Omega-3, omega-6, and total dietary polyunsaturated fat for prevention and treatment of type 2 diabetes mellitus: systematic review and meta-analysis of randomised controlled trialsBMJ 2019; 366 doi: https://doi.org/10.1136/bmj.l4697 (Published 21 August 2019) Cite this as: BMJ 2019;366:l4697
All rapid responses
Reply to Dr Henderson and Professor Sheriff: Omega-3, omega-6, and total dietary polyunsaturated fat for prevention and treatment of type 2 diabetes mellitus: systematic review and meta-analysis of randomised controlled trials
Dear Dr Henderson and Professor Sheriff,
Thank you for your responses to our systematic review. You both mention mechanisms which would be expected to lead to increased polyunsaturated fat intake being harmful to diabetic control. “Excessive free fatty acid flux from adipose tissue followed by upregulation of oxidation of polyunsaturated fats” and “increased generation of free radicals” both suggest that higher intakes of polyunsaturated fats would lead to higher levels of oxidation products, exacerbating insulin resistance, damage pancreatic beta-cells and aggravate inflammation. These mechanisms sit alongside experimental studies suggesting that increasing PUFA and omega-3 raise fasting glucose significantly, and worries about harmful effects of pollutants in fish oils.1-3
Despite these suggestions there is little evidence of such harm when increasing long-chain omega-3 fats in this large set of long-term randomised trials, except at very high intakes.4 Increasing alpha-linolenic acid (ALA) also appears to have little or no effect across most outcomes. Evidence of effects of omega-6 and total polyunsaturated fats is more limited but where data exist again they suggest little or no effect. This confirms Dr Henderson’s suggestion that the polyunsaturated content of the diet is of less importance than other factors such as weight loss, or that changes of polyunsaturated intake within the normal dietary range are insufficient to cause problems. It also suggests that the dietary intakes of participants in these trials are consistently sufficient in antioxidants to prevent harm from additional polyunsaturated fats.
Alongside our systematic review others have systematically reviewed the relationships between diabetes risk and glucose metabolism and total fat intake5, carbohydrate intake6 and non-dietary weight loss7 (to reference a few) so we did not currently feel the need to reassess these relationships.
We confirm that there is a large and consistent body of research suggesting that increasing omega-3 and total polyunsaturated fats have little or no effect on prevention or treatment of type 2 diabetes.
Yours sincerely, Lee Hooper, Tracey Brown, Julii Brainard, Asmaa Abdelhamid, Xia Wang and Fujian Song.
1. Glauber H, Wallace P, Griver K, et al. Adverse Metabolic Effect of Omega-3 Fatty Acids in Non-Insulin-Dependent Diabetes Mellitus. Ann Intern Med 1988;108(5):663-68. doi: 10.7326/0003-4819-108-5-663
2. Vessby B, Karlstrom B, Boberg M, et al. Polyunsaturated fatty acids may impair blood glucose control in Type 2 diabetic patients. Diabet Med 1992;9(2):126-33.
3. Lee D-H, Lee I-K, Song K, et al. A Strong Dose-Response Relation Between Serum Concentrations of Persistent Organic Pollutants and Diabetes. Results from the National Health and Examination Survey 1999–2002 2006;29(7):1638-44. doi: 10.2337/dc06-0543
4. Brown TJ, Brainard J, Song F, et al. Omega-3, omega-6, and total dietary polyunsaturated fat for prevention and treatment of type 2 diabetes mellitus: systematic review and meta-analysis of randomised controlled trials. Br Med J 2019;366:l4697. doi: DOI: 10.1136/bmj.l4697
5. Schwab U, Lauritzen L, Tholstrup T, et al. Effect of the amount and type of dietary fat on cardiometabolic risk factors and risk of developing type 2 diabetes, cardiovascular diseases, and cancer: a systematic review. Food Nutr Res 2014;58(1):25145. doi: 10.3402/fnr.v58.25145
6. Snorgaard O, Poulsen GM, Andersen HK, et al. Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes. BMJ Open Diabetes Research & Care 2017;5(1):e000354. doi: 10.1136/bmjdrc-2016-000354
7. Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis York (UK): Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK78198/, 2009.
Competing interests: No competing interests
Type 2 diabetes is a disease of fat accumulation in the liver and pancreas and excessive FFA flux from insulin-resistant adipose tissue. This state saturates mitochondrial beta-oxidation of fatty acids and up-regulates microsomal oxidation of polyunsaturated fatty acids, which forms excessive levels of 4-HNE, 9-ONE and other oxidative stressors capable of exacerbating insulin resistance and damaging pancreatic beta-cells.[2, 3, 4]
This stress can only be relieved by calorie restriction or carbohydrate restriction, which may be combined with exercise, sufficient to increase mitochondrial beta-oxidation of fatty acids and decrease intrahepatic and intrapancreatic fat[1, 5]. In such a state 4-HNE, 9-ONE and other peroxides will be drawn into mitochondria and beta-oxidised and the levels normalized .
When this happens the PUFA content of the diet is of less importance - NAFLD and T2D have been both reversed and prevented using carbohydrate-restricted diets both high in PUFA (15% in the study of Browning), or relatively limited in PUFA (only that found in whole food proteins and some olive oil in the study of Unwin et al.).[7, 8, 9]
I suggest these authors look next at data from trials where total fat rather than PUFA is increased and carbohydrate restricted to a level consistent with increased beta-oxidation, as might be inferred from the phenomenon of weight loss, improved waist-to-hip ratio, or improved fasting TG/HDL ratio in such a trial.
 Taylor R. Banting Memorial lecture 2012: reversing the twin cycles of type 2 diabetes. Diabet Med. 2013;30(3):267–275. doi:10.1111/dme.12039
 Nicolas J. Pillon, Marine L. Croze, Roxane E. Vella, Laurent Soulère, Michel Lagarde, Christophe O. Soulage, The Lipid Peroxidation By-Product 4-Hydroxy-2-Nonenal (4-HNE) Induces Insulin Resistance in Skeletal Muscle through Both Carbonyl and Oxidative Stress, Endocrinology, Volume 153, Issue 5, 1 May 2012, Pages 2099–2111, https://doi.org/10.1210/en.2011-1957
 Heathcote J. Weighty issues in hepatitis C. Gut. 2002;51(1):7-8.
 Sasson S. Nutrient overload, lipid peroxidation and pancreatic beta cell function. Free Radic Biol Med. 2017 Oct;111:102-109. doi: 10.1016/j.freeradbiomed.2016.09.003. Epub 2016 Sep 4.
 Gepner Y, Shelef I, Schwarzfuchs D et al. Effect of Distinct Lifestyle Interventions on Mobilization of Fat Storage Pools: CENTRAL Magnetic Resonance Imaging Randomized Controlled Trial. Circulation. 2018 Mar 13;137(11):1143-1157. doi: 10.1161/CIRCULATIONAHA.117.030501. Epub 2017 Nov 15.
 Li Q, Tomcik K, Zhang S, Puchowicz MA, Zhang G-F. Dietary-regulation of catabolic disposal of 4-hydroxynonenal analogs in rat liver. Free radical biology & medicine. 2012;52(6):1043-1053. doi:10.1016/j.freeradbiomed.2011.12.022
 Browning JD, Baker JA, Rogers T et al. Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction. Am J Clin Nutr. 2011 May; 93(5): 1048–1052.
 Maekawa S, Kawahara T, Nomura R, et al. Retrospective study on the efficacy of a low-carbohydrate diet for impaired glucose tolerance. Diabetes Metab Syndr Obes. 2014;7:195–201. Published 2014 Jun 13. doi:10.2147/DMSO.S62681
[9} Unwin DJ, Cuthbertson DJ, Feinman R, Sprung VS. A pilot study to explore the role of a low-carbohydrate intervention to improve GGT levels and HbA1c. Diabesity in Practice. 2015;4:102–8.
Competing interests: I work for PreKure, a health coach certification service which supplies courses including training in the use of carbohydrate restricted diets and fasting in diabetes.
Re: Omega-3, omega-6, and total dietary polyunsaturated fat for prevention and treatment of type 2 diabetes mellitus: systematic review and meta-analysis of randomised controlled trials
• Type 2 Diabetes Melltius (T2DM) is a dysfunctional metabolic state with lower insulin effect with abnormal influence of counter regulatory hormones on the metabolism of the individual. Impaired insulin secretion and sensitivity in type 2 diabetes includes oxidative stress, endoplasmic reticulum stress, amyloid deposition in the pancreas, ectopic lipid deposition in muscle, liver and pancreas, and lipotoxicity and glucotoxicity. The cumulative effects of these stressors make T2DM an inflammatory state.
• The inclusion of a diet rich in poly unsaturated fatty acids (PUFA) whether omega 3 or omega 6 fatty acids may lead to increased generation of free radicals that may aggravate the inflammatory state of T2DM. The additional provision of antioxidants may be required in a diet rich in PUFA.
• Therefore studies replete with data regarding Omega 3 and omega 6 fatty acids on the health of diabetic patients need to be considered holistically.
Competing interests: No competing interests