Association of Plasma Phospholipid n-3 and n-6 Polyunsaturated Fatty Acids with Type 2 Diabetes: The EPIC-InterAct Case-Cohort Study

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Whether and how n-3 and n-6 polyunsaturated fatty acids (PUFAs) are related to type 2 diabetes (T2D) is debated. Objectively measured plasma PUFAs can help to clarify these associations.

Methods and Findings

Plasma phospholipid PUFAs were measured by gas chromatography among 12,132 incident T2D cases and 15,919 subcohort participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study across eight European countries. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox regression and pooled by random-effects meta-analysis. We also systematically reviewed published prospective studies on circulating PUFAs and T2D risk and pooled the quantitative evidence for comparison with results from EPIC-InterAct. In EPIC-InterAct, among long-chain n-3 PUFAs, α-linolenic acid (ALA) was inversely associated with T2D (HR per standard deviation [SD] 0.93; 95% CI 0.88–0.98), but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not significantly associated. Among n-6 PUFAs, linoleic acid (LA) (0.80; 95% CI 0.77–0.83) and eicosadienoic acid (EDA) (0.89; 95% CI 0.85–0.94) were inversely related, and arachidonic acid (AA) was not significantly associated, while significant positive associations were observed with γ-linolenic acid (GLA), dihomo-GLA, docosatetraenoic acid (DTA), and docosapentaenoic acid (n6-DPA), with HRs between 1.13 to 1.46 per SD. These findings from EPIC-InterAct were broadly similar to comparative findings from summary estimates from up to nine studies including between 71 to 2,499 T2D cases. Limitations included potential residual confounding and the inability to distinguish between dietary and metabolic influences on plasma phospholipid PUFAs.

Conclusions

These large-scale findings suggest an important inverse association of circulating plant-origin n-3 PUFA (ALA) but no convincing association of marine-derived n3 PUFAs (EPA and DHA) with T2D. Moreover, they highlight that the most abundant n6-PUFA (LA) is inversely associated with T2D. The detection of associations with previously less well-investigated PUFAs points to the importance of considering individual fatty acids rather than focusing on fatty acid class.

Abstract

Using a large European cohort, Nita Forouhi and colleagues investigate the association between the concentration of polyunsaturated fatty acids measured in plasma and risk of developing type 2 diabetes.

Author Summary

Why Was This Study Done?

Most dietary guidelines recommend the consumption of polyunsaturated fatty acids for cardiovascular health, but it is unclear whether or how n-3 and n-6 types of polyunsaturated fatty acids are related to type 2 diabetes.
Health concerns have been raised previously about a diet high in linoleic acid (n-6 fatty acid), but its association with type 2 diabetes is unclear.
Major limitations in previous studies have included the error-prone subjective assessment of the habitual consumption of polyunsaturated fatty acids when dietary intakes were evaluated and a small number of type 2 diabetes cases ( n = 71 to 673) when objective biomarkers of polyunsaturated fatty acids were measured.

What Did the Researchers Do and Find?

We measured circulating individual polyunsaturated fatty acids in the blood samples of individuals within a large study from across eight countries of Europe among a reference sample of 15,919 individuals as well as 12,132 individuals who subsequently developed diabetes. Individuals were followed up for an average of approximately 10 y.
We investigated the association between individual polyunsaturated fatty acids and the risk of future type 2 diabetes using statistical analyses that accounted for factors that could be potential alternative explanations for any observed associations.
We found that higher levels of blood alpha-linolenic acid, a plant-origin n-3 fatty acid, and n-6 linoleic acid, the most abundant type of polyunsaturated fatty acid, were associated with a lower risk of future type 2 diabetes. In contrast, higher levels of four other minor individual n-6 fatty acids were associated with higher type 2 diabetes risk, while the blood marine-origin n-3 fatty acids were not associated with future diabetes.

What Do These Findings Mean?

Our findings show that it is important to consider individual circulating polyunsaturated fatty acids for association with type 2 diabetes risk, rather than placing emphasis on the class of circulating polyunsaturated fatty acids.
We found that blood n-6 linoleic acid, the most abundant polyunsaturated fatty acid, is inversely associated with type 2 diabetes.
We found no evidence that blood total n-6 polyunsaturated fatty acids may elevate the risk of type 2 diabetes, but several individual minor blood n-6 polyunsaturated fatty acids were associated with increased type 2 diabetes risk, highlighting the importance of polyunsaturated fatty acid metabolism in the development of type 2 diabetes.

Related collections

Most cited references 21

Record: found
Abstract: found
Article: found

Is Open Access

Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis

Christopher E Ramsden, Daisy Zamora, Boonseng Leelarthaepin … (2013)

Objective To evaluate the effectiveness of replacing dietary saturated fat with omega 6 linoleic acid, for the secondary prevention of coronary heart disease and death. Design Evaluation of recovered data from the Sydney Diet Heart Study, a single blinded, parallel group, randomized controlled trial conducted in 1966-73; and an updated meta-analysis including these previously missing data. Setting Ambulatory, coronary care clinic in Sydney, Australia. Participants 458 men aged 30-59 years with a recent coronary event. Interventions Replacement of dietary saturated fats (from animal fats, common margarines, and shortenings) with omega 6 linoleic acid (from safflower oil and safflower oil polyunsaturated margarine). Controls received no specific dietary instruction or study foods. All non-dietary aspects were designed to be equivalent in both groups. Outcome measures All cause mortality (primary outcome), cardiovascular mortality, and mortality from coronary heart disease (secondary outcomes). We used an intention to treat, survival analysis approach to compare mortality outcomes by group. Results The intervention group (n=221) had higher rates of death than controls (n=237) (all cause 17.6% v 11.8%, hazard ratio 1.62 (95% confidence interval 1.00 to 2.64), P=0.05; cardiovascular disease 17.2% v 11.0%, 1.70 (1.03 to 2.80), P=0.04; coronary heart disease 16.3% v 10.1%, 1.74 (1.04 to 2.92), P=0.04). Inclusion of these recovered data in an updated meta-analysis of linoleic acid intervention trials showed non-significant trends toward increased risks of death from coronary heart disease (hazard ratio 1.33 (0.99 to 1.79); P=0.06) and cardiovascular disease (1.27 (0.98 to 1.65); P=0.07). Conclusions Advice to substitute polyunsaturated fats for saturated fats is a key component of worldwide dietary guidelines for coronary heart disease risk reduction. However, clinical benefits of the most abundant polyunsaturated fatty acid, omega 6 linoleic acid, have not been established. In this cohort, substituting dietary linoleic acid in place of saturated fats increased the rates of death from all causes, coronary heart disease, and cardiovascular disease. An updated meta-analysis of linoleic acid intervention trials showed no evidence of cardiovascular benefit. These findings could have important implications for worldwide dietary advice to substitute omega 6 linoleic acid, or polyunsaturated fats in general, for saturated fats. Trial registration Clinical trials NCT01621087.

0 comments Cited 154 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Dietary fat and meat intake in relation to risk of type 2 diabetes in men.

R M van Dam, W Willett, E B Rimm … (2002)

To examine dietary fat and meat intake in relation to risk of type 2 diabetes. We prospectively followed 42,504 male participants of the Health Professionals Follow-Up Study who were aged 40-75 years and free of diagnosed diabetes, cardiovascular disease, and cancer in 1986. Diet was assessed by a validated food frequency questionnaire and updated in 1990 and 1994. During 12 years of follow-up, we ascertained 1,321 incident cases of type 2 diabetes. Intakes of total fat (multivariate RR for extreme quintiles 1.27, CI 1.04-1.55, P for trend=0.02) and saturated fat (1.34, 1.09-1.66, P for trend=0.01) were associated with a higher risk of type 2 diabetes. However, these associations disappeared after additional adjustment for BMI (total fat RR 0.97, CI 0.79-1.18; saturated fat 0.97, 0.79-1.20). Intakes of oleic acid, trans-fat, long-chain n-3 fat, and alpha-linolenic acid were not associated with diabetes risk after multivariate adjustment. Linoleic acid was associated with a lower risk of type 2 diabetes in men or = 5/week vs. <1/month, P for trend <0.0001). Total and saturated fat intake were associated with a higher risk of type 2 diabetes, but these associations were not independent of BMI. Frequent consumption of processed meats may increase risk of type 2 diabetes.

0 comments Cited 146 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Design and cohort description of the InterAct Project: an examination of the interaction of genetic and lifestyle factors on the incidence of type 2 diabetes in the EPIC Study.

C. Langenberg, S. Sharp, N G Forouhi … (2011)

Studying gene-lifestyle interaction may help to identify lifestyle factors that modify genetic susceptibility and uncover genetic loci exerting important subgroup effects. Adequately powered studies with prospective, unbiased, standardised assessment of key behavioural factors for gene-lifestyle studies are lacking. This case-cohort study aims to investigate how genetic and potentially modifiable lifestyle and behavioural factors, particularly diet and physical activity, interact in their influence on the risk of developing type 2 diabetes. Incident cases of type 2 diabetes occurring in European Prospective Investigation into Cancer and Nutrition (EPIC) cohorts between 1991 and 2007 from eight of the ten EPIC countries were ascertained and verified. Prentice-weighted Cox regression and random-effects meta-analyses were used to investigate differences in diabetes incidence by age and sex. A total of 12,403 verified incident cases of type 2 diabetes occurred during 3.99 million person-years of follow-up of 340,234 EPIC participants eligible for InterAct. We defined a centre-stratified subcohort of 16,154 individuals for comparative analyses. Individuals with incident diabetes who were randomly selected into the subcohort (n = 778) were included as cases in the analyses. All prevalent diabetes cases were excluded from the study. InterAct cases were followed-up for an average of 6.9 years; 49.7% were men. Mean baseline age and age at diagnosis were 55.6 and 62.5 years, mean BMI and waist circumference values were 29.4 kg/m(2) and 102.7 cm in men, and 30.1 kg/m(2) and 92.8 cm in women, respectively. Risk of type 2 diabetes increased linearly with age, with an overall HR of 1.56 (95% CI 1.48-1.64) for a 10 year age difference, adjusted for sex. A male excess in the risk of incident diabetes was consistently observed across all countries, with a pooled HR of 1.51 (95% CI 1.39-1.64), adjusted for age. InterAct is a large, well-powered, prospective study that will inform our understanding of the interplay between genes and lifestyle factors on the risk of type 2 diabetes development.

0 comments Cited 104 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Ronald C. W. Ma: Role: Academic Editor

Journal

Journal ID (nlm-ta): PLoS Med

Journal ID (iso-abbrev): PLoS Med

Journal ID (publisher-id): plos

Journal ID (pmc): plosmed

Title: PLoS Medicine

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Print): 1549-1277

ISSN (Electronic): 1549-1676

Publication date (Electronic): 19 July 2016

Publication date Collection: July 2016

Volume: 13

Issue: 7

Electronic Location Identifier: e1002094

Affiliations

[1 ]MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom

[2 ]MRC Human Nutrition Research, Cambridge, UK

[3 ]Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Germany

[4 ]University Medical Center Utrecht, Utrecht, the Netherlands

[5 ]Navarre Public Health Institute (ISPN), Pamplona, Spain

[6 ]CIBER Epidemiología y Salud Pública (CIBERESP), Spain

[7 ]Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain

[8 ]Wageningen University, The Netherlands

[9 ]Inserm, CESP, U1018, Villejuif, France

[10 ]Univ Paris-Sud, UMRS 1018, Villejuif, France

[11 ]Gustave Roussy Institute, Villejuif, France

[12 ]Public Health Division of Gipuzkoa, San Sebastian, Spain

[13 ]Instituto BIO-Donostia, Basque Government, San Sebastian, Spain

[14 ]German Institute of Human Nutrition Potsdam-Rehbruecke, Germany

[15 ]Lund University, Malmö, Sweden

[16 ]Umeå University, Umeå, Sweden

[17 ]Catalan Institute of Oncology (ICO), Barcelona, Spain

[18 ]German Cancer Research Centre (DKFZ), Heidelberg, Germany

[19 ]University of Oxford, Oxford, United Kingdom

[20 ]University of Cambridge, Cambridge, United Kingdom

[21 ]Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark

[22 ]Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark

[23 ]Aalborg University Hospital, Aalborg, Denmark

[24 ]Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

[25 ]Cancer Research and Prevention Institute (ISPO), Florence, Italy

[26 ]Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy

[27 ]Public Health Directorate, Asturias, Spain

[28 ]Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA. Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain

[29 ]Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin and Center for Cancer Prevention (CPO), Turin, Italy

[30 ]Human Genetics Foundation (HuGeF), Turin, Italy

[31 ]International Agency for Research on Cancer, Lyon, France

[32 ]National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands

[33 ]Danish Cancer Society Research Center, Copenhagen, Denmark

[34 ]Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain

[35 ]Cancer Registry and Histopathology Unit, Civic and M.P.Arezzo Hospital, ASP Ragusa, Italy

[36 ]School of Public Health, Imperial College London, London, United Kingdom

Chinese University of Hong Kong, CHINA

Author notes

PWF has received consulting honoraria from Ely Lily & Co and Sanofi Aventis. CL receives a stipend as a specialty consulting editor for PLOS Medicine and serves on the journal's editorial board. NJW served as a guest editor on PLOS Medicine’s Diabetes Prevention Special Issue.

Conceived and designed the experiments: NGF FI SJS AK MBS JZ ZY IS MG JMH JK LYW KS JLG EJMF AA PA HB CD GF PWF CG RK TJK KTK TK LMM PMN KO VP DP SP JRQ MRB OR CS AS NS AMWS AT MJT RT DLvA YTvdS CL ER NJW. Performed the experiments: NGF FI SJS AK MBS JZ ZY IS MG JMH JK LYW KS JLG EJMF AA PA HB CD GF PWF CG RK TJK KTK TK LMM PMN KO VP DP SP JRQ MRB OR CS AS NS AMWS AT MJT RT DLvA YTvdS CL ER NJW. Analyzed the data: SJS FI. Contributed reagents/materials/analysis tools: NGF FI SJS AK MBS JZ ZY IS MG JMH JK LYW KS JLG EJMF AA PA HB CD GF PWF CG RK TJK KTK TK LMM PMN KO VP DP SP JRQ MRB OR CS AS NS AMWS AT MJT RT DLvA YTvdS CL ER NJW. Wrote the first draft of the manuscript: NGF. Contributed to the writing of the manuscript: NGF FI SJS AK MBS JZ ZY IS MG JMH JK CL NJW. Enrolled patients: NGF FI SJS MBS JZ ZY IS MG JMH JK EJMF AA PA HB CD GF PWF CG RK TJK KTK TK LMM PMN KO VP DP SP JRQ MRB OR CS AMWS AT MJT RT DLvA YTvdS CL ER NJW. Agree with the manuscript’s results and conclusions: NGF FI SJS AK MBS JZ ZY IS MG JMH JK LYW KS JLG EJMF AA PA HB CD GF PWF CG RK TJK KTK TK LMM PMN KO VP DP SP JRQ MRB OR CS AS NS AMWS AT MJT RT DLvA YTvdS CL ER NJW. All authors have read, and confirm that they meet, ICMJE criteria for authorship.

* E-mail: Nita.Forouhi@ 123456mrc-epid.cam.ac.uk

Author information

Fumiaki Imamura http://orcid.org/0000-0002-6841-8396

Stephen J. Sharp http://orcid.org/0000-0003-2375-1440

Albert Koulman http://orcid.org/0000-0001-9998-051X

Ivonne Sluijs http://orcid.org/0000-0001-7758-4911

Marcela Guevara http://orcid.org/0000-0001-9242-6364

José María Huerta http://orcid.org/0000-0002-9637-3869

Miguel Rodriguez-Barranco http://orcid.org/0000-0002-9972-9779

Maria-Jose Tormo http://orcid.org/0000-0003-1474-5233

Yvonne T. van der Schouw http://orcid.org/0000-0002-4605-435X

Claudia Langenberg http://orcid.org/0000-0002-5017-7344

Nicholas J. Wareham http://orcid.org/0000-0003-1422-2993

Article

Publisher ID: PMEDICINE-D-16-01429

DOI: 10.1371/journal.pmed.1002094

PMC ID: 4951144

PubMed ID: 27434045

SO-VID: 3e47329c-d528-4189-bf0a-81ab1dd25c47

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 6 May 2016

Date accepted : 16 June 2016

Page count

Figures: 3, Tables: 2, Pages: 17

Funding

Funded by: EU FP6 programme

Award ID: LSHM_CT_2006_037197

Award Recipient :

ORCID: http://orcid.org/0000-0003-1422-2993

Nicholas J. Wareham

Funded by: Medical Research Council Epidemiology Unit

Award ID: MC_UU_12015/5

Award Recipient : Nita G. Forouhi

Funded by: Medical Research Council Human Nutrition Research

Award ID: MC_UP_A090_1006

Award Recipient :

ORCID: http://orcid.org/0000-0001-9998-051X

Albert Koulman

Funded by: Medical Research Council Epidemiology Unit

Award ID: MC_UU_12015/1

Award Recipient :

ORCID: http://orcid.org/0000-0003-1422-2993

Nicholas J. Wareham

Funding for the InterAct project was provided by the EU FP6 programme (grant number LSHM_CT_2006_037197). In addition, InterAct investigators acknowledge funding from the following sources: Medical Research Council Epidemiology Unit MC_UU_12015/1 and MC_UU_12015/5, and Medical Research Council Human Nutrition Research MC_UP_A090_1006 and Cambridge Lipidomics Biomarker Research Initiative G0800783; TJK: Cancer Research UK; JMH and MJT: Health Research Fund of the Spanish Ministry of Health; Murcia Regional Government (N° 6236); MG: Regional Government of Navarre; -IS, DLvdA, AMWS, YTvdS: Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands; Verification of diabetes cases in EPIC-NL was additionally funded by NL Agency grant IGE05012 and an Incentive Grant from the Board of the UMC Utrecht; PWF: Swedish Research Council, Novo Nordisk, Swedish Diabetes Association, Swedish Heart-Lung Foundation; RK: German Cancer Aid, German Ministry of Research (BMBF); KTK: Medical Research Council UK, Cancer Research UK; PMN: Swedish Research Council; KO and AT: Danish Cancer Society; JRQ: Asturias Regional Government; OR: The Västerboten County Council; RT: AIRE-ONLUS Ragusa, AVIS-Ragusa, Sicilian Regional Government; ER: Imperial College Biomedical Research Centre. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Custom metadata

Data Availability EPIC-InterAct Study data cannot be deposited publicly as these collaborative data originate from multiple research institutions across eight European countries with different legal frameworks. The authors confirm that researchers seeking the analysis dataset for this work can submit a data request to the EPIC-InterAct study central contact point by emailing interact@ 123456mrc-epid.cam.ac.uk .

ScienceOpen disciplines: Medicine

Data availability:

ScienceOpen disciplines: Medicine

Comments

Comment on this article

scite_

Cited by 74

See all cited by

- Version 1

Association of Plasma Phospholipid n-3 and n-6 Polyunsaturated Fatty Acids with Type 2 Diabetes: The EPIC-InterAct Case-Cohort Study

Read this article at

Abstract

Background

Methods and Findings

Conclusions

Abstract

Author Summary

Why Was This Study Done?

What Did the Researchers Do and Find?

What Do These Findings Mean?

Related collections

CHAIN Network Collection

Most cited references 21

Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis

Dietary fat and meat intake in relation to risk of type 2 diabetes in men.

Design and cohort description of the InterAct Project: an examination of the interaction of genetic and lifestyle factors on the incidence of type 2 diabetes in the EPIC Study.

Author and article information

Contributors

Journal

Affiliations

Author notes

Author information

Article

History

Page count

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 207

Cited by 74