RESUMEN
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.
Asunto(s)
Glucemia/análisis , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 2/sangre , Lipoproteínas LDL/sangre , Adulto , Anciano , HDL-Colesterol/sangre , VLDL-Colesterol/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Electroquímica , Femenino , Hemoglobina Glucada/análisis , Glicosilación , Humanos , Insulina/uso terapéutico , Peroxidación de Lípido , Lipoproteínas LDL/química , Masculino , Persona de Mediana Edad , Oxidación-Reducción , Triglicéridos/sangreRESUMEN
BACKGROUND: We have previously reported the finding of an acute increment in the susceptibility of low-density lipoprotein (LDL) to oxidation and in the proportion of electronegative LDL [LDL(-)] after intense exercise. We have now studied the effect of oral supplementation with 1 g ascorbic acid, immediately before a 4-h athletic race, on the susceptibility of LDL to oxidation, the proportion of LDL(-), and the alpha-tocopherol and lipid peroxides content in LDL, in order to inhibit such deleterious changes, and to confirm the oxidative nature of modifications of LDL induced by exercise. METHODS: We studied seven highly trained runners who received a supplement of 1 g ascorbic acid and a control group of seven who did not receive the supplement. The susceptibility of LDL to oxidation was assessed by measurement of conjugated dienes after CuSO4-induced oxidation, the proportion of LDL(-) was determined by anion exchange chromatography, alpha-tocopherol was quantified by reverse-phase high performance liquid chromatography, and lipid peroxides were measured by the thiobarbituric acid-reactive substances (TBARS) method. RESULTS: After exercise, in the control group there was an increase in both the susceptibility of LDL to oxidation (change in lag phase from 51.4 +/- 4.7 min to 47.0 +/- 4.6 min, P < 0.05) and the proportion of LDL(-) (from 11.1 +/- 1.4% to 13.0 +/- 2.2%, P < 0.05), but these did not occur in the ascorbic acid group (change in lag phase from 49.7 +/- 2.3 min to 50.4 +/- 4.2 min, and in LDL(-) from 9.7 +/- 1.7% to 10.1 +/- 1.7%). No significant changes in the absolute amount of LDL alpha-tocopherol were observed after exercise (ascorbic acid group: 6.65 +/- 0.94 mol/mol apoB before the race, 7.13 +/- 0.88 mol/mol apoB after the race; control group: 7.34 +/-0.69 mol/mol apoB before the race, 7.06 +/- 0.69 mol/mol apoB after the race), but significant differences were found when increments or decrements of alpha-tocopherol were tested (alpha-tocopherol increased 9.9 +/- 11.5% in the ascorbic acid group, and decreased 0.6 +/- 7.3% in the control group; P < 0.018). TBARS did not change after exercise. CONCLUSIONS: We conclude that 1 g ascorbic acid inhibits the increase in LDL susceptibility to oxidation after exercise, preventing this acute pro-atherogenic effect. In addition, the observation that LDL(-) enhancement is prevented by ascorbic acid supports the hypothesis that at least some of the circulating LDL(-) originates from oxidative processes.
Asunto(s)
Ácido Ascórbico/farmacología , Ejercicio Físico , Lipoproteínas LDL/metabolismo , Adulto , Cromatografía Líquida de Alta Presión , Electroquímica , Humanos , Lipoproteínas LDL/química , Masculino , Oxidación-Reducción , Carrera , Sustancias Reactivas al Ácido Tiobarbitúrico/análisis , Vitamina E/análisisRESUMEN
Insulin Lispro (IL) is a short-acting insulin analog that better reproduces the physiological postprandial insulin profile. The aim of this study was to compare the effects of intensive insulin therapy on lipid metabolism using preprandial IL and regular insulin (RI) in 10 insulin-dependent diabetes mellitus (IDDM) subjects. The mean hemoglobin A1c (HbA1c) at baseline was 7.13% +/- 1.2% and did not change after both treatments. In IDDM patients, total cholesterol and triglyceride levels appeared lower after RI than after IL. The low-density lipoprotein (LDL) to high-density lipoprotein (HDL) ratio significantly decreased only after RI (baseline, 2.01 +/- 0.6; IL, 1.88 +/- 0.6; RI, 1.71 +/- 0.5, P < .05). Although no very-low-density lipoprotein (VLDL) composition abnormalities were observed at baseline, the protein content was lower (P < .05) after IL (8.13% +/- 2.93%) than after RI (11.93% +/- 3.41%). Intermediate-density lipoprotein (IDL) protein depletion at baseline (6.14% +/- 6.84%) was normalized after both treatments (IL, 11.09% +/- 12.14%; RI, 10.38% +/- 16.68%, P < .05). LDL, HDL, HDL2, and HDL3 composition abnormalities were similar after both treatments and did not normalize. IDDM and control subjects showed similar LDL subfraction distribution at baseline and after both treatments. Two-hour postprandial VLDL composition alterations, although improved after RI, completely normalized after IL (P < .05). Lipoprotein lipase (LPL) and cholesteryl ester transfer protein (CETP) activities were similar to the control group and did not change after both treatments. Hepatic lipase (HL) activity was lower in diabetic patients (39.6 +/- 35.2 v 87.0 +/- 27.1 U/L, P < .01) and remained lower after both treatments. In conclusion, in IDDM patients, IL (injected immediately before the meal) may offer small different effects on lipoprotein metabolism versus RI (injected 30 minutes before the meal) that, taken together, do not seem relevant.
Asunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/análogos & derivados , Insulina/uso terapéutico , Lípidos/sangre , Adulto , Estudios Cruzados , Diabetes Mellitus Tipo 1/sangre , Ayuno/sangre , Femenino , Heparina/farmacología , Humanos , Insulina Lispro , Lipólisis/efectos de los fármacos , Lipoproteínas VLDL/sangre , Masculino , Periodo PosprandialRESUMEN
Small dense LDL particles (B phenotype) are considered to be more atherogenic than large buoyant LDL particles. The influence of glycemic control on LDL particle size and density is still under debate. The aim of this study was to determine LDL subfraction phenotype in both IDDM and NIDDM patients in poor glycemic control compared with that of respective matched control groups. In addition, we evaluated the effect of a 3-month period of optimized glycemic control on this parameter. Thirty-seven IDDM patients and 33 NIDDM patients, together with two respective age-, sex-, and BMI-matched control groups were studied. Non-A phenotype prevalence in IDDM patients before (19%) and after blood glucose optimization (11%) was similar to that of their control group (12%). However, NIDDM patients displayed a higher proportion of the non-A phenotype (51%) than did the control group (28%), but it became closer (30%, P < 0.05) after glycemic control improved. All subjects with non-A phenotype that changed to A phenotype showed triglyceride levels below 1.63 mmol/l and a greater decrease in HbA1c than did subjects whose phenotype did not change (4.9 +/- 1.5 vs. 3.1 +/- 1.4%, P < 0.05). A higher proportion of small dense LDL was observed in NIDDM women than in nondiabetic women (LDL5 10.0 +/- 4.8 vs. 6.3 +/- 1.5%, LDL6 6.1 +/- 2.2 vs. 4.2 +/- 0.8%, P < 0.05) during both stages of glycemic control, but no differences were observed between NIDDM and nondiabetic men. In conclusion, these findings provide new evidence for the relevance of near-normal glycemic control in the prevention of macrovascular disease and could contribute to an explanation of the loss of protection for cardiovascular disease in diabetic women.
Asunto(s)
Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 2/sangre , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Lipoproteínas LDL/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Glucemia/análisis , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/fisiopatología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Humanos , Metabolismo de los Lípidos , Lípidos/sangre , Lipoproteínas LDL/efectos de los fármacos , Masculino , Persona de Mediana EdadRESUMEN
We evaluated the effect of improving glycaemic control with intensive insulin therapy on LDL susceptibility to oxidation, electronegative LDL proportion, and LDL subfraction phenotype in a group of 25 patients with short-duration insulin-dependent diabetes mellitus (IDDM); 25 matched healthy control subjects were also studied. LDL susceptibility to oxidation was measured by continuous monitoring of conjugated diene formation. Electronegative LDL was isolated by anion exchange chromatography, and quantified as percentage of total LDL. Six LDL subfractions were isolated by density gradient ultracentrifugation and phenotype A or B classified as the quotient (LDL1-LDL3)/(LDL4-LDL6). Compared to the control group, IDDM subjects with poor glycaemic control showed higher electronegative LDL (19.03 +/- 10.09 vs 9.59 +/- 2.98%, p < 0.001), similar LDL subfraction phenotype and lower susceptibility to oxidation (lag phase 45.6 +/- 8.8 vs 41.2 +/- 4.7 min, p < 0.05). After three months of intensive insulin therapy, HbA1c decreased from 10.88 +/- 2.43 to 5.69 +/- 1.54% (p < 0.001), and electronegative LDL to 13.84 +/- 5.15% (p < 0.05). No changes in LDL susceptibility to oxidation or LDL subfraction phenotype were observed. Electronegative LDL appeared significantly correlated to HbA1c and fructosamine (p < 0.01 and p < 0.001) only in poorly controlled IDDM patients. These findings suggest that high electronegative LDL in IDDM subjects is related to the degree of glycaemic control, and could therefore be due to LDL glycation rather than to LDL oxidation or changes in LDL subfraction phenotype.