ABSTRACT
Background:
Leptin has been suggested as a possible cause of atherosclerotic disease. The small dense low-density lipoprotein cholesterol (LDL-C) has also been regarded as a new surrogate marker in atherosclerotic disease. The aim of this study was to evaluate the relationship between the leptin concentration and the small dense LDL-C concentration in Korean type 2 diabetic patients.
Methods:
One hundred-ninety one type 2 diabetic patients, who did not use any medication that could affect the concentration of lipid such as statin, fibrate, thiazolidinediones and corticosteroid, were enrolled in this study. We analyzed the relationship between leptin, the small dense LDL-C and the other metabolic parameters.
Results:
The small dense LDL-C concentrations were higher in the group with the highest tertile of the leptin value, both in males and females than those patients in the group with the lowest tertile of the leptin value. The small dense LDL-C concentrations were also higher in the group with the highest tertile of leptin divided by the BMI value both in males and females than those patients in the group with the lowest tertile of the leptin value. The leptin concentration was positively correlated with the small dense LDL-C, total cholesterol, triglyceride, LDL-C, insulin and HOMAIR values after adjusting for age, gender and BMI.
References
1. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 339:229–234. 1998.
2. Abate N. Obesity and cardiovascular disease. Pathogenetic role of the metabolic syndrome and therapeutic implications. Diabetes Complications. 14:154–174. 2000.
3. Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV. Leptin: the tale of an obesity gene. Diabetes. 45:1455–1462. 1996.
4. Chu NF, Spiegelman D, Rifai N, Hotamisligil GS, Rimm EB. Glycemic status and soluble tumor necrosis factor receptor levels in relation to plasma leptin concentrations among normal weight and overweight US men. Int J Obes Relat Metab Disord. 24:1085–1092. 2000.
5. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 395:763–770. 1998.
6. Shek EW, Brands MW, Hall JE. Chronic leptin infusion increases arterial pressure. Hypertension. 31:409–414. 1998.
7. Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI. Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest. 100:270–278. 1997.
8. Konstantinides S, Schafer K, Koschnick S, Loskutoff DJ. Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity. J Clin Invest. 108:1533–1540. 2001.
9. Soderberg S, Ahren B, Jansson JH, Johnson O, Hallmans G, Asplund K, Olsson T. Leptin is associated with increased risk of myocardial infarction. J Intern Med. 246:409–418. 1999.
10. Soderberg S, Ahren B, Stegmayr B, Johnson O, Wiklund PG, Weinehall L, Hallmans G, Olsson T. Leptin is a risk marker for first-ever hemorrhagic stroke in a population-based cohort. Stroke. 30:328–337. 1999.
11. Soderberg S, Stegmayr B, Stenlund H, Sjostrom LG, Agren A, Johansson L, Weinehall L, Olsson T. Leptin, but not adiponectin, predicts stroke in males. J Intern Med. 256:128–136. 2004.
12. Wallace AM, McMahon AD, Packard CJ, Kelly A.
Shepherd J., Gaw A., Sattar N: P. lasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS). Circulation. 104:3052–3056. 2001.
13. Wolk R, Berger P, Lennon RJ, Brilakis ES, Johnson BD, Somers VK. Plasma leptin and prognosis in patients with established coronary atherosclerosis. J Am Coll Cardiol. 44:1819–1824. 2004.
14. J de Graaf, HL Hak-Lemmers, MP Hectors, PN Demacker, JC Hendriks, AF Stalenhoef. Enhanced susceptibility to in vitro oxidation of the dense low density lipoprotein subfraction in healthy subjects. Arterioscler Thromb. 11:298–306. 1991.
15. Teng B, Sniderman AD, Soutar AK, Thompson GR. Metabolic basis of hyperapobetalipoproteinemia. Turnover of apolipoprotein B in low density lipoprotein and its precursors and subfractions compared with normal and familial hypercholesterolemia. J Clin Invest. 77:663–672. 1986.
16. Galeano NF, Al-Haideri M, Keyserman F, Rumsey SC, Deckelbaum RJ. Small dense low density lipoprotein has increased affinity for LDL receptor-independent cell surface binding sites: a potential mechanism for increased atherogenicity. J Lipid Res. 39:1263–1273. 1998.
17. T Björnheden, A Babyi, G Bondjers, O Wiklund. Accumulation of lipoprotein fractions and subfractions in the arterial wall, determined in an in vitro perfusion system. Atherosclerosis. 123:43–56. 1996.
18. Austin MA, Breslow JL, Hennekens CH, Buring JE, Willett WC, Krauss RM. Low density lipoprotein subclass patterns and risk of myocardial infarction. JAMA. 260:1917–1921. 1988.
19. Koba S, Hirano T, Yoshino G, Sakai K, Sakaue T, Adachi M, Katagiri T. Remarkably high prevalence of small dense low-density lipoprotein in Japanese men with coronary artery disease, irrespective of the presence of diabetes. Atheroslcerosis. 160:249–256. 2002.
20. Hirano T, Ito Y, Saegusa H, Yosino G. A novel and simple method for quantification of small dense LDL. J Lipid Res. 44:2193–2220.
21. Capell WH, Zambon A, Austin MA, Brunzell JD, Hokanson JE. Compositional differences of LDL particles in normal subjects with LDL particles in normal subjects with LDL subclass phenotype A and LDL subclass phenotype B. Arteriosler Thromb Vasc Biol. 16:1040–1046. 1996.
22. Griffin BA, Freedman DJ, Tait GW, Thomson J, Caslake MJ, Packard CJ, Shepherd J. Role of plasma triglyceride in the regulation of plasma low density lipoprotein (LDL) subfractions: relative contribution of small, dense LDL to coronary heart disease risk. Atherosclerosis. 106:241–253. 1994.
23. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 334:292–295. 1996.
24. Oda A, Taniguchi T, Yokoyama M. Leptin stimulates rat aortic smooth muscle cell proliferation and migration. Kobe J Med Sci. 47:141–150. 2001.
25. Parhami F, Tintut Y, Ballard A, Fogelman AM, Demer LL. Leptin enhances the calcification of vascular cells: artery wall as a target of leptin. Circ Res. 2001; 88:954–960.
26. Yamagishi SI, Edelstein D, Du XL, Kaneda Y, Guzman M, Brownlee M. Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. J Biol Chem. 276:25096–25100. 2001.
27. Yen TT, Allan JA, Pearson DV, Schinitsky MR. Dissociation of obesity, hypercholesterolemia and diabetes from atherosclerosis in ob/ob mice. Experientia. 33:995–996. 1977.
28. Nishina PM, Naggert JK, Verstuyft J, Paigen B. Atherosclerosis in genetically obese mice: the mutants obese, diabetes, fat, tubby, and lethal yellow. Metabolism. 43:554–558. 1994.
29. Couillard C, Lamarche B, Mauriege P, Cantin B, Dagenais GR, Moorjani S, Lupien PJ, Despres JP. Leptinemia is not a risk factor for ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study. Diabetes Care. 21:782–786. 1998.
30. Piemonti L, Calori G, Mercalli A, Lattuada G, Monti P, Garancini MP, Costantino F, Ruotolo G, Luzi L, Perseghin G. Fasting plasma leptin, tumor necrosis factor-alpha receptor 2, and monocyte chemoattracting protein 1 concentration in a population of glucose-tolerant and glucose-intolerant women: impact on cardiovascular mortality. Diabetes Care. 2003; 26:2883–2889.
31. Hirano T, Ito Y, Koba S, Toyoda M, Ikejiri A, Saegusa H, Yamazaki J, Yoshino G. Clinical significance of small dense low-density lipoprotein cholesterol levels determined by the simple precipitation method. Arterioscler Thromb Vasc Biol. 2004; 24:558–563.
32. Scheffer PG, Bos G, Volwater HG, Dekker JM, Heine RJ, Teerlink T. Associations of LDL size with in vitro oxidizability and plasma levels of in vivo oxidized LDL in type 2 diabetic patients. Diabet Med. 20:563–567.
33. Porreca E, Di Febbo C, Moretta V, Angelini A, Guglielmi MD, Di Nisio M, Cuccurullo F. Circulating leptin is associated with oxidized LDL in postmenopausal women. Atherosclerosis. 175:139–143. 2004.
34. Zimmet PZ, Collins VR. de Courten MP, Hodge AM, Collier GR, Dowse GK, Alberti KG, Tuomilehto J, Hemraj F, Gareeboo H, Chitson P, Fareed D: Is there a relationship between leptin and insulin sensitivity independent of obesity? A population-based study in the Indian Ocean nation of Mauritius. Mauritius NCD Study Group. Int J Obes Relat Metab Disord. 22:171–177. 1998.
Table 1.
Table 2.
Tertile of leptin | 1 | 2 | 3 |
---|---|---|---|
N | 33 | 34 | 34 |
Range of leptin (ng/mL) | 1.12 ~ 2.85 | 2.86 ~ 5.37 | 5.38 ~ 17.68 |
Age (years) | 54.5 ± 10.0 | 54.9 ± 14.1 | 56.4 ± 12.0 |
Duration of diabetes (years) | 6.1 ± 8.1 | 6.0 ± 6.9 | 8.3 ± 8.3 |
BMI (kg/m2) | 23.4 ± 1.9 | 25.1 ± 2.0* | 26.7 ± 2.5*† |
Fasting glucose (mmol/L) | 7.53 ± 2.13 | 8.87 ± 2.93 | 8.80 ± 2.56 |
HbA1c (%) | 7.5 ± 1.7 | 8.1 ± 2.0 | 7.9 ± 1.2 |
Total cholesterol (mmol/L) | 4.64 ± 0.88 | 4.73 ± 0.91 | 5.03 ± 0.65 |
Triglyceride (mmol/L) | 1.25 ± 1.33 | 1.82 ± 1.41* | 2.01 ± 0.97* |
HDL-C (mmol/L) | 1.33 ± 0.33 | 1.14 ± 0.24 | 1.19 ± 0.24 |
LDL-C (mmol/L) | 2.90 ± 0.80 | 3.01 ± 0.91 | 3.26 ± 0.66 |
sd-LDL-C (mmol/L) | 0.67 ± 0.39 | 0.78 ± 0.39 | 0.98 ± 0.51* |
Percentage of sd-LDL-C (%) | 24.1 ± 15.9 | 26.0 ± 12.4 | 30.3 ± 14.8 |
lb-LDL-C (mmol/L) | 2.23 ± 0.81 | 2.23 ± 0.73 | 2.28 ± 0.69 |
Percentage of lb-LDL-C (%) | 75.9 ± 15.9 | 74.0 ± 12.4 | 69.7 ± 14.8 |
Insulin (pmol/L) | 37.1 ± 24.1 | 50.5 ± 25.0* | 74.5 ± 33.5*† |
HOMAIR | 1.69 ± 1.15 | 2.58 ± 1.18* | 4.06 ± 2.70*† |
Table 3.
Tertile of leptin | 1 | 2 | 3 |
---|---|---|---|
N | 29 | 31 | 30 |
Range of leptin (ng/mL) | 4.19 ~ 8.52 | 8.90 ~ 12.86 | 13.13 ~ 37.52 |
Age (years) | 56.7 ± 9.9 | 59.5 ± 9.2 | 62.0 ± 9.4 |
Duration of diabetes (years) | 5.4 ± 5.9 | 5.8 ± 6.4 | 8.4 ± 8.3 |
BMI (kg/m2) | 22.9 ± 2.1 | 25.7 ± 3.0* | 28.1 ± 3.6*† |
Fasting glucose (mmol/L) | 7.30 ± 2.20 | 8.15 ± 1.89 | 7.52 ± 1.74 |
HbA1c (%) | 7.3 ± 1.6 | 7.9 ± 1.8 | 8.2 ± 1.5 |
Total cholesterol (mmol/L) | 4.82 ± 0.69 | 5.43 ± 0.76* | 5.34 ± 0.86* |
Triglyceride (mmol/L) | 1.53 ± 1.05 | 1.78 ± 0.84 | 1.88 ± 1.01 |
HDL-C (mmol/L) | 1.33 ± 0.28 | 1.32 ± 0.23 | 1.26 ± 0.22 |
LDL-C (mmol/L) | 2.98 ± 0.72 | 3.43 ± 0.74 | 3.29 ± 0.73 |
sd-LDL-C (mmol/L) | 0.59 ± 0.33 | 0.88 ± 0.43* | 0.84 ± 0.39* |
Percentage of sd-LDL-C (%) | 19.7 ± 11.1 | 27.0 ± 16.4 | 25.6 ± 10.7 |
lb-LDL-C (mmol/L) | 2.40 ± 0.62 | 2.55 ± 0.80 | 2.44 ± 0.66 |
Percentage of lb-LDL-C (%) | 80.3 ± 11.1 | 73.0 ± 16.4 | 74.4 ± 10.7 |
Insulin (pmol/L) | 51.5 ± 44.0 | 66.5 ± 41.0* | 78.3 ± 38.4* |
HOMAIR | 2.42 ± 2.36 | 3.11 ± 1.93* | 3.77 ± 2.27* |