The dyslipidemia of type 2 diabetes includes the accumulation of small dense LDL particles in plasma that have an increased propensity to glycation and oxidation and may contribute to the endothelial dysfunction in type 2 diabetic patients. We recently reported that both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the two major dietary long-chain n-3 fatty acids, significantly reduced triglycerides and increased HDL2 cholesterol without changing total, LDL, or HDL cholesterol in a group of type 2 diabetic subjects (1). We now report additional data on the differential effects of EPA and DHA on LDL particle size in the same subjects.

Nonsmoking treated hypertensive diabetic men and postmenopausal women, aged 40–75 years, were stratified by sex, age, and BMI and randomized to receive 4 g/day purified EPA, DHA, or olive oil (placebo) for 6 weeks in a double-blinded trial. LDL particle diameter was determined by gradient gel electrophoresis (2).

At baseline there were no significant differences among the olive oil, EPA, and DHA groups in plasma LDL cholesterol level and LDL particle size (25.69 ± 0.13 nm, 26.0 ± 0.16 nm, and 25.74 ± 0.16 nm, respectively). Relative to placebo, LDL particle size was decreased by 0.12 ± 0.10 nm (P = 0.49) with EPA and increased by 0.26 ± 0.10 nm (P = 0.02) with DHA after adjusting for multiple comparisons (Bonferroni).

These data support our previous study in overweight hypercholesterolemic subjects, in whom LDL particle size increased after supplementation with DHA but not EPA (2). While the increase in LDL particle size with DHA supplementation seen in our present study appears relatively small, a significant difference in size of 1.02 nm distinguished between middle-aged healthy men with no risk factors and men with the metabolic syndrome (3). The differential effects on LDL particle size after EPA and DHA cannot be explained by the reduction in triglycerides alone, since both EPA and DHA significantly decreased serum triglycerides by a similar extent relative to placebo (19 and 15%, respectively) (1). Additionally, the association between the change in LDL size and triglycerides was only weak (r = −0.30, P = 0.04).

Supplementation with purified DHA increases LDL particle size, reduces serum triglycerides, and increases HDL2 cholesterol (1), as well as improves vascular function (4) and blood pressure (5). Therefore, for subjects with type 2 diabetes, DHA may have more therapeutic value than EPA as a food additive, but longer-term prospective studies are needed to address this issue.

1
Woodman RJ, Mori TA, Burke V, Puddey IB, Watts GF, Beilin LJ: Effects of purified eicosapentaenoic acid and docosahexaenoic acid on glycemic control, blood pressure and serum lipids in treated-hypertensive type 2 diabetic patients.
Am J Clin Nutr
76
:
1007
–1015, 2002
2
Mori TA, Burke V, Puddey IB, Watts GF, O’Neal DN, Best JD, Beilin LJ: Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men.
Am J Clin Nut
71
:
1085
–1094,
2000
3
Hulthe J, Bokemark L, Wikstrand J, Fagerberg B: The metabolic syndrome, LDL particle size, and atherosclerosis: the Atherosclerosis and Insulin Resistance (AIR) study.
Arterioscler Thromb Vasc Biol
20
:
2140
–2147,
2000
4
Mori TA, Watts GF, Burke V, Hilme E, Puddey IB, Beilin LJ: Differential effects of eicosapentaenoic acid and docosahexaenoic acid on vascular reactivity of the forearm microcirculation in hyperlipidemic, overweight men.
Circulation
102
:
1264
–1269,
2000
5
Mori TA, Bao DQ, Burke V, Puddey IB, Beilin LJ: Docosahexaenoic acid but not eicosapentaenoic acid lowers ambulatory blood pressure and heart rate in humans.
Hypertension
34
:
253
–260,
1999

Address correspondence to Richard Woodman, Department of Medicine, University of Western Australia, P.O. Box x2213, Perth, WA, Australia 6847. E-mail: rwoodman@cyllene.uwa.edu.au.