,65,69-72,74,75]. Eight of those studies reported that the between-group differences were statistically significant [50,51,53,61,66,71,74,75].
Increasing evidence suggests that adipokines, leptin and adiponectin, produced and secreted by adipocytes, are involved in regulating systemic inflammation and may be important targets for interventions to reduce the chronic systemic inflammation linked to some conditions common in aging (e.g., atherosclerosis). Lower leptin levels and higher adiponectin levels in peripheral circulation have been associated with less systemic inflammation. While some studies have shown that marine-derived omega-3 fatty acids (eicosapentaenoic acid [EPA] and/or docosahexaenoic acid [DHA]) have effects on leptin and adiponectin in the context of inflammation, the extent of their effects remain unclear. The purpose of this systematic review was to summarize findings from randomized, controlled trials that measured effects of EPA+DHA supplementation on circulating levels of leptin and adiponectin to determine the state of the science. PubMed, CINAHL, Web of Science, Scopus, and Cochrane Trials were searched up to June 2018 for studies meeting inclusion criteria. Thirty-one studies included in this review were conducted in 16 countries. Eighteen studies reported lower leptin and/or higher adiponectin levels with EPA+DHA supplementation versus placebo at study end point (9 reported statistically significant differences), but doses, supplementation duration, and population characteristics varied across studies. In 9 studies reporting significantly lower leptin and/or higher adiponectin levels the EPA+DHA dose was 0.52 to 4.2 g/day for 4 to 24 weeks. Additional studies are warranted which assess dose parameters and patient populations similar to studies reporting significant effects of EPA+DHA on leptin or adiponectin in order to evaluate the extent of reproducibility before recommending EPA+DHA as a therapy to target these adipokines.
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Omega-3 fatty acids (omega-3 FAs) supplementation effects on oxidants and antioxidants are always controversial. Oxidative stress (OS) is one of the major mechanisms that contribute to the pathogenesis of several chronic diseases. The present systematic review and meta-analysis aimed to summarize the finding of randomized clinical trials (RCTs) examining the effects of omega-3 FAs on OS markers. Five databases including PubMed, Embase, Scopus, Web of science, and Cochrane were searched up to May 5th, 2019 with no language restriction. RCTs included if they compared OS indices among subjects who received omega-3 FAs supplements and subjects who supplemented with placebo. To estimate the effects of omega-3 FAs supplementation, standardized mean difference (SMD) with 95% confidence intervals (95% CI) were pooled using random effects model. Of 5,887 publications, 39 trials involving 2,875 participants were included for the meta-analysis. The pooled analysis of data indicated that omega-3 FAs significantly increased serum total antioxidant capacity (TAC) (SMD: 0.48, 95% CI: 0.23, 0.72, P< 0.001; I²= 60%), glutathione peroxidase (GPx) (SMD: 0.73, 95% CI: 0.30, 1.16, P= 0.001; I²= 83%) activity and decreased malondialdehyde (MDA) (SMD= −0.42, 95% CI: −0.62, −0.21; P < 0.001; I²= 74%) compared to the placebo group. However, the effects of omega-3 FAs on nitric oxide (NO) (SMD: −0.17 , 95% CI: −0.77, 0.43, P = 0.57; I²= 91%), reduced glutathione (GSH) (SMD= 0.23, 95% CI= −0.17, 0.64, P= 0.25; I²= 75%), superoxide dismutase (SOD) (0.12 , 95% CI: −0.40, 0.65, P= 0.64; I²= 89%) and catalase (CAT) (0.16, 95% CI: −0.33, 0.65, P= 0.52; I²= 75%,) activities was not significant. Supplementation with omega-3 FAs significantly improves MDA, TAC levels, and GPx activity. Thus, omega-3 FAs can be mentioned as enhancer factors in antioxidant defense against reactive oxygen species (ROS).
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This was a double-blind, placebo-controlled cross-over study with 34 FH patients on statin treatment (mean age 46.6 years). In random order, all individuals were treated for 3 months with high-dose n-3 PUFA (2 g, ×2) and 3 months placebo (olive oil, 2 g ×2), separated by a 3-month washout period. Anthropometric data, blood samples, and PAT were collected at 4 time points.
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Fish oil supplementation improves endothelial function in normoglycemic offspring of patients with type 2 diabetes

Abstract

Objective

Methods and design

Results

Conclusion

Introduction

Section snippets

Subjects

Experimental results

Discussion

Conflict of interest

Acknowledgements

J Am Coll Cardiol

Metabolism

Nutr Metab Cardiovasc Dis

Metabolism

Atherosclerosis

JACC

Clin Nutr

Chem Phys Lipids

Prostaglandins Leukot Essent Fatty Acids

Atherosclerosis

Atherosclerosis

Cross-sectional relations of multiple biomarkers from distinct biological pathways to brachial artery endothelial function

Circulation

Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study

Circulation

Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance

Circulation

Concomitant impairment in endothelial function and neural cardiovascular regulation in offspring of type 2 diabetic subjects

Hypertension

Effects of troglitazone in young first-degree relatives of patients with type 2 diabetes

Diabetes Care

Endothelial function, insulin action and cardiovascular risk factors in young healthy adult offspring of parents with Type 2 diabetes: effect of vitamin E in a randomized double-blind, controlled clinical trial

Diabet Med

Metformin improves endothelial vascular reactivity in first-degree relatives of type 2 diabetic patients with metabolic syndrome and normal glucose tolerance

Diabetes Care