Clinical ResearchLow density lipoprotein non-esterified fatty acids and lipoprotein lipase in diabetes
Introduction
It has been suggested that raised non-esterified fatty acids (NEFAs) play a key role in the development of insulin resistance and type 2 diabetes [1], [2]. Diabetes is associated with an increase in cardiovascular disease [3] and the concept that NEFAs may be directly related to coronary events [4] has been strengthened by the recent finding that elevated NEFAs were related to sudden death [5]. In clinical practice, however, NEFAs are usually ignored as a risk factor for atherosclerosis and their effect in diabetes on low density lipoprotein (LDL) composition has not been explored. We have previously shown that LDL from normocholesterolaemic diabetic subjects contained an excess of fatty acids as compared to control subjects although there was no significant difference in triglyceride, phospholipid or cholesteryl esters [6]. We suggested that these findings were compatible with a considerable amount of NEFAs being attached to LDL in diabetes. In other studies, we found that LDL from normocholesterolaemic diabetic subjects had an increased susceptibility to oxidation and that LDL oxidisability was related to glycation and to increase in LDL fatty acids [7], [8], [9]. NEFAs are known to be carried not only on albumin but also on other plasma lipoproteins depending on the NEFA concentration in relation to albumin [10]. It is possible that the increase in fatty acids, which we found in LDL, may be free fatty acids attached to the LDL particle, the amount being related to the elevation of plasma free fatty acid commonly found in diabetic subjects. Lipoprotein lipase (LPL) functions to hydrolyse triglyceride from VLDL and chylomicrons and it is normally attached to the vascular endothelium. However, there is also circulating LPL in human plasma, some of which is attached to LDL [11]. It has been shown that LDL-bound LPL acts as an important ligand for the proteoglycans found on the endothelium and collagen surfaces [12] and it therefore seems possible that the atherogenicity of LDL may relate in part to the amount of LPL on the LDL particle. The binding of LPL to LDL is dependent on lipids but not on apoB, the vast majority of LPL being in very loose association and disrupted by high salt concentrations and centrifugal forces [13]. The LPL on the LDL particle is mostly in the inactive monomer form rather than the active dimer form [11] and therefore is inactive in relation to triglyceride hydrolysis. However, its ability to bind lipoproteins to the endothelium may be an important function. LPL has been shown to have a greater effect on binding to proteoglycans when added to oxidised LDL compared to native LDL [14]. Patients with diabetes have LDL which contains more fatty acids and is more easily oxidised [7]. The purpose of this study was to examine the relationship between plasma free fatty acids, LDL composition and lipoprotein lipase attached to LDL in diabetic subjects in an effort to explain the atherogenicity of LDL in diabetes.
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Subjects
Eight type 2 diabetic patients (four male, four female) recruited from the diabetic clinic and eight control subjects of similar age (four male, four female clinical and laboratory personnel) agreed to take part in the study. In acute experiments, six of the control subjects were examined before and 30 min following intravenous heparin (50 IU/kg body weight). Diabetic patients were moderately poorly controlled with HbA1c of 7.8% (normal value 4.6–5.8% DCCT standardised). Patients were treated
Plasma lipids
The diabetic patients were not well controlled with HbA1c of 7.8% (Table 1). Fasting plasma cholesterol, LDL cholesterol and HDL cholesterol were similar in diabetic and control subjects, and plasma triglycerides were higher in the diabetic patients (median 1.6 mmol/l versus 1.1 mmol/l, p < 0.05). Postprandial plasma NEFA were similar in the in the two groups.
LDL composition
LDL composition is shown in Table 2. LDL protein expressed as μmol/ml plasma (molar value in parenthesis) was almost 35% higher in the
Discussion
The delivery of cholesterol to the atherosclerotic plaque by LDL depends, at least in part, on its composition. Modification of LDL by oxidation and glycation results in an atherogenic LDL which is taken up by the scavenger receptor and does not up regulate LDL receptor expression or down regulate cholesterol synthesis, leading to cholesterol accumulation in the artery wall [18]. Oxidation of LDL depends on the polyunsaturated fat content of the LDL [8], [9] and its degree of glycation [19].
Acknowledgements
This study was funded by The Irish Heart Foundation and a grant from Pfizer Pharmaceuticals
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