Lipoprotein patterns in diet,sulphonylurea, and insulin treated diabetics

Summary In order to study the lipoprotein pattern in diabetes mellitus, plasma lipoproteins were isolated by rate zonal centrifugation in 12 control subjects (median fasting blood glucose level: 80 mg/dl (range: 74–86)), 14 diabetic patients treated by diet alone 104 mg/dl (76–153), 27 patients treated by diet plus insulin (180 mg/dl (106–404)), and 32 patients treated by diet plus sulphonylurea [178 mg/dl (103–361)]. No significant differences of median relative body weight existed between the four groups. Neither the diabetic group on diet alone nor the insulin-treated group differed significantly from control subjects with respect to lipid and lipoprotein concentrations. Diabetics treated with diet plus sulphonylurea, however, differed significantly from the control group with regard to the following parameters (median and range); plasma triglycerides (210 [75–620) mg/dl; p<0.01)] and intermediate density lipoproteins (65 (10–338) mg/dl; p<0.05)) were higher; low density lipoproteins (236 (82–418) mg/ dl; p<0.05)) and high density lipoproteins₂ (HDL₂) [51 (12–121) mg/dl; p<0.01)] concentrations were lower. When data from all 85 studied individuals were analysed together, significant positive correlations were observed between fasting blood glucose and plasma triglyceride concentration (r = 0.28, p<0.01), and between fasting blood glucose and plasma very low density lipoproteins (VLDL) (r = 0.23, p<0.05). A negative correlation was found between blood glucose and plasma HDL₂ (r = -0.29, p<0.01). In addition, VLDL correlated negatively with HDL₂ (r = -0.89, p<0.001) but not with plasma HDL₃ concentration. It is concluded that the deranged lipoprotein metabolism in diabetes mellitus may be better controlled by insulin than by sulphonylureas.     

High density and low density lipoprotein subfractions in survivors of myocardial infarction and in control subjects

The major lipoprotein classes (very low, low and high density lipoproteins, VLDL, LDL and HDL) and three lipoprotein subfractions (HDL₂, HDL₃ and LDL₂) of 31 male survivors of myocardial infarction (MI) have been compared with those of 24 ostensibly normal subjects. The two groups had similar ages, relative weights, smoking and dietary habits, and physical activities. The MI survivors had significantly higher concentrations of total and VLDL-triglyceride and total and LDL-cholesterol than the control subjects. The differences in HDL-cholesterol, and total apolipoproteins A-1 and B were of borderline significance. HDL₂ was significantly lower and LDL₂ was higher in the MI survivors. There was no difference in HDL₃. The differences in lipoprotein subfractions could be ascribed to differences in cholesterol, phospholipid and proteins, but not in triglyceride. The data suggest that the minor HDL₂ subfraction shows a closer association with established coronary heart disease than does total HDL-cholesterol. The increased LDL-cholesterol concentration in the MI survivors can be ascribed at least partly to an increase in the major subfraction, LDL₂.     

Plasma lipoproteins and apolipoproteins in insulin-dependent and young non-insulin-dependent Arab women

Summary Plasma lipids, lipoproteins and apolipoproteins (apo) were analysed in 30 young Arab IDDM and 50 young insulin-requiring NIDDM women. The mean age of IDDM and NIDDM groups was 20.2 and 34.5 years, and mean duration of diabetes was 5.7 and 4.6 years, respectively. Two groups of 40 and 60 healthy women (matched for age and BMI) provided corresponding control groups. In comparison with control subjects, diabetics showed marked increases in the following parameters: total cholesterol (TC), low density lipoprotein (LDL) cholesterol, total triglycerides (TG), very low density lipoprotein (VLDL) triglycerides, phospholipids, apoB, LDL apoB, glucose and glycosylated hemoglobin (HbA_1c) as well as the ratios of total cholesterol/high density lipoprotein (HDL) cholesterol, LDL-cholesterol/HDL-cholesterol, LDL cholesterol/high density lipoprotein 2 (HDL₂) cholesterol and apoB/apoAI. Plasma LCAT activity, concentrations of HDL₃ apoAI and apoAII in plasma and lipoprotein fractions were normal in both the diabetic groups. Levels of C-peptide, HDL, HDL₂ and HDL₃ cholesterol, plasma apoAI, HDL apoAI and HDL₂ apoAI were markedly decreased in the diabetic groups as compared to their corresponding controls. There was no significant correlation between fasting glucose or HbA_1c and any of the above parameters. Despite insulin therapy in both the diabetic groups studied, abnormalities in lipids, apoB and apoAI still persisted. Our data suggest a possible higher risk of atherosclerosis in these patients.     

The effect of low density lipoprotein composition on the regulation of cellular cholesterol synthesis: a comparison in diabetic and non-diabetic subjects

This study investigates compositional differences in low density lipoprotein (LDL) subfractions and their relationship to cellular cholesterol synthesis. We examined ten normocholesterolaemic (serum cholesterol <6.5 mM) non-diabetic subjects (group 1) and compared them with ten normocholesterolaemic (group 2) and ten hypercholesterolaemic (group 3) (serum cholesterol >6.5 mM) type 2 (non-insulin-dependent) diabetic patients. Serum cholesterol levels for groups 1, 2 and 3 were 5.19±0.27, 5.20±0.27 and 7.51±0.31 mM. LDL₁ (density 1.006–1.028 g/l) and LDL₂ (1.028–1.063 g/l) were isolated by density gradient ultracentrifugation. A significantly greater proportion of cholesterol was carried in LDL₂ than LDL₁ in all groups. There was a significantly lower cholesterol/protein ratio in LDL₁ from the hypercholesterolaemic diabetic patients compared with controls. The LDL esterified/free cholesterol ratio was significantly greater in both LDL₁ and LDL₂ in the hypercholesterolaemic diabetic patients compared with the other two groups. There was a negative correlation between inhibition of cholesterol synthesis and the esterified/free cholesterol ratio of both LDL₁ (r=0.56,P<0.002) and LDL₂ (r=0.63,P<0.001). Cellular cholesterol of 41.0±0.3 g/mg cell protein in the hypercholesterolaemic diabetic patients was also significantly higher compared with values of 30.32±2.0 and 34.1±4.2 g/mg cell protein for the normocholesterolaemic non-diabetic and diabetic groups. In vitro LDL esterification led to a decrease in LDL receptor-mediated binding and resulted in a 40% reduction in the ability of the LDL to suppress cholesterol synthesis. The study demonstrates a relationship between the LDL esterified/free cholesterol ratio, LDL receptor binding and cellular cholesterol and may have implications for the understanding of hypercholesterolaemia in diabetes.     

Effect of glipizide treatment on postprandial lipaemia in patients with NIDDM

Summary The primary goal of the present study was to examine the effects of improved glycaemic control associated with glipizide treatment on postprandial lipaemia in non-insulin-dependent diabetic patients. The metabolism of triglyceride-rich lipoproteins of intestinal origin was assessed by measuring the retinyl palmitate content in plasma and the Svedberg flotation index (Sf)>400 and Sf 20–400 lipoprotein fractions. Fasting plasma glucose concentrations (14.5±0.5 vs 9.0±0.5 mmol/l), glycated haemoglobin levels (13.1±0.6 vs 9.7±0.6%), and daylong plasma glucose concentrations were all significantly lower after glipizide treatment (p<0.001). The improvement in glycaemic control was associated with increases in insulin-mediated glucose uptake (p<0.001) and plasma post-heparin lipoprotein and hepatic lipolytic activities (p<0.02). Both fasting plasma triglyceride (3.09±0.51 vs 2.37±0.34 mmol/l), and postprandial triglyceride concentrations (p<0.05–0.001) were lower following glipizide treatment, associated with a significant fall in retinyl palmitate content in all three lipoprotein fractions (p<0.02–0.001), with the most substantial decrease seen in the Sf 20–400 fraction. These data indicate that glipizide-induced improvement in glycaemic control was associated with changes in the metabolism of triglyceride-rich lipoproteins of intestinal origin that would be anticipated to reduce risk of coronary heart disease in non-insulin-dependent diabetic patients.Abbreviations RP Retinyl palmitate - Sf Sverdberg flotation index - CHD coronary heart disease - SSPI steady-state plasma insulin concentration - SSPG steady-state plasma glucose concentration - IDL intermediate density lipoprotein - NEFA non-esterified fatty acid; non-insulin-dependent diabetes mellitus     

Lecithin:cholesterol acyltransferase activity and high-density lipoprotein subfraction composition in type 1 diabetic patients with improving metabolic control

On initial diagnosis or when metabolic control is poor, subjects with type 1 (insulin-dependent) diabetes mellitus often exhibit decreased high density lipoprotein (HDL) cholesterol levels, which have been associated in numerous studies in non-diabetic subjects with atherosclerosis and coronary artery disease. We measured the activities of plasma lecithin:cholesterol acyltransferase (LCAT), post-heparin lipoprotein lipase, and the composition of the HDL subfractions HDL₂ and HDL₃, in ten poorly controlled type 1 diabetic patients admitted to a metabolic ward (six women and four men, aged 18–37 years). The measurements were repeated after metabolic control had been optimised and again a week after discharge. The results were compared with those of ten healthy normolipidaemic subjects matched for age, sex and body mass. LCAT activity increased significantly (P<0.05) with improved metabolic control in the diabetic patients, and showed positive within — person correlation with HDL₂ cholesterol ester (r=0.67;P<0.01), HDL₂ free cholesterol (r=0.67;P<0.01), phosphatidylcholine (r=0.49;P<0.05), total phospholipids (r=0.50;P<0.01) and apolipoprotein A-I (apo A-I:r=0.72;P<0.01). With improving metabolic control HDL₂ lipid levels increased more than twofold and the compositional changes in HDL₂ were reflected by an increased apo A-I:apo A-II ratio (P<0.05) and a decreased triglyceride:apo A-I ratio (P<0.05). Changes in HDL₃ levels and composition were minor. The results of this study indicate that an increase in LCAT activity increases the concentration and changes the composition of HDL₂ in type 1 diabetic patients with improved metabolic control.     

Effect of simvastatin on high density lipoprotein subfractions and apolipoproteins in Type IIa hypercholesterolemia

Summary Changes in plasma concentrations of high density lipoproteins (HDL) and triglycerides may partly explain the ability of cholesterol-lowering drugs to decrease the incidence of coronary heart disease. We measured the response of fasting plasma lipids, lipoproteins, and apolipoproteins in 46 subjects with Type IIa hypercholesterolemia treated with simvastatin for 3 months. The initial dose of simvastatin (10 mg/day) was subsequently increased up to 40 mg/day if the plasma cholesterol concentration had not fallen below 5.2 mmol/l. Plasma concentrations of HDL cholesterol and of the apolipoproteins AI and AII were increased by simvastatin. The increase in HDL cholesterol (9%) was due to increases in both subfractions (HDL₂ 17%; HDL₃ 7%), changes that would be consistent with a beneficial effect on cardiovascular risk. Simvastatin decreased plasma triglyceride concentrations by 25%. Plasma total cholesterol concentrations fell by 35% after 3 months of treatment; this fall was proportional to the initial concentration and was due almost entirely to a 45% fall in low density lipoprotein cholesterol. In contrast, plasma concentrations of lipoprotein Lp(a) were not affected by simvastatin.     

Abnormal distribution of VLDL subfractions in Type 1 (insulin-dependent) diabetic patients: could plasma lipase activities play a role?

Summary Very low density lipoproteins (VLDL) have an abnormal lipid composition in Type 1 (insulin-dependent) diabetic patients. Since VLDL represent a heterogeneous lipoprotein class, this might be due either to a shift in the distribution or to an abnormal composition of VLDL subclasses or both. In order to investigate these possibilities and to evaluate possible pathogenetic mechanisms, lipid composition (non-esterified and esterified cholesterol, triglycerides, phospholipids) of four VLDL subfractions of decreasing size (A: Svedberg flotation unit [S_f]>400, B: S_f, 175–400, C: S_f 100–175, D: S_f 20–100), isolated by density gradient preparative ultracentrifugation, and plasma post-heparin lipolytic activity (lipoprotein lipase and hepatic lipase) were evaluated in 13 male normolipidaemic insulin-dependent diabetic patients in good glycaemic control (HbA_1c 6.9±0.5%) (mean±SEM) and 9 male control subjects matched for age, body mass index and plasma lipid values. Compared to control subjects, diabetic patients showed a reduced total lipid concentration of VLDL of intermediate size (B and C) reaching statistical significance only for VLDL C (0.16±0.02 vs 0.24±0.03 mmol/l; p <0.05). Expressing each VLDL subfraction as percent of the total VLDL lipid concentration, a significant decrease in particles of intermediate size (C) (20.5±1.6 vs 27.9±1.5%; p <0.005) was present, which was compensated by an increase in the smallest ones (D) (50.5±2.7 vs 37.4±3.1%; p <0.05). VLDL of smaller size were also the only particles with an abnormal composition consisting of a significant increase in esterified cholesterol (12.2±0.8 vs 8.7±1.2%, p <0.01). Post-heparin hepatic lipase activity was significantly reduced in diabetic patients as compared to control subjects (232.9±27.9 vs 332±42.3 mU/ml; p <0.05) while post-heparin lipoprotein lipase activity was similar in the two groups. Furthermore, hepatic lipase activity was inversely related to the percentage of smaller VLDL (D)(r=–0.72; p <0.01) in diabetic patients and this relationship was independent of changes in intermediate VLDL (VLDL C). In conclusion the data suggest that Type 1 diabetic patients, although normolipidaemic and in good blood glucose control, show a shift in the distribution of VLDL subclasses toward VLDL of a smaller size which also have an abnormal composition. The different distribution of VLDL subfractions seems to be related to a reduced hepatic lipase activity.     

Plasma lipoproteins from patients with poorly controlled diabetes mellitus and “in vitro” glycation of lipoproteins enhance the transfer rate of cholesteryl ester from HDL to apo-B-containing lipoproteins

Summary Alterations in the reverse cholesterol transport system have been described in diabetic mellitus patients in several but not all studies. Furthermore, recently published investigations suggest that a faster “in vitro” transfer rate of cholesteryl ester from high density lipoproteins to apoB-containing lipoproteins could be solely ascribed to variation of the plasma lipoprotein composition and concentration in the diabetic state. The present study analysed the influence of lipoprotein glycation on the cholesteryl ester transfer protein-mediated transfer of esterified cholesterol from high density lipoprotein and its subfractions to lighter density lipoproteins. For this purpose two sets of “in vitro” experiments were carried out utilizing:1) plasma lipoproteins drawn from diabetic and from normal subjects and; 2) normal lipoproteins or partially purified cholesteryl ester transfer protein submitted to “in vitro” glycation. The transfer rate of ¹⁴C-cholesteryl ester labelled HDL subfractions to low or very low density lipoproteins was measured in all experiments. After incubations with plasma d > 1.21 g/ml or with purified cholesteryl ester transfer protein, apoB-containing lipoproteins were precipitated with a dextran sulfate/MgCl₂ solution. The “in vitro” glycation of the partially purified cholesteryl ester transfer protein markedly impaired its activity. However, greater transfer rates were observed when lipoproteins from diabetic individuals or the “in vitro” glycated lipoproteins were utilized. This effect was attributed to glycation of the protein component of HDL. In conclusion, lipoprotein glycation elicits an enrichment of the apoB-containing lipoproteins with cholesteryl ester that is likely related to the premature atherosclerosis in patients with poorly controlled diabetes. [Diabetologia (1997) 40: 1085–1093] Received: 14 January 1997 and in revised form: 7 May 1997     

Changes of lipolytic enzymes cluster with insulin resistance syndrome

Summary The activities of hepatic and lipoprotein lipase and the levels of lipo- and apoproteins were compared in two groups of normoglycaemic men representing the highest (n=18) and lowest (n=15) fasting insulin quintiles of first degree male relatives of non-insulin-dependent diabetic patients. The high insulin group representing insulin-resistant individuals had significantly lower post-heparin plasma lipoprotein lipase activity than the low insulin group (14.2±4.0 vs 20±5.8 mol NEFA·ml^–1·h^–1, p<0.001); hepatic lipase activity did not differ between the two groups (24.2±11 vs 18.0±5.3 mol NEFA·ml^–1·h^–1, NS). The lipoprotein lipase/hepatic lipase ratio in the high insulin group was decreased by 66% as compared to the low insulin group (0.75±0.57 vs 1.25±0.65, p<0.01). In the high insulin group both total and VLDL triglycerides were higher than in the low insulin group (1.61±0.57 vs 0.86±0.26 mmol/l, p< 0.001 and 1.00±0.47 vs 0.36±0.16 mmol/l, p<0.001, respectively) whereas HDL cholesterol and HDL₂ cholesterol were lower (1.20±0.30 vs 1.43±0.22 mmol/l, p<0.05 and 0.49±0.21 vs 0.71±0.17 mmol/l, p<0.05, respectively). Total cholesterol, LDL cholesterol or HDL₃ cholesterol did not differ between the two groups. The mean particle size of LDL was smaller in the high insulin group than in the low insulin group (258±7 vs 265±6 å, p<0.05). We propose that the changes of lipoprotein lipase and lipoprotein lipase/hepatic lipase ratio cluster with insulin resistance and provide a possible mechanism to explain the lowering of HDL cholesterol and elevation of triglyceride concentrations observed in insulin-resistant subjects.Abbreviations LPL Lipoprotein lipase - HL hepatic lipase - VLDL very low density lipoprotein - IDL intermediate density lipoprotein - LDL low density lipoprotein - HDL high density lipoprotein - chol cholesterol - TG triglycerides - NEFA non-esterified fatty acids     

Influence of puberty on lipids and lipoprotein profile in children with type 1 diabetes mellitus

In order to assess whether or not the lipoprotein profile worsens throughout puberty in children with type 1 diabetes mellitus and if this change is related to dietary compliance, we studied 46 (20 female, 26 male) children. At the beginning of the study, the mean age (±SD) was 10.9±1.1 years; all the children studied had reached a pubertal stage of P1, G1. The mean duration of diabetes (±SD) was 4.9±1.8 years. The diet and the lipoprotein profile of diabetic children were analysed at the beginning of the study and after 6 years. The quality of metabolic control of subjects studied had not changed significantly at the end of the study (haemoglobin HbA_1c 7.6%±2.1% vs 7.9%±2.0%; NS). After puberty, the diabetic patients received more energy from carbohydrate and less from lipids. Total serum cholesterol and triglycerides and levels of low-density lipoproteins were significantly higher and of high-density lipoproteins lower in the diabetic patients after puberty than before (4.47±0.7 mmol/l vs 5.99±0.6,P<0.01; 0.90±0.02 mmol/l vs 1.45±0.03,P<0.01; 2.2±0.3 mmol/l vs 2.8±0.5,P<0.01; 1.5±0.2 vs 1.1±0.2,P<0.01, respectively). These results suggest a detrimental effect of puberty on lipoproteins; probably, dietary compliance plays a role in this worsening. Dietary education should be intensified during adolescence in order to present these changes.     

Low density lipoprotein cholesterol: An association with the severity of diabetic retinopathy

Summary Diurnal profiles of total and lipoprotein cholesterol and triglycerides were measured in 11 insulin-dependent diabetic subjects without retinopathy, 10 with background and 10 with proliferative retinopathy. The groups were closely matched for age and duration of diabetes. Total cholesterol levels were higher in patients with proliferative (5.6±0.5 mmol/l) than background (5.1±0.7 mmol/l) or no retinopathy (4.6±0.8 mmol/l, trend test; p < 0.003), due to raised levels of low density lipoprotein (LDL) cholesterol (3.8±0.9, 3.2±0.6 and 2.8±0.8 mmol/l respectively; p < 0.02). High density lipoprotein (HDL) levels were similar in patients with and without retinopathy and HDL/ LDL ratios were lower with more severe retinopathy (p < 0.025). Cholesterol levels were similar in diabetic subjects without retinopathy and in 12 normal subjects. Triglyceride levels were not related to retinopathy and no measure of plasma lipids correlated with HbA₁ or 24-h mean plasma glucose. Total and LDL cholesterol were weakly inversely correlated with creatinine clearance but the association with retinopathy was independent of this effect.     

Lowering LDL cholesterol in adults: a prospective, community-based practice initiative

Purpose

The purpose of our study was to see if a clinic-wide initiative, with low-density lipoprotein cholesterol (LDL)-lowering interventions, could be an effective health maintenance strategy to decrease LDL levels to <100 mg/dL in a community-based, internal medicine outpatient setting.

Methods

There were 1375 patients screened with an initial/baseline LDL (LDL₁) measurement. Patients whose LDL₁ levels were >100 mg/dL were put on a lipid-lowering action plan and re-evaluated with a follow-up LDL (LDL₂) in 3-4 months. An additional action plan was given to patients whose LDL₂ values were still too high, and their values retested in 3-4 months for a third LDL (LDL₃). LDL₁ levels versus postintervention LDL measurement (LDL₂ or LDL₃) levels were the primary endpoints, with secondary endpoints of total cholesterol, total triglyceride, and high-density lipoprotein cholesterol (HDL) levels over the 3 measurement periods.

Results

Of 514 patients who were given action plans, 443 returned for their follow-up lipid assessment. LDL levels in this group fell from 140.7 ± 29.2 (mean ± 1 SD) mg/dL (LDL₁) to 110.9 (29.6) mg/dL (LDL₂) (P <.05). Of these 443 patients, 167 individuals had LDL₂ levels that now met National Cholesterol Education Program/Third Adult Treatment Panel III guidelines (<100 mg/dL) and 87 were now considered by their primary care provider as controlled (LDL 100-130 mg/dL). However, 158 individuals had LDL₂ levels that were either not controlled or not meeting National Cholesterol Education Program/Third Adult Treatment Panel guidelines. These 158 patients were provided with a second action plan, and of these, 50 (32%) returned to the clinic for a third lipid panel. Their LDLs, as a group, subsequently fell from an LDL₂ of 139.9 (24.4) mg/dL to 112.5 (28.2) mg/dL (LDL₃) (P <.05). Sixteen of 50 now had LDLs <100 mg/dL, and 26 of 50 were considered controlled. Initial HDL (HDL₁) levels rose from 55.4 (17.2) mg/dL to 57.3 (14.6) mg/dL (HDL₂) (n = 443). Blood levels of triglycerides and cholesterol also decreased in our returning patients over this time period (P <.05).

Conclusions

Community-based physicians can help their patients realize significant reductions in low-density lipoprotein cholesterol levels by implementing and closely monitoring lipid-lowering initiatives for their patients, resulting in potentially large positive impacts on the long-term health and well-being of their patients.     

Abnormalities in plasmas concentrations of lipoproteins and fibrinogen in Type 1 (insulin-dependent) diabetic patients with increased urinary albumin excretion

Summary Type 1 (insulin-dependent) diabetic patients with clinical nephropathy have a more than ten-fold increase in mortality of cardiovascular diseases compared with diabetic patients without nephropathy. The risk factors for cardiovascular disease, plasma concentrations of lipoproteins and fibrinogen, were investigated in 74 long-term diabetic patients: 37 with normal urinary albumin excretion, 20 with incipient nephropathy and 17 with overt clinical nephropathy based on urinary albumin excretion. The groups were matched according to sex, age and diabetes duration. The concentration of plasma cholesterol, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, triglyceride and fibrinogen rose with increasing urinary albumin excretion. The plasma concentrations of these lipoproteins and fibrinogen were 11–14% higher in the patients with incipient nephropathy and 26–87% higher in the patients with overt clinical ne phropathy compared with the patients without nephropathy. The plasma concentration of high density lipoprotein cholesterol was unaffected by albuminuria. Patients with normal urinary albumin excretion and HbA_1c>8.0% had significantly higher very low density lipoprotein- and lower high density lipoprotein cholesterol concentrations compared with patients with HbA_1c<8.0%. Simple addition of the described risk factors can only account for a minor part of the greatly increased cardiovascular mortality in patients with diabetic nephropathy. An additional and possibly more decisive factor might be a change in the arterial wall, a change which promotes lipid accumulation and/or facilitates thrombus formation.     

Serum lipids and apolipoproteins in children with Type 1 (insulin-dependent) diabetes during the first two years of the disease

Summary Serum lipoproteins and apolipoproteins were studied at diagnosis and 6,12 and 24 months later in 30 consecutive children aged 3–15 years with newly detected Type 1 (insulin-dependent) diabetes mellitus (December 1982–October 1984) and in 44 healthy control children. Serum triglycerides at diagnosis were significantly higher than after 6–24 months and also higher than in the control group (p<0.001). At follow-up, triglycerides in the very low density lipoproteins and low density lipoproteins were restored to normal, while high density lipoprotein triglycerides remained high. Serum cholesterol at onset of diabetes was significantly higher than in the control children (p<0.01), mainly because of increased very low density lipoprotein cholesterol (p<0.001). Cholesterol in serum and in the serum lipoprotein fractions was similar to that in the control children at follow-up, except that high density lipoprotein cholesterol was higher in the diabetic children after 6 months. The concentrations of the serum apolipoproteins A-I, A-II and B were higher at onset of diabetes than in the control children (p<0.001, p<0.01, p<0.05 respectively), with a significantly increased ratio of apolipoprotein A-I to A-II in the diabetic children (p<0.001). The serum apolipoprotein concentrations were normalised during treatment. The ratio of apolipoprotein A-I to B did not differ from that in control children. On admission, there were strong positive correlations between HbA_1c and the concentrations of the very low density lipoproteins and the low density and high density lipoprotein triglycerides. There were also significantly positive correlations (p<0.01) between HbA_1c and apolipoprotein A-I and apolipoprotein B respectively. After treatment these correlations disappeared, except for a positive correlation with very low density lipoprotein triglycerides at 2 years. In conclusion, at diagnosis, when the diabetic children were in an insulin-deficient state, all apolipoproteins and serum lipoprotein fractions, except cholesterol in high density lipoproteins and low density lipoproteins were increased. During the first two years of treatment the concentrations of lipoproteins and apolipoproteins in serum are similar to those in healthy children.     

Elevated plasma phospholipid transfer protein activity is a determinant of carotid intima-media thickness in type 2 diabetes mellitus

Aim/hypothesis The plasma activity of phospholipid transfer protein (PLTP), which has putative pro- and anti-atherogenic roles in lipoprotein metabolism, is increased in type 2 diabetes mellitus. We analysed the relationship between carotid artery intima–media thickness (IMT), an established marker of atherosclerosis, and PLTP activity in diabetic patients and control subjects. Methods The IMT (mean of three segments in both carotid arteries by ultrasonography), clinical variables, plasma PLTP activity (phospholipid vesicle–HDL system), lipoproteins, C-reactive protein and insulin were measured in 87 non-smoking men and women, who had type 2 diabetes mellitus, no cardiovascular disease, and were not on insulin or lipid-lowering medication, and in 83 age-matched control subjects. Results In diabetic patients, carotid IMT (p=0.02), pulse pressure (p=0.003), plasma PLTP activity (p<0.001), triglycerides (p=0.01), C-reactive protein (p<0.01) and insulin (p<0.001) were higher, whereas HDL cholesterol was lower (p<0.001) than in control subjects. Multiple stepwise linear regression analysis demonstrated that in type 2 diabetic patients IMT was independently associated with age (p<0.001), sex (p=0.001), pulse pressure (p=0.003), plasma PLTP activity (p=0.03) and HDL cholesterol (p=0.03), but not with very low density lipoprotein+LDL cholesterol, triglycerides, C-reactive protein and insulin (all p>0.20). The relationship between plasma PLTP activity and IMT was not significant in control subjects. Conclusions/interpretation Plasma PLTP activity is a positive determinant of IMT in type 2 diabetes mellitus, suggesting that high PLTP activity is involved in accelerated atherosclerosis in this disease.     

Treatment effects on serum lipoprotein lipids,apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT)

Objectives. To investigate the mechanisms by which bezafibrate retarded the progression of coronary lesions in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT), we examined the relationships of on-trial lipoproteins and lipoprotein subfractions to the angiographic outcome measurements.Background. BECAIT, the first double-blind, placebo-controlled, randomized serial angiographic trial of a fibrate compound, showed that progression of focal coronary atherosclerosis in young survivors of myocardial infarction could be retarded by bezafibrate treatment.Methods. A total of 92 dyslipoproteinemic men who had survived a first myocardial infarction before the age of 45 years were randomly assigned to treatment for 5 years with bezafibrate (200 mg three times daily) or placebo; 81 patients underwent baseline and at least one post-treatment coronary angiography.Results. In addition to the decrease in very low density lipoprotein (VLDL) cholesterol (−53%) and triglyceride (−46%) and plasma apolipoprotein (apo) B (−9%) levels, bezafibrate treatment resulted in a significant increase in high density lipoprotein-3 (HDL₃) cholesterol (+9%) level and a shift in the low density lipoprotein (LDL) subclass distribution toward larger particle species (peak particle diameter +0.32 nm). The on-trial HDL₃cholesterol and plasma apo B concentrations were found to be independent predictors of the changes in mean minimum lumen diameter (r = −0.23, p < 0.05), and percent (%) stenosis (r = 0.30, p < 0.01), respectively. Decreases in small dense LDL and/or VLDL lipid concentrations were unrelated to disease progression.Conclusions. Our results suggest that the effect of bezafibrate on progression of focal coronary atherosclerosis could be at least partly attributed to a rise in HDL₃cholesterol and a decrease in the total number of apo B-containing lipoproteins.     

Very low density lipoprotein subfraction abnormalities in IDDM patients: any effect of blood glucose control?

Summary Normolipidaemic insulin-dependent diabetic (IDDM) patients are characterized by an increase in the smaller VLDL particles, considered to be the most atherogenic. Since blood glucose control is one of the main regulators of lipid metabolism in diabetic patients, it could influence the shift in the distribution of VLDL subfractions towards smaller particles. To evaluate this possibility, VLDL subfractions, post-heparin lipoprotein lipase and hepatic lipase activities have been evaluated in male IDDM patients with either unsatisfactory blood glucose control (group 1, HbA_1c>8%, n=18) or good blood glucose control (group 2, HbA_1c<8%, n=16) and in 16 normoglycaemic individuals. The three groups were comparable for sex, age, body mass index, and plasma lipid levels. Three VLDL subfractions (large, Svedberg flotation unit (Sf) 175–400; intermediate, Sf 100–175; small, Sf 20–100) were separated by density gradient ultracentrifugation and analysed for cholesterol, triglyceride, and phospholipid levels. When compared to control subjects both groups of IDDM patients showed a clear shift in VLDL subfraction distribution with a significant increase in the proportion of small VLDL (group 1; 49±2%; p<0.005; group 2: 51±3%, p<0.01; control subjects 40±2%) (mean ± SEM) in relation to total VLDL. By contrast, the absolute lipid concentration of small VLDL was higher only in group 1, compared to control subjects (35±4 vs 27±3 mg/dl, p=0.05). Post-heparin hepatic lipase activity was significantly reduced in both IDDM groups (group 1: 254±19 mU/ ml, p<0.05; group 2: 202±19 mU/ml, p<0.005; control subjects 317±31 mU/ml). In conclusion, normolipidaemic IDDM patients show an increase in the smallest VLDL, whatever their degree of blood glucose control. However, this abnormality may be clinically relevant only in patients with unsatisfactory blood glucose control, since absolute lipid concentration of these potentially atherogenic particles is only increased in this group.Abbreviations IDDM Insulin-dependent diabetes mellitus - VLDL very low density lipoprotein - LPL lipoprotein lipase - HL hepatic lipase     

Heterogeneity of human high density lipoprotein: Presence of lipoproteins with and without apoE and their roles as substrates for lecithin:cholesterol acyltransferase reaction

By affinity chromatography on heparin-Sepharose, two classes of lipoproteins were separated from high density lipoproteins (HDL) isolated from patients with primary or secondary lecithin:cholesterol acyltransferase (LCATase; EC 2.3.1.43) deficiency and from normal subjects. The unretained fraction, HDL_A, was characterized by having apoA-I as a major apoprotein; it also contained apoA-II, -C-II, and -C-III but it contained only traces of immunodetectable apoE and no apoB. The retained fraction, HDL_E, had apoE as the major apoprotein; it also contained apoA-I, -A-II, -B, -C-II, and -C-III. The relative concentration of apoA-I increased with increasing density in the HDL_E subclass. Compared to HDL_A, HDL_E had a significantly higher cholesterol content and a lower protein concentration. HDL_E was mainly (90%) contained within the HDL₂ subfraction. Contamination of HDL_E by low density lipoproteins (LDL) or Lp(a) was minimal on the basis of pre-β-electrophoretic mobility and absence of albumin, respectively. Contamination by LDL or Lp(a) could be resolved in part by application of HDL_E to concanavalin A-Sepharose or to heparin-Sepharose with a shallow gradient. When evaluated as substrates for a highly purified LCATase preparation, the initial reaction rates and V_max obtained with HDL_A were always higher than those obtained with HDL_E in any given plasma. However, both HDL subclasses from LCATase-deficient subjects were better substrates than the corresponding HDL subclasses from normal plasma. Also, both HDL_3A and HDL_3E isolated from normal HDL₃ were better substrates than the corresponding subclasses isolated from normal HDL₂. The recognition of this compositional and functional heterogeneity within HDL will allow a better understanding of the metabolism of this lipoprotein class.     

Normal metabolism of apolipoprotein B100-containing lipoproteins despite qualitative abnormalities in type 1 diabetic men

Aims/hypothesis Type 1 diabetic subjects are at increased risk of cardiovascular disease and exhibit multiple qualitative abnormalities of apolipoprotein (apo) B100-containing lipoproteins. This stable isotope kinetic experiment was designed to study whether these abnormalities are associated with changes in the synthesis and fractional catabolic rates of VLDL-, IDL- and LDL-apoB100.Methods Using a bolus followed by a 16-h constant infusion of ¹³C-leucine, we performed a kinetic study in eight men with type 1 diabetes treated with a continuous subcutaneous insulin infusion administered by an external pump and in seven healthy men, in the fed state.Results The mean HbA₁c level in the type 1 diabetic patients was 8.00±1.48%. Plasma triglyceride, and total, LDL and HDL cholesterol levels were similar in patients and control subjects. VLDL were less triglyceride rich in type 1 diabetic patients than in control subjects (VLDL triglyceride : apoB 6.91±0.81 vs 8.29±1.24 mmol/g, p=0.05). Conversely, the IDL and LDL of the type 1 diabetic patients contained relatively higher levels of triglycerides (IDL triglycerides : apoB 2.16±0.36 vs 1.57±0.30 mmol/g, p<0.01; LDL triglycerides : apoB 0.27±0.06 vs 0.16±0.04 mmol/g, p<0.05). The apoB100 pool size, production and fractional catabolic rates in the two groups of subjects were similar for all lipoprotein fractions.Conclusions/interpretation Despite qualitative abnormalities, especially abnormalities of triglyceride content, the metabolism of apoB100-containing lipoproteins is not altered in type 1 diabetic men with fair glycaemic control with continuous subcutaneous insulin infusion. The high risk of atherosclerosis in these patients cannot be explained by kinetic abnormalities of apoB100-containing lipoproteins.