Diabetologia

, Volume 39, Issue 4, pp 453–461 | Cite as

Regulation of low-density lipoprotein particle size distribution in NIDDM and coronary disease: importance of serum triglycerides

  • S. LahdenperÄ
  • M. SyvÄnne
  • J. Kahri
  • M. -R. Taskinen
Originals

Summary

An increase of low-density lipoprotein triglycerides (LDL-Tg) was found to be an independent coronary artery disease (CAD) risk factor for non-insulin-dependent diabetic (NIDDM) patients in a recent prospective study. We examined the composition and size of LDL particles in 50 NIDDM men with angiographically verified CAD (NIDDM+ CAD+) and in 50 NIDDM men without CAD (NIDDM+ CAD−) as compared to 50 non-diabetic men with CAD (NIDDM− CAD+) and 31 non-diabetic men without CAD (NIDDM− CAD−). The groups had similar ranges of age and BMI LDL particle size was determined by gradient gel electrophoresis, and LDL was isolated by sequential ultracentrifugation for compositional analyses. Serum Tg was increased in NIDDM patients as compared to non-diabetic subjects (p<0.05), and in patients with CAD as compared to subjects without the disease (p<0.05). LDL cholesterol was lower in NIDDM patients than in non-diabetic subjects (p<0.001). Mean diameter of LDL particles was less than 255 å, but closely comparable in all groups. The presence of NIDDM was associated with increases of Tg and protein but lowering of free cholesterol in LDL (p<0.005 for all). In multivariate regression analyses neither NIDDM nor CAD were associated with LDL particle size, but serum Tg was the major determinant of LDL size in both NIDDM and non-diabetic subjects (p<0.001). When the patients were divided into quartiles according to fasting serum Tg levels, the LDL particle size and free cholesterol content decreased, but Tg and protein contents of LDL particles increased from the lowest to the highest Tg quartile (analysis of variance p<0.001 for all). When the subjects were categorized into two groups according to the median of VLDL-Tg (1.10 mmol/l) LDL size was associated with VLDL-Tg in the high but not in the low VLDL-Tg group. We conclude that in NIDDM patients with or without CAD serum Tg is the major determinant of the properties of LDL particles. The clinical implication is that in NIDDM serum Tg should be as low as possible to prevent atherogenic changes in LDL.

Keywords

Non-insulin-dependent diabetes mellitus coronary artery disease LDL composition small dense LDL electrophoresis 

Abbreviations

NIDDM

Non-insulin-dependent diabetes mellitus

CAD

coronary artery disease

HDL

high-density lipoprotein

LDL

low-density lipoprotein

VLDL

very-low-density lipoprotein

apoB

apolipoprotein B

HL

hepatic lipase

LPL

lipoprotein lipase

CETP

cholesteryl ester transfer protein

PL

phospholipids

ANOVA

analysis of variance

Tg

triglycerides

FC

free cholesterol

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References

  1. 1.
    Kannel WB, McGee DL (1979) Diabetes and cardiovascular disease: the Framingham Study. JAMA 241: 2035–2038PubMedGoogle Scholar
  2. 2.
    Nathan DM (1993) Long-term complications of diabetes mellitus. N Engl J Med 328: 1676–1685CrossRefPubMedGoogle Scholar
  3. 3.
    Wingard DL, Barrett-Connor E, Criqui MH, Suarez L (1983) Clustering of heart disease risk factors in diabetic compared to nondiabetic adults. Am J Epidemiol 117: 19–26PubMedGoogle Scholar
  4. 4.
    PyörÄlÄ K, Laakso M, Uusitupa M (1987) Diabetes and atherosclerosis: an epidemiological view. Diabetes Metab Rev 3: 463–524PubMedGoogle Scholar
  5. 5.
    Stamler J, Vaccaro O, Neaton JD, Wenthworth D (1993) Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the multiple risk factor intervention trial. Diabetes Care 16: 434–444PubMedGoogle Scholar
  6. 6.
    Howard BJ (1987) Lipoprotein metabolism in diabetes mellitus. J Lipid Res 28: 613–628PubMedGoogle Scholar
  7. 7.
    Taskinen M-R (1990) Hyperlipidemia in diabetes. Clin Endocrinol Metab 4: 743–775Google Scholar
  8. 8.
    Taskinen M-R (1992) Quantitative and qualitative lipoprotein abnormalities in diabetes mellitus. Diabetes 41 [Suppl 2]: 12–17Google Scholar
  9. 9.
    Pfeiffer MA, Brunzell JD, Best JD, Judgewitsch RG, Halter JB, Porte D Jr (1983) The response of plasma triglyceride, cholesterol, and lipoprotein lipase to treatment in non-insulin-dependent diabetic subjects without familial hypertriglyceridemia. Diabetes 32: 525–531PubMedGoogle Scholar
  10. 10.
    Fontbonne A, Eschwege E, Cambien F et al. (1989) Hypertriglyceridaemia as a risk factor of coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes. Results from the 11-year follow-up of the Paris Prospective Study. Diabetologia 32: 300–304CrossRefPubMedGoogle Scholar
  11. 11.
    Laakso M, Lehto S, PenttilÄ I, PyörÄlÄ K (1993) Lipids and lipoproteins predicting coronary heart disease mortality and morbidity in patients with non-insulin-dependent diabetes. Circulation 88 [Part 1]: 1421–1430PubMedGoogle Scholar
  12. 12.
    Fisher WJ (1983) Heterogeneity of plasma low density lipoproteins; manifestations of the physiologic phenomenon in man. Metabolism 32: 283–291CrossRefPubMedGoogle Scholar
  13. 13.
    Krauss RM, Burke DJ (1982) Identification of multiple subclasses of plasma low density lipoproteins in normal humans. J Lipid Res 23: 97–104PubMedGoogle Scholar
  14. 14.
    Austin MA, Breslow JL, Hennekens CH, Buring JE, Willett WC, Krauss RM (1988) Low density lipoprotein subclass patterns and risk of myocardial infarction. JAMA 260: 1917–1921PubMedGoogle Scholar
  15. 15.
    Austin MA, King MC, Vranizan KM, Krauss RM (1990) Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation 82: 495–506PubMedGoogle Scholar
  16. 16.
    Campos H, Blijlevens E, McNamara JR et al. (1992) LDL particle size distribution. Results from the Framingham offspring study. Arterioscler Thromb 12: 1410–1419PubMedGoogle Scholar
  17. 17.
    Barrett-Connor E, Grundy SM, Holdbrook MJ (1982) Plasma lipids and diabetes mellitus in an adult community. Am J Epidemiol 115: 657–663PubMedGoogle Scholar
  18. 18.
    Rönnemaa T, Laakso M, Kallio V, PyörÄlÄ K, Marniemi J, Puukka P (1989) Serum lipids, lipoproteins, and apolipoproteins and the excessive occurrence of coronary heart disease in non-insulin-dependent diabetic patients. Am J Epidemiol 130: 632–645PubMedGoogle Scholar
  19. 19.
    Uusitupa MIJ, Niskanen LK, Siitonen O, Voutilainen E, PyörÄlÄ K (1993) Ten-year cardiovasular mortality in relation to risk factor and abnormalities in lipoprotein composition in type 2 (non-insulin-dependent) diabetic and nondiabetic subjects. Diabetologia 36: 1175–1184PubMedGoogle Scholar
  20. 20.
    Tilly-Kiesi M, SyvÄnne M, Kuusi T, LahdenperÄ S, Taskinen M-R (1992) Abnormalities of low-density lipoproteins in normolipidemic type 2 diabetic and non-diabetic patients with coronary heart disease. J Lipid Res 33: 333–342PubMedGoogle Scholar
  21. 21.
    Deckelbaum RJ, Granot E, Oschry Y, Rose L, Eisenberg S (1984) Plasma triglyceride determines structure-composition in low and high density lipoproteins. Arteriosclerosis 4: 225–231PubMedGoogle Scholar
  22. 22.
    Barakat HA, Carpenter JW, McLendon VD et al. (1990) Influence of obesity, impaired glucose tolerance, and NIDDM on LDL structure and composition: possible link between hyperinsulinemia and atherosclerosis. Diabetes 39: 1527–1533PubMedGoogle Scholar
  23. 23.
    Coresh J, Kwiterovich PO, Smith HH, Bachorik PS (1993) Association of plasma triglyceride concentration and LDL particle diameter, density, and chemical composition with premature coronary artery disease in men and women. J Lipid Res 34: 1687–1697PubMedGoogle Scholar
  24. 24.
    McNamara JR, Campos H, Ordovas JM, Peterson J, Wilson PWF, Schaefer EJ (1987) Effect of gender, age, and lipid status on low density lipoprotein subfraction distribution. Results from the Framingham offspring study. Arteriosclerosis 7: 483–490PubMedGoogle Scholar
  25. 25.
    SyvÄnne M, Kahri J, Virtanen KS, Taskinen M-R (1995) High density lipoproteins containing apolipoproteins A-I and A-II (LpA-I∶A-II) as markers of coronary artery disease in men with non-insulin-dependent diabetes mellitus. Circulation (in press)Google Scholar
  26. 26.
    World Health Organization (1980) WHO Expert Committee on Diabetes Mellitus, Second Report. Geneva, World Health Organization, (Techn. Rep. Ser., no. 646)Google Scholar
  27. 27.
    Kupari M, Virtanen KS, Turto H et al. (1992) Exclusion of coronary artery disease by exercise thallium-201 tomography in patients with aortic valve stenosis. Am J Cardiol 70: 635–640CrossRefPubMedGoogle Scholar
  28. 28.
    Havel JR, Eder HA, Bragdon JH (1955) Distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest 34: 1345–1353PubMedGoogle Scholar
  29. 29.
    Taskinen M-R, Kuusi T, Helve E, NikkilÄ E, Yki-JÄrvinen H (1988) Insulin therapy induces antiatherogenic changes of serum lipoproteins in non-insulin-dependent diabetes. Arteriosclerosis 8: 168–177PubMedGoogle Scholar
  30. 30.
    Nichols AV, Krauss RM, Musliner TA (1986) Nondenaturing polyacrylamide gel electrophoresis. In: Segrest JP, Albers JJ (eds). Methods in enzymology: plasma lipoproteins. Vol. 128. Academic Press London, p. 417Google Scholar
  31. 31.
    LahdenperÄ S, Tilly-Kiesi M, Vuorinen-Markkola H, Kuusi T, Taskinen M-R (1993) Effects of gemfibrozil on low-density lipoprotein particle size, density distribution, and composition in patients with type II diabetes. Diabetes Care 16: 584–592PubMedGoogle Scholar
  32. 32.
    Huttunen JK, Ehnholm C, Kinnunen PJ, NikkilÄ EA (1975) An immunochemical method for measurement of two triglyceride lipases in human postheparin plasma. Clin Chim Acta 63: 335–347CrossRefPubMedGoogle Scholar
  33. 33.
    Groener JEM, Pelton RW, Kostner GM (1986) Improved estimation of cholesteryl ester transfer activities. Clin Chem 32: 283–286PubMedGoogle Scholar
  34. 34.
    Kahri J, SyvÄnne M, Taskinen M-R (1994) Plasma cholesteryl ester transfer protein activity in NIDDM patients with and without coronary artery disease. Metabolism 43: 1498–1502CrossRefPubMedGoogle Scholar
  35. 35.
    Kashyap MR, Hynd BA, Robinson K (1980) A rapid and simple method for measurement of total protein in very low density lipoprotein by the Lowry assay. J Lip Res 21: 491–495Google Scholar
  36. 36.
    SyvÄnne M, Ahola M, LahdenperÄ S et al. (1995) High density lipoprotein subfractions in non-insulin-dependent diabetes mellitus and coronary artery disease. J Lip Res 36: 573–582Google Scholar
  37. 37.
    Feingold KR, Grunfeld C, Coerrler W, Krauss RM (1992) LDL subclass phenotypes and triglyceride metabolism in non-insulin-dependent diabetes. Arterioscler Thromb 12: 1496–1502PubMedGoogle Scholar
  38. 38.
    Haffner SM, MykkÄnen L, Stern MP, Paidi M, Howard BV (1994) Greater effect of diabetes on LDL size in women than in men. Diabetes Care 17: 1164–1171PubMedGoogle Scholar
  39. 39.
    Griffin BA, Freeman DJ, Tait GW et al. (1994) Role of plasma triglyceride in the regulation of plasma low density lipoprotein (LDL) subfractions: relative contribution of small, dense LDL to coronary heart risk. Atherosclerosis 106: 241–253PubMedGoogle Scholar
  40. 40.
    Pometta D, James RW (1993) Factors affecting lipoprotein in diabetes. International symposium on the lipid triad (triglycerides, HDL, LDL) and cardiovascular diseases. Milan, Italy July 5–8, 1993 (Abstract)Google Scholar
  41. 41.
    American Diabetes Association (1993) Detection and management of lipid disorders in diabetes. Diabetes Care 16: 828–834Google Scholar
  42. 42.
    NIH Consensus Development Panel (1993) Triglyceride, high-density lipoprotein, and coronary heart disease. JAMA 269: 505–510Google Scholar
  43. 43.
    Manzato E, Zambon S, Zambon A, Cortella A, Sartore G, Grepaldi G (1993) Levels and physiochemical properties of lipoprotein subclasses in moderate hypertriglyceridemia. Clin Chem Acta 219: 57–65CrossRefGoogle Scholar
  44. 44.
    Cohen JC, Grundy SM (1993) Normal postprandial lipemia in men with low plasma HDL concentrations. Arterioscler Thromb 12: 972–975Google Scholar
  45. 45.
    Taskinen M-R, Packard CJ, Shepherd J (1990) Effect of insulin therapy on metabolic fate of apolipoprotein B-containing lipoproteins in NIDDM. Diabetes 39: 1017–1027PubMedGoogle Scholar
  46. 46.
    Packard CJ, Gaw A, Demant T, Shepherd J (1995) Development and application of a multicompartmental model to study very low density lipoprotein subfraction metabolism. J Lipid Res 36: 172–187PubMedGoogle Scholar
  47. 47.
    Nigon F, Lesnik P, Rouis M, Chapman MJ (1991) Discrete subspecies of human low density lipoproteins are heterogeneous in their interaction with the cellular LDL receptor. J Lipid Res 32: 1741–1753PubMedGoogle Scholar
  48. 48.
    Lagrost L, Gambert P, Lallemant C (1994) Combined effects of lipid transfers and lipolysis on gradient gel patterns of human plasma LDL. Arterioscler Thromb 14: 1327–1336PubMedGoogle Scholar
  49. 49.
    Taskinen M-R (1995) Insulin resistance and lipoprotein metabolism. Current Opinion in Lipidology 6: 153–160PubMedGoogle Scholar
  50. 50.
    McKeone BJ, Patsch JR, Pownall HJ (1993) Plasma triglycerides determine low density lipoprotein composition, physical properties, and cell-specific binding in cultured cells. J Clin Invest 91: 1926–1933PubMedGoogle Scholar
  51. 51.
    Chait A, Brazg RL, Tribble DL, Krauss RM (1993) Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B. Am J Med 94: 350–356CrossRefPubMedGoogle Scholar
  52. 52.
    Galeano NF, Milne R, Marcel YL et al. (1994) Apoprotein B structure and receptor recognition of triglyceride-rich low density lipoprotein (LDL) is modified in small LDL but not in triglyceride-rich LDL of normal size. J Biol Chem 269: 511–519PubMedGoogle Scholar
  53. 53.
    Fielding CJ, Reaven GM, Liu G, Fielding PE (1984) Increased free cholesterol in plasma low and very low density lipoproteins in non-insulin-dependent diabetes mellitus: its role in the inhibition of cholesteryl ester transfer. Proc Natl Acad Sci 81: 2512–2516PubMedGoogle Scholar
  54. 54.
    Owens D, Maher V, Collins P, Johnson A, Tomkin GH (1990) Cellular cholesterol regulation — a defect in the type 2 (non-insulin-dependent) diabetic patient in poor metabolic control. Diabetologia 33: 93–99PubMedGoogle Scholar
  55. 55.
    Kuksis A, Myher JJ, Geher K et al. (1982) Decreased plasma phosphatidylcholine/free cholesterol ratio as an indicator of risk for ischemic vascular disease. Arteriosclerosis 2: 296–302PubMedGoogle Scholar
  56. 56.
    Vakakis N, Redgrave TG, Small DM, Castelli WP (1983) Cholesterol content of red blood cells and low density lipoproteins in hypertriglyceridemia. Biochim Biophys Acta 751: 280–285PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • S. LahdenperÄ
    • 1
  • M. SyvÄnne
    • 1
  • J. Kahri
    • 1
  • M. -R. Taskinen
    • 1
  1. 1.Department of MedicineHelsinki University Central HospitalHelsinkiFinland

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