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Departments of Biochemistry (J.L.S.-Q., S.B., J.O.-L.) and Endocrinology and Nutrition (A.P., A.C., M.R.), Hospital de la Santa Creu i Sant Pau, and Department of Biochemistry and Molecular Biology (J.O.-L.), Universitat Autónoma de Barcelona, Barcelona 08025, Spain
Address correspondence and requests for reprints to: Jordi Ordóñez-Llanos, M.D., Servei de Bioquímica, Hospital de la Santa Creu i Sant Pau, C/. Antoni María Claret 167, Barcelona 08025, Spain. E-mail: 2038{at}hsp santpau.es.
Abstract
The effect of insulin therapy on low-density lipoprotein (LDL) oxidizability, proportion of electronegative LDL [LDL(-)] and LDL composition was studied in 33 type 2 diabetic patients. Before glycemic control improvement, type 2 diabetic subjects presented higher triglyceride and very low-density lipoprotein cholesterol and lower high-density lipoprotein cholesterol than 25 healthy matched subjects. Furthermore, their LDL was more susceptible to oxidation (lag phase 45.9 ± 5.4 min vs. 49.7 ± 7.6 min, P < 0.05), contained a higher proportion of LDL(-) (19.0 ± 8.7% vs. 14.3 ± 5.5%, P < 0.05), and was enriched in triglyceride and depleted in cholesterol and phopholipids. Lipoprotein profile improved after glycemic optimization but failed to change either LDL oxidizability (45.3 ± 6.2 min) or LDL(-) (17.9 ± 8.2%). These data suggest that oxidation rather than nonenzymatic glycosylation could be related to the high LDL(-) found in these patients and disagree with results obtained in a previous study of type 1 diabetic patients. A second study was conducted in 10 type 1 and 10 type 2 diabetic subjects under insulin therapy, and the proportions of glycated LDL (gLDL) and LDL(-) were determined. Basal gLDL (2.8 ± 0.6%) and LDL(-) (20.7 ± 6.1%) decreased in type 1 diabetics after glycemic optimization (1.9 ± 0.6% and 15.4 ± 3.4%, respectively; P < 0.05). In type 2 patients, even though gLDL decreased (from 2.2 ± 0.6% to 1.6 ± 0.6%, P < 0.05) no effect was observed on LDL(-) (from 17.3 ± 2.9% to 16.0 ± 4.3%). We conclude that nonenzymatic glycosylation, which appears as a determinant of the high proportion of LDL(-) in type 1 diabetes, does not play a major role in LDL(-) generation in type 2 diabetes.
COMPLICATIONS DERIVED FROM atherosclerosis are the leading cause of death in diabetic patients. Although both type 1 and type 2 diabetic subjects show abnormalities in lipid and lipoprotein metabolism, diabetes appears as an independent cardiovascular risk factor (1, 2). Optimization of glycemic control usually restores normal lipoprotein concentration, but does not normalize the qualitative characteristics of lipoproteins (3, 4, 5). Growing evidence indicates that modification of low-density lipoprotein (LDL) enhances its atherogenicity (6). Lipoperoxidation is the most extensively studied modification of LDL, but other processes that also increase the negative charge of LDL result in lipoprotein particles with atherogenic properties (7). As a result of hyperglycemia most plasma apolipoproteins from diabetic subjects show nonenzymatic glycosylation that affects their biological function (8). Glycated LDL is catabolized more slowly than normal LDL (9, 10) and is degraded by the scavenger pathway, thereby promoting foam cell formation (11). Several authors have related oxidation to nonenzymatic glycosylation in a process named glycoxidation (12, 13). Both oxidation and glycosylation share an increase in the electronegativity of LDL as a common characteristic (14). Several reports have described the presence in plasma of an electronegative fraction of LDL [LDL(-)] (15, 16, 17) with some atherogenic characteristics such as cytotoxicity (18, 19) and interleukin 8 and monocyte chemoattractant protein-1 release by endothelial cells (20). We previously reported (4) that poorly controlled type 1 diabetic subjects presented an abnormally elevated proportion of LDL(-) that was statistically related to parameters of glycemic control, and diminished after near-normalization of glycemic control by intensive insulin therapy. However, in that study LDL(-) was not associated with LDL susceptibility to oxidation. These data suggested that nonenzymatic glycosylation, but not oxidation, could be related to high LDL(-) proportion in type 1 diabetic patients. Concerning type 2 diabetic patients, several studies report that LDL from these patients is more susceptible to oxidation (21, 22, 23, 24, 25, 26) and contains an increased proportion of LDL(-) (27, 28), but the effect of glycemic optimization on these qualitative modifications of LDL has not been previously studied. The aim of the current work was to study the effect in the improvement of glycemic control by insulin therapy on the qualitative characteristics of LDL obtained from type 2 diabetic patients, including susceptibility to oxidation, LDL(-) proportion, and composition. Discrepancies between current results and those previously obtained with type 1 diabetic patients (4) led us to develop a second study to evaluate the relationship between nonenzymatic glycosylation and LDL(-) by measuring the percentage of glycated LDL (gLDL) and LDL(-) in both type 1 and type 2 patients before and after normalization of glycemic control.
Subjects and Methods
Patients
Study 1. Thirty-three type 2 diabetic patients (19 males and 14 females) were included in this study. They were recruited from the diabetes clinic on the basis of poor glycemic control [glycated hemoglobin (HbA1c) >8%]. Diabetes was defined according to the National Diabetes Data Group criteria (29). Mean age was 59.6 ± 9.7 yr, body mass index (BMI) was 25.9 ± 3.5 kg/m2, and known diabetes duration was 6.1 ± 6.4 yr (range, 0–21). Ten patients (30.3%) had not received any previous treatment, 12 (36.4%) who had been on hypoglycemic oral agents (sulfonylureas) were in secondary failure, and 11 (33.3%) were already on insulin therapy. Five patients had background retinopathy, and two had coronary heart disease. Twenty-five healthy subjects matched for sex, age, and BMI were recruited as a control group (14 males and 11 females; mean age, 61.2 ± 10.2 yr; BMI, 25.5 ± 3.0 kg/m2). None of the patients or controls were taking drugs (other than insulin) or vitamins, or had any disease known to influence lipoprotein metabolism. All patients were included in a conventional insulin therapy program with two injections of intermediate insulin plus regular insulin before breakfast and dinner. Patients were instructed in observing an isocaloric or hypocaloric diet, providing 50–55% carbohydrate and 30–35% fat. All were provided with a specific diabetes education program and were seen in the outpatient unit every 2–4 weeks. Assessment was carried out at baseline and after 3 months of insulin therapy. Data concerning LDL subclass phenotype in these patients have been published previously (3). The study was approved by the Hospital Ethics Committee, and all patients and control subjects gave informed consent.
Study 2. Ten type 2 (4 males and 6 females; mean age, 61.8 ± 9.8 yr; BMI, 25.5 ± 3.9 kg/m2) and 10 type 1 (5 males and 5 females; mean age, 28.1 ± 7.3 yr; BMI, 21.6 ± 3.2 kg/m2) diabetic patients with poor glycemic control (HbA1c >8%) were included in the study. All type 1 diabetics were newly diagnosed patients, and mean diabetes duration of type 2 diabetic patients was 10.7 ± 3.0 yr. Type 1 diabetic patients were treated with multiple insulin doses, and type 2 diabetic subjects were treated with two insulin doses. Two control groups of 10 subjects matched for BMI and age for both type 1 and type 2 patients were also studied.
Biochemical analysis
Glucose was determined by a standardized automatized method adapted to a Hitachi 747 autoanalyzer (Roche, Bassel, Switzerland). Fructosamine was measured by a colorimetric method adapted to a Cobas Integra autoanalyzer (Roche) using glycated albumin as a standard (reference interval, 205–285 µmol/L). Lipoproteins were quantified by the combined ultracentrifugation-precipitation method, as recommended by the Lipid Research Clinics Program (30). Cholesterol and triglyceride concentrations were determined from plasma and lipoprotein fractions by enzymatic methods (Roche) in a Hitachi 911 autoanalyzer (Roche).
LDL isolation
Plasma was obtained from venous blood drawn into EDTA-containing Vacutainer tubes by centrifugation at 1500 x g for 15 min at 4 C and stored at -80 C until processed (before 20 weeks). Native LDL (density range, 1020–1050 g/L) was isolated by sequential ultracentrifugation (31). Ultracentrifugation was performed at 4 C with KBr solutions containing 1 mmol/L EDTA to avoid oxidative modifications of lipoproteins. LDL composition was calculated from plasma-isolated LDL. Total and free cholesterol, triglyceride (Roche), phospholipid (Wako, Neuss, Germany), and protein (Bio-Rad Laboratories, Inc., Munchen, Germany) contents were expressed as the percentage of total LDL mass.
LDL susceptibility to oxidation
LDL was dialyzed against phosphate-buffered saline (pH 7.4) by
gel filtration chromatography in a G-25 Sephadex column (Pharmacia,
Uppsala, Sweden), diluted to a concentration of 50 mg of
protein/L, and incubated with 2.5 µmol/L CuSO4
at 30 C. Conjugated dienes formation of an aliquot of LDL was
continuously monitoried at 234 nm for 3 h as described (4, 32). Lag phase time (expressed as minutes) and dienes rate
formation (maximal curve slope expressed as 
abs/min) were measured.
Pre- and posttreatment samples corresponding to the same diabetic
patient and a sample from a control subject were assayed in the same
batch.
Chromatographic assays
HbA1c. HbA1c was routinely determined by standarized anion- exchange high-performance liquid chromatography (Hi-AutoA1c HA-8121 Analyzer; Dic-Kioto, Kioto, Japan). The reference range in our laboratory is 3.7–5.5%.
LDL(-). LDL(-) was isolated from total LDL by anion exchange chromatography (Mono Q 5/5) in a Fast Protein Liquid Chromatography system (Pharmacia) as described (4, 33). Briefly, LDL was dialyzed against degassed buffer A [1 mmol/L EDTA and 10 mmol/L Tris-HCl buffer (pH 7.4)] by gel filtration chromatography (G25 M, PD10 column; Pharmacia). Buffer A and buffer B [1 mol/L NaCl, 1 mmol/L EDTA, and 10 mmol/L Tris-HCl buffer (pH 7.4)] were used as eluents of the chromatography. LDL was eluted at 1 mL/min for 10 min with a linear gradient of 0–0.1 mol/L NaCl, followed by a multistep gradient procedure: 10–20 min 0.2 mol/L NaCl, 20–28 min 0.3 mol/L NaCl, 28–35 min 1 mol/L NaCl, and 35–40 min 0 mol/L NaCl. Two LDL forms, a major form named LDL(+) (elution at 0.2 mol/L NaCl) and a minor form named LDL(-) (elution at 0.3 mol/L NaCl), differing in their electrical charge, were identified at 280 nm and their relative proportion quantified by peak integration.
gLDL. gLDL percentage was evaluated by affinity chromatography using phenyl-boronate agarose (Glycogel II; Pierce Chemical Co., Rockford, IL), as described (34). Three milliliters of this resin were degassed by sonication and packed in an HR5/5 column (Pharmacia) at a flow of 1 mL/min with a P-1 peristaltic pump (Pharmacia), with care taken to avoid the formation of air bubbles. The column was connected to the Fast Protein Liquid Chromatography system and equilibrated with 25 mL degassed binding buffer [250 mmol/L ammonium acetate and 50 mmol/L MgCl2 (pH 8.05)], as indicated by the manufacturer. An aliquot of LDL was dialyzed against binding buffer by gel filtration chromatography (G25M; Pharmacia), and 0.5 mL LDL (200–400 µg apoB) were injected into the column. Nonbound fraction (non-gLDL) was eluted with 10 mL binding buffer at a flow of 1 mL/min. Bound fraction (gLDL) was eluted with 10 mL elution buffer [100 mmol/L Tris and 200 mmol/L sorbitol (pH 8.5)], and the column was reequilibrated with 10 mL binding buffer. Two peaks of LDL, corresponding to gLDL and non-gLDL, were detected at 280 nm and their corresponding peak areas were integrated. Lyophilized preparations from nondiabetic and diabetic whole blood were used as normal and abnormal controls (Glycosylated hemoglobin; Pierce Chemical Co.). The percentage of glycated hemoglobin was 4.5 ± 0.4% for the normal control and 10.8 ± 0.9% for the abnormal control, with an interday imprecision of 8.9 and 8.3%, respectively (measured for 10 consecutive days).
Statistical methods
Statistical differences between both periods of glycemic control were assessed by nonparametric Wilcoxon t test or by paired Student’s t test when appropriate. Mann-Whitney U test or unpaired Sudent’s t test were used to compare diabetic patients with the control group. An association between variables was tested by Spearman ordinal correlation (r). In all cases, a P less than 0.05 was considered statistically significant. All data are expressed as mean ± SD.
Results
Study 1
Anthropometric characteristics, glycemic control parameters, and
lipid profile of control and type 2 diabetic subjects are shown in
Table 1
. Lipid profile at baseline was
characteristic of poorly controlled type 2 diabetic patients with low
concentration of high-density lipoprotein (HDL) cholesterol and high
concentrations of triglycerides and very low- density lipoprotein
(VLDL) cholesterol. After 3 months of insulin therapy, glycemic control
was optimized in all patients and resulted in improvement in lipid
profile with a significant increase in HDL cholesterol and decreases in
triglyceride and VLDL cholesterol. However, VLDL cholesterol and
triglyceride remained higher than those of controls (Table 1).
|
).
|
).
Concerning LDL composition, glycemic optimization increased the content
of cholesterol and phospholipids and diminished that of triglyceride,
but statistical differences remained for cholesterol and triglyceride
content compared with that of control subjects. Neither LDL susceptibility to oxidation nor the proportion of LDL(-) showed statistical associations with the other parameters of lipid profile, LDL composition or glycemic control in type 2 diabetic patients. In the control group, LDL(-) correlated positively with total cholesterol (r = 0.516, P = 0.008) and LDL cholesterol (r = 0.471, P = 0.017).
Study 2
The lack of change in LDL(-) proportion after glycemic optimization observed in study 1 were in contrast with results reported by our group in type 1 diabetic subjects (4), in which LDL(-) decreased after insulin therapy. Study 2 was developed to determine the possible relationship between the abnormally high proportion of LDL(-) previously found in both type 1 (4) and now in type 2 diabetic subjects and the enhanced nonenzymatic glycosylation characteristic of chronic hyperglycemia. For this purpose, gLDL and LDL(-) were measured in two groups of type 1 and type 2 diabetic patients before and after glycemic optimization.
Anthropometric characteristics, glycemic control parameters, and lipid
profile of diabetic subjects included in this study and their
respective control groups are shown in Table 3. Significant decreases in glucose,
fructosamine, and HbA1c were achieved after insulin therapy. In
addition, VLDL cholesterol decreased and HDL cholesterol increased
after treatment in both diabetic groups.
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Type 2 diabetic patients with poor glycemic control also presented
increased proportion of gLDL (2.2 ± 1.7%) and LDL(-) (17.5
± 1.8%) compared with their control group (gLDL, 1.3 ± 0.3%;
LDL(-), 14.7 ± 1.8%; P < 0.05 and
P = 0.063, respectively). However, although the
proportion of gLDL decreased (1.6 ± 0.6%, P < 0.05),
the percentage of LDL(-) remained unchanged after glycemic
optimization (16.0 ± 4.3%, P = 0.139). Individual
changes in gLDL and LDL(-) in type 1 and type 2 diabetic patients are
shown in Fig. 1.
|
. Glycemic control
improved LDL composition in type 1 patients but did not modify LDL
composition in type 2 diabetic subjects.
|
Qualitative characteristics of LDL, such as the surface electric charge, are involved in the atherogenic properties of this lipoprotein. Modifications that increase LDL electronegativity in vitro, such as oxidation or nonenzymatic glycosylation, have been demonstrated to impair LDL binding to the hepatic receptor and contribute to the accumulation of cholesterol in macrophages (6, 7, 11, 13). The proportion of LDL(-), an electronegatively charged LDL subfraction present in blood, correlates with plasma cholesterol (19, 35) and is abnormally increased in some groups of subjects at high cardiovascular risk, such as familial hypercholesterolemic (36) and type 1 diabetic patients (4). It has been suggested that this subfraction could be generated by lipid peroxidation (15, 18, 37, 38, 39, 40, 41, 42), but also by nonenzymatic glycation or abnormal content of apoproteins or sialic acid (4, 17, 19, 33). The relationship between LDL susceptibility to oxidation and atherosclerotic risk has been established by a large number of studies (43, 44, 45, 46, 47, 48). However, the role of LDL(-) in the development of atherosclerosis is not so evident, and related data are insufficient and nonconclusive. Nevertheless, LDL(-) has cytotoxic properties for cultured endothelial cells (18, 19) and induces the release of chemotactic molecules such as interleukin 8 and monocyte chemoattractant protein-1 (20). Thus, the increased cardiovascular risk observed in the diabetic population, only partially explained by quantitative lipid profile abnormalities, could also be related to the presence of a high proportion of LDL(-) (4).
In the current work, we demonstrate a higher proportion of LDL(-) and increased LDL susceptibility to oxidation in poorly controlled type 2 diabetic patients compared with controls. This could be related to the demonstrated higher prevalence of subjects with LDL subclasses phenotype AB or B in the diabetic group at baseline (51%) compared with controls (28%) (3), because small dense LDL particles predominant in these phenotypes are more susceptible to oxidation (49). In this respect, a trend toward shorter lag phase was observed in patients with phenotype AB or B (44.2 ± 5.2 min) compared with those with phenotype A (47.8 ± 5.6 min, P = 0.086). However, despite normalization of the prevalence of LDL subclass phenotype after glycemic optimization (30% of phenotype B or AB) (3), both LDL susceptibility to oxidation and LDL(-) remained increased compared with the control group. Thus, these parameters could be related not only to LDL size but also to compositional abnormalities or other modifications not evaluated in this work. The increased LDL susceptibility to oxidation in type 2 diabetic patients has been previously found in other studies (21, 22, 23, 24, 25, 26) and two recent works described a concomitant increase in electronegative LDL proportion (27, 28). However, to our knowledge, this is the first study to evaluate the effect of glycemic control improvement on these parameters in type 2 diabetes. Our results indicate that the proportion of LDL(-) and LDL susceptibility to oxidation are not related to the degree of glycemic control in type 2 diabetic patients, as suggested by the lack of correlation between LDL(-) and LDL susceptibility to oxidation with glycemic control, and the lack of effect of glycemic optimization after insulin therapy on these parameters.
These findings do not concur with those we obtained previously in type 1 diabetic subjects (4). In that work we reported that poorly controlled type 1 diabetic patients presented a high proportion of LDL(-) (with no increased LDL susceptibility to oxidation), which was positively associated with parameters of blood glucose control. Optimization of glycemic control significantly decreased the percentage of LDL(-), and statistical associations disappeared. Furthermore, no relationship between LDL(-) and LDL susceptibility to oxidation was found, and no changes in LDL susceptibility to oxidation were observed after improvement of glycemic control. As nonenzymatic glycosylation is able to increase the negative charge of LDL (14), we suggested that the main proportion of LDL(-) in type 1 diabetes could be due to this process. Thus, a second study was conducted to gain insight into the relation between LDL(-) and nonenzymatic glycosylation, and to clarify the discrepancies observed between current results in type 2 diabetic patients and those previously obtained in type 1 diabetic patients. For this purpose, the percentages of LDL(-) and gLDL were measured in 10 type 1 and 10 type 2 diabetic patients before and after glycemic control optimization with insulin therapy.
Current results in type 1 diabetic subjects concur with those previously obtained and are in accordance with the possibility that LDL(-) could be related to processes of nonenzymatic glycosylation, since LDL(-) and gLDL proportions decreased after the optimization of glycemic control. In contrast, nonenzymatic glycosylation does not seem to be the major cause of the presence of high LDL(-) proportion in type 2 diabetes because LDL(-) did not change despite the optimization of glycemic control and the decrease in gLDL proportion. Because lipoperoxidation increase the negative charge of LDL, and LDL susceptibility to oxidation was increased compared with controls and was not modified by optimization of glycemic control, we suggest that lipoperoxidation could play an important role in the generation of LDL(-) in type 2 diabetes. In turn, a high proportion of LDL(-) could contribute to the enhanced LDL susceptibility to oxidation. In agreement with this assumption, other authors previously described that the higher the proportion of LDL(-), the higher the susceptibility of total LDL to oxidation (40).
Differential characteristics of type 1 vs. type 2 diabetic patients, which support an important role of lipoperoxidation in the generation of LDL(-), are age, duration of diabetes, and the possibility of underlying atherosclerosis. In this respect, numerous studies that report enhanced plasma lipoperoxidation in diabetes indicate that it may result not from hyperglycemia but from underlying atherosclerosis (13, 50, 51). Thus, elevated levels of lipid peroxides may be a consequence rather than a cause of diabetic vascular complications. Although only 7 of 33 type 2 diabetic patients had chronic diabetic complications (5 background retinopathy and 2 coronary heart disease), the possibility of underlying vascular complications that could contribute to increased LDL susceptibility to oxidation and to the generation of LDL(-) in this group of patients cannot be ruled out. By contrast, all the type 1 diabetic subjects studied were young newly diagnosed patients who presumably had not developed vascular complications. Oxidation is not likely to play a significant role in the generation of LDL(-) in these group of patients since LDL susceptibility to oxidation is not increased in short-term type 1 diabetes (4, 52, 53, 54, 55). Conversely, increased glycation, which is present from the onset of the disease, could be responsible for the increment in LDL(-) proportion in type 1 diabetic subjects. However, differences between the percentages of LDL(-) and gLDL, the lack of statistical correlation between them and the absence of total normalization of LDL(-) after the optimization of glycemic control suggest that other secondary mechanisms unrelated to nonenzymatic glycosylation may also be involved.
In summary, LDL from poorly controlled type 2 diabetic patients is more susceptible to oxidation and contains a higher proportion of LDL(-) than that of healthy subjects. Optimization of glycemic control is not able to modify these qualitative characteristics of LDL. Thus, insulin therapy seems to be a proper approach to decreasing LDL(-) in type 1, but not in type 2, diabetes. Current data suggest that different mechanisms may be involved in the increased production of LDL(-) in both groups of patients and, in consequence, the atherogenic characteristics of this electronegative lipoprotein may differ between both types of diabetes. More detailed studies are required to characterize LDL(-) in both types of diabetes.
Acknowledgments
Editorial assistance was provided by Christine O’Hara.
Footnotes
1 Partially financed by Grants SAF98-0125 from the Ministerio de
Educación y Ciencia and Telemarató TV3 Cardiovascular
Diseases 1999 (to J.O.-L.), FISS 95/1552 from Fondo de Investigaciones
Sanitarias (to A.P.), and Fournier Laboratories-Sociedad Española
de Arteriosclerosis 1997 (to J.L.S.-Q.). A.C. (1994 FI/942102) and S.B.
(1997 FI/00781) are recipients of predoctoral fellowships from the
CIRIT/Direcció General de Recerca de la Generalitat de
Catalunya. 
Received October 3, 2000.
Revised February 26, 2001.
Accepted March 6, 2001.
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