Research Article| Volume 146, ISSUE 2, P361-367, October 1999

Long-term effects of fish oil on lipoprotein subfractions and low density lipoprotein size in non-insulin-dependent diabetic patients with hypertriglyceridemia


      The effects of fish oil on lipoprotein subfractions and low density lipoprotein (LDL) size in non-insulin-dependent diabetes mellitus (NIDDM) patients with hypertriglyceridemia are unknown. To elucidate this, 16 NIDDM hypertriglyceridemic patients (plasma triglyceride 2.25–5.65 mmol/l, plasma cholesterol ≤7.75 mmol/l) were randomly assigned to a 6-month period with either moderate amounts of fish oil (n=8) or placebo (n=8) after 4 weeks of wash-out and 3 weeks of run-in. Diet and hypoglycemic treatment were unchanged throughout the experiment. LDL size were evaluated at baseline and after 6 months. Three VLDL and LDL subfractions were measured at the end of the two periods. The total lipid concentration of all very low density lipoprotein (VLDL) subfractions was lower at the end of fish oil treatment compared with placebo (large VLDL 124.3±19.7 mg/dl vs 156.7±45.5 mg/dl; intermediate VLDL 88.5±9.5 mg/dl vs 113.9±23.2 mg/dl; small VLDL 105.9±9.7 mg/dl vs 128.9±40.7 mg/dl) (mean±SEM), although the difference was not statistically significant. Moreover, at the end of the two treatments, the percentage distribution of VLDL subfractions was very similar (large 37.5±3.3% vs 37.6±2.6%, intermediate 27.6±0.9% vs 31.0±2.4%; small 34.9±3.7% vs 31.4±2.1%). Concerning LDL, no significant change in LDL size was observed after the two treatments (255.4±2.2 Å vs 254.2±1.7 Å, fish oil; 253.7±2.0 Å vs 253.3±1.7 Å, placebo). LDL subfraction distribution was also very similar (large 17±3% vs 17±2%; intermediate 62±3% vs 65±3%; small 21±3% vs 18±2%), at the end of the two periods, confirming the lack of effects on LDL size. In conclusion, our study indicates that in NIDDM patients with hypertriglyceridemia, fish oil does not induce any improvement in LDL distribution and LDL size despite its positive effects on plasma triglycerides.


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        • Austin M.A
        • King M.-C
        • Vranizan K.M
        • Krauss R.M
        Atherogenic lipoprotein phenotype: a proposed genetic marker for coronary heart disease risk.
        Circulation. 1990; 82: 495-506
        • Austin M.A
        • Krauss R.M
        LDL density and atherosclerosis.
        J Am Med Assoc. 1995; 273: 115
        • Stampfer M.J
        • Krauss R.M
        • Ma J
        • Blanche P.J
        • Holl L.G
        • Sacks F.M
        • Hennekens C.H
        A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction.
        J Am Med Assoc. 1996; 276: 882-888
        • Gardner C.D
        • Fortmann S.P
        • Krauss R.M
        Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women.
        J Am Med Assoc. 1996; 276: 875-881
        • Coresh J
        • Kwiterovich P.O
        Small, dense low-density lipoprotein particles and coronary heart disease risk. A clear association with uncertain implications.
        J Am Med Assoc. 1996; 276: 914-915
        • Mack W.J
        • Krauss R.M
        • Hodis H.N
        Lipoprotein subclasses in the Monitored Atherosclerosis Regression Study (MARS).
        Arterioscler Thromb Vasc Biol. 1996; 16: 697-704
        • Lahdenperä S
        • Syvanne M
        • Kahri J
        • Taskinen M.R
        Regulation of low density lipoprotein particle size distribution in NIDDM and coronary disease: importance of serum triglycerides.
        Diabetologia. 1996; 39: 453-461
        • Siegle R.D
        • Cupples A
        • Shaefer E.J
        • Wilson P.W.F
        Lipoproteins, apolipoproteins, and low density lipoprotein size among diabetics in the Framingham Offspring Study.
        Metabolism. 1996; 45: 1267-1272
        • Singh A.T.K
        • Rainwater D.L
        • Haffner S.M
        • Vandeberg J.L
        • Shelledy W.R
        • Moore Jr., P.H
        • Dyer T.D
        Effect of diabetes on lipoprotein size.
        Arterioscler Thromb Vasc Biol. 1995; 15: 1805-1811
        • Harris W.S
        Dietary fish oil and blood lipids.
        Curr Opin Lipidol. 1996; 7: 3-7
        • Malasanos T.H
        • Stacpoole P.W
        Biological effects of ω-3 fatty acids in diabetes mellitus.
        Diab Care. 1991; 14: 1160-1179
        • Annuzzi G
        • Rivellese A
        • Capaldo B
        • Di Marino L
        • Iovine C
        • Marotta C
        • Riccardi G
        A controlled study on the effects of ω-3 fatty acids on lipid and glucose metabolism in non-insulin-dependent diabetic patients.
        Atherosclerosis. 1991; 87: 65-73
        • Rivellese A.A
        • Maffettone A
        • Iovine C
        • Di Marino L
        • Annuzzi G
        • Mancini M
        • Riccardi G
        Long-term effects of fish oil on insulin resistance and plasma lipoproteins in NIDDM patients with hypertriglyceridemia.
        Diab Care. 1996; 19: 1207-1213
        • Tan C.E
        • Forster L
        • Caslake M.J
        • Bedford D
        • Watson T.D.G
        • McConnell M
        • Packard C.J
        • Shepherd J
        Relations between plasma lipids and postheparin plasma lipases and VLDL and LDL subfraction patterns in normolipidemic men and women.
        Atherioscler Thromb Vasc Biol. 1995; 15: 1839-1848
        • Superko H.R
        • Krauss R.M
        Differential effects of nicotinic acid in subjects with different LDL subclass patterns.
        Atherosclerosis. 1992; 95: 69-76
      1. WHO Expert Committee on Diabetes Mellitus: Second report. Geneva: World Health Organization, 1980:7–14 (Tech Rep Ser, no. 646).

        • Sirtori C.R
        • Paoletti R
        • Mancini M
        • Crepaldi G
        • Manzato E
        • Rivellese A
        • Pamparana F
        • Stragliotto E
        • Italian Fish oil Multicenter Study
        ω-3 Fatty acids do not lead to an increased diabetic risk in patients with hyperlipidemia and abnormal glucose tolerance.
        Am J Clin Nutr. 1997; 65: 1874-1881
        • Hatch F.T
        • Lees R.S
        Practical methods for plasma lipoprotein analysis.
        in: Paoletti R Kritchevsky D Advances in Lipid Research. Academic Press, London1968: 1-68
        • Redgrave F.T
        • Carlson L.A
        Changes in plasma very low density and low density lipoprotein content, composition and size after a fatty meal in normo and hypertriglyceridemic men.
        J Lipid Res. 1979; 20: 217-229
        • Patti L
        • Romano G
        • Di Marino L
        • Annuzzi G
        • Mancini M
        • Riccardi G
        • Rivellese A.A
        Abnormal distribution of VLDL subfractions in Type 1 (insulin dependent) diabetic patients: could plasma lipase activities play a role?.
        Diabetologia. 1993; 36: 155-160
        • Griffin B.A
        • Caslake M.J
        • Yip B
        • Tait G.W
        • Packard C.J
        • Shepherd J
        Low density lipoprotein subfractions.
        Atherosclerosis. 1990; 83: 59-67
        • Tilly-Kiesi M
        • Quiping Z
        • Ehnholm S
        • Kahri J
        • Lahdenperä S
        • Ehnholm C
        • Taskinen M.R
        Apo A-Ihelsinki (Lys107®O) associated with reduced HDL cholesterol and Lp A-I:AII deficiency.
        Arterioscl Thromb Vasc Biol. 1995; 15: 1294-1306
        • Yamone K
        • Kataoka S
        • Le N.-A
        • Paidi M
        • Howard W.J
        • Hannah J.S
        • Howard B.V
        Binding affinity and particle size of LDL in subjects with moderate hypercholesterolemia: relationship with in vivo LDL metabolism.
        J Lipid Res. 1996; 37: 1646-1654
        • McNamara J.R
        • Campos H
        • Ordovas J.M
        • Wilson P.W.F
        • Schaefer E.J
        Effect of gender, age, and lipid status on low density lipoprotein subfraction distribution: results of the Framingham offsprig study.
        Arterioscler Thromb. 1987; 7: 483-490
        • Austin M.A
        • Breslow J.L
        • Hennekens C.H
        • Buring J.E
        • Willet W.C
        • Krauss R.M
        Low-density lipoprotein subclass pattern and risk of myocardial infarction.
        J Am Med Assoc. 1988; 260: 1917-1921
        • Staehler F
        • Gruber W
        • Stinshoff K
        • Roeschlau P
        Eine praktischgerechte enzymatische Cholesterin-Bestimmung.
        Med Lab. 1977; 30: 29-30
        • Seidel J
        • Schlumberger H
        • Klose S
        • Ziegenhorm J
        • Wahlefeld A.W
        Improved reagent for enzymatic determination of serum cholesterol.
        J Clin Chem Clin Biochem. 1981; 19: 838-839
        • Wahlefeld A.W
        Triglycerides determination after enzymatic hydrolysis.
        in: Bergmeyer H.U Methods of enzymatic analysis. 2nd ed. Academic Press, New York1974: 1831-1874
        • Takaiama M
        • Itoh S
        • Nagasaki T
        • Tanimizu I
        A new enzymatic method for determination of serum choline containing phospholipids.
        Clin Chim Acta. 1977; 79: 93-98
        • Grafnetter D
        World Heath Organization (WHO) coordinated quality control in the lipid laboratory.
        Giorn Arterioscler. 1977; 2: 113-128
        • Nilsson-Ehle P
        • Ekman R
        Rapid, simple and specific assays for lipoprotein lipase and hepatic lipase.
        Artery. 1977; 3: 194-209
        • Snedecor G.W
        • Cochran W.G
        Statistical methods. 7th ed. The Iowa State University Press, Ames1980
        • Harris W.S
        • Connor W.E
        • Illingworth D.R
        • Rothrock D.W
        • Foster D.M
        Effects of fish oil on VLDL triglyceride kinetics in humans.
        J Lipid Res. 1990; 31: 1549-1558
        • Inagaki M
        • Harris W.S
        Changes in lipoprotein composition in hypertriglyceridemic patients taking cholesterol-free fish oil supplements.
        Atherosclerosis. 1990; 82: 237-246
        • Gardner C.D
        • Fortmann S.P
        • Krauss R.M
        Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women.
        J Am Med Assoc. 1996; 276: 875-881
        • Reaven G.M
        • Chen Y.D.I
        • Jeppesen J
        • Maheux P
        • Krauss R.M
        Insulin resistance and hyperinsulinemia in individuals with small, dense, low density lipoprotein particles.
        J Clin Invest. 1993; 92: 141-146
        • Watson T.D.G
        • Caslake M.J
        • Freeman D.J
        • Griffin B.A
        • Hinnie J
        • Packard C.J
        • Shepherd J
        Determinants of LDL subfraction distribution and concentrations in young normolipdemic subjects.
        Arterioscler Thromb. 1994; 14: 902-910
        • Abbey M
        • Clifton P
        • Kestin M
        • Belling B
        • Nestel P
        Effect of fish oil on lipoproteins, lecithin:cholesterol acyltransferase, and lipid transfer protein activity in humans.
        Arteriosclerosis. 1990; 10: 85-94
        • Suzukawa M
        • Abbey M
        • Howe P.R.C
        • Nestel P.J
        Effects of fish oil fatty acids on low density lipoprotein size, oxidability, and uptake by macrophages.
        J Lipid Res. 1995; 36: 473-484
        • Franceschini G
        • Lovati M.R
        • Manzoni C
        • Michelagnoli S
        • Pazzucconi F
        • Gianfranceschi G
        • Vecchio G
        • Sirtori C.R
        Effect of gemfibrozil treatment in hypercholesterolemia on low density lipoprotein (LDL) subclass distribution and LDL-cell interaction.
        Atherosclerosis. 1995; 114: 61-71
        • Lahdenperä S
        • Tilly-Kiesi M
        • Vuorinen-Markkola H
        • Kuusi T
        • Taskinen M.R
        Effects of gemfibrozil on low-density lipoprotein particle size, density distribution, and composition in patients with type II diabetes.
        Diab Care. 1993; 16: 584-590
        • Nikkilä E.A
        • Ylikahri R
        • Huttunen J.K
        Gemfibrozil: effect on serum lipids, lipoproteins, postheparin plasma lipase activities and glucose tolerance in primary hypertriglyceridemia.
        Proc R Soc Med. 1976; 69: 58-63
        • Kesäniemi Y.A
        • Grundy S.M
        Influence of gemfibrozil and clofibrate on metabolism of cholesterol and triglycerides in man.
        J Am Med Assoc. 1984; 251: 2241-2246
        • Selby J.V
        • Austin M.A
        • Newman B
        • Zhang D
        • Quesenberry C.P
        • Mayer E.J
        • Krauss R.M
        LDL subclass phenotypes and the insulin resistance syndrome in women.
        Circulation. 1993; 85: 381-387
        • Bagdade J.D
        • Ritter M
        • Subbaiah P.V
        Marine lipids normalize cholesteryl ester transfer in IDDM.
        Diabetologia. 1996; 39: 487-491