Conclusions This is the most extensive systematic review of trials to date to assess effects of polyunsaturated fats on newly diagnosed diabetes and glucose metabolism, including previously unpublished data following contact with authors. Evidence suggests that increasing omega-3, omega-6, or total PUFA has little or no effect on prevention and treatment of type 2 diabetes mellitus.

Results 83 randomised controlled trials (mainly assessing effects of supplementary long chain omega-3) were included; 10 were at low summary risk of bias. Long chain omega-3 had little or no effect on likelihood of diagnosis of diabetes (relative risk 1.00, 95% confidence interval 0.85 to 1.17; 58 643 participants, 3.7% developed diabetes) or measures of glucose metabolism (HbA 1c mean difference −0.02%, 95% confidence interval −0.07% to 0.04%; plasma glucose 0.04, 0.02 to 0.07, mmol/L; fasting insulin 1.02, −4.34 to 6.37, pmol/L; HOMA-IR 0.06, −0.21 to 0.33). A suggestion of negative outcomes was observed when dose of supplemental long chain omega-3 was above 4.4 g/d. Effects of α-linolenic acid, omega-6, and total PUFA on diagnosis of diabetes were unclear (as the evidence was of very low quality), but little or no effect on measures of glucose metabolism was seen, except that increasing α-linolenic acid may increase fasting insulin (by about 7%). No evidence was found that the omega-3/omega-6 ratio is important for diabetes or glucose metabolism.

Introduction

Type 2 diabetes mellitus is a leading cause of death and increases risks of cardiovascular disease, blindness, kidney failure, and lower limb amputation.1 More than 400 million adults worldwide live with diabetes. This figure is rising,12 causing excess mortality, morbidity, and substantial economic cost. The global annual cost of diabetes is estimated at more than $800bn (£636bn; €709bn) and is increasing.13 Type 2 diabetes mellitus occurs as glycaemic control worsens leading to dyslipidaemia (higher triglycerides and lower concentrations of high density lipoprotein cholesterol) and is due to defects in production and/or action of insulin.45 The global rise in diabetes can be attributed mainly to increased body fatness and inactivity,16 so diet and body weight are key in treating, preventing, and delaying onset of type 2 diabetes mellitus.1

Polyunsaturated fatty acids (PUFA) include omega-3, omega-6, and omega-9 fats. Omega-3 fats include long chain omega-3 fats such as eicosapentaenoic acid and docosahexaenoic acid, commonly found in fish, and α-linolenic acid found in some plant oils (including flaxseed and rapeseed or canola). Many plant oils are rich in omega-6 fats, particularly linoleic acid. The UK government recommends that all adults should consume 6.5% of energy as PUFA and suggests eating a portion of oily fish each week (providing ~0.45 g/d long chain omega-3) but limiting oily fish in pregnancy and lactation owing to potential methylmercury contamination; supplements are not recommended.789 The American Diabetes Association endorses a Mediterranean-style diet high in polyunsaturates, long chain omega-3, and α-linolenic acid without supplements.10 Oily fish intake, but not supplementation, is also recommended in UK patients with type 2 diabetes mellitus, and reduction of total and saturated fat is recommended for prevention of diabetes, replacing saturated with polyunsaturated fats.1011 The American Heart Association recommends supplementation for adults not eating enough oily fish.12 The Global Burden of Disease Study suggests that optimal omega-6 intake is 11% of energy, although global intakes average under 5% of energy intake; optimal intake of long chain omega-3 is 0.25 g/d, and mean global intake is 0.10 g/d.13 Despite the consistency of advice to eat oily fish, oily fish intakes in the UK have been stable for a decade at less than half of recommended levels.1415 US adults’ intakes of long chain omega-3 are higher from dietary supplements (0.72 g/d eicosapentaenoic acid and docosahexaenoic acid) than from foods (0.41 g/d).16

Worries about effects of long chain omega-3 on control of diabetes have long existed, and experimental studies suggest that omega-3 supplementation and diets high in PUFA and omega-3 raise fasting glucose significantly.1718 Methylmercury and polychlorinated biphenyl levels exceeding recommended thresholds have been reported in seafoods and fish oil supplements81920; elevated mercury levels interrupt insulin signalling, raising fasting glucose, in mouse models.21 Body concentrations of organic pollutants are correlated with prevalence of diabetes in the US,22 but other cross sectional studies have suggested either no association with or benefits of eating fish on glycaemic control.2324 Systematic reviews of observational studies have suggested both positive and negative associations with glucose metabolism,25262728 but strong evidence shows that omega-3 supplements reduce raised triglycerides and have little or no effect on body weight.29 Although analysis of Global Burden of Disease data suggests that both long chain omega-3 and omega-6 need to be increased globally, theories suggest that omega-3 and omega-6 fats compete in some metabolic pathways so that the omega-3/omega-6 ratio is more important than absolute intakes of either.30 A Cochrane systematic review assessed effects of omega-3 in people with diabetes, including trials randomising 1075 participants in 23 trials for a mean of nine weeks, finding reductions in triglycerides but no changes in glycated haemoglobin (HbA 1c ), fasting glucose, or insulin.31 A more recent review included 1209 participants with diabetes in 20 randomised controlled trials of at least two weeks’ duration and found little effect apart from an almost statistically significant rise in fasting glucose but little or no effect on HbA 1c .32