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.     

Cellular cholesterol efflux to plasma from moderately hypercholesterolaemic type 1 diabetic patients is enhanced, and is unaffected by simvastatin treatment

Aim/hypothesis Cellular cholesterol efflux to plasma is important in reverse cholesterol transport and may be affected by simvastatin in type 1 diabetes mellitus.Methods In 14 moderately hypercholesterolaemic type 1 diabetic and 13 healthy men we determined plasma (apo)lipoproteins, pre- HDL formation, cholesteryl ester transfer protein (CETP) activity, phospholipid transfer protein (PLTP) activity, cholesterol esterification, cholesteryl ester transfer and the capacity of plasma to induce cholesterol efflux out of Fu5AH cells and fibroblasts. After diet run-in, diabetic patients were randomly treated with simvastatin 10, 20, 40 mg and placebo, once daily each, for 6 weeks in a double-blind crossover design.Results Plasma very low density lipid protein (VLDL)+LDL cholesterol, LDL cholesterol, HDL phospholipids, apolipoprotein (apo) A-I, apo B, CETP activity, PLTP activity, cholesterol esterification, cholesteryl ester transfer and the capacity of plasma to induce cholesterol efflux from Fu5AH cells and fibroblasts were higher in diabetic patients. Pre- HDL formation was unaltered. Simvastatin treatment decreased VLDL+LDL cholesterol, LDL cholesterol, triglycerides and apo B, CETP activity, cholesterol esterification and cholesteryl ester transfer. HDL cholesterol increased and its change was correlated with the change in cholesteryl ester transfer. The ability to promote cholesterol efflux from Fu5AH cells and fibroblasts did not change after simvastatin.Conclusions/interpretation The capacity of plasma from moderately hypercholesterolaemic type 1 diabetic patients to induce cholesterol efflux out of Fu5AH cells and fibroblasts is enhanced, probably due to higher apo A-I, HDL phospholipids and PLTP activity. Simvastatin increases HDL cholesterol in type 1 diabetic patients via lowering of plasma cholesteryl ester transfer. The HDL changes after simvastatin do not increase cellular cholesterol efflux further.     

Hypertriglyceridaemia and its influence on low density lipoprotein regulation of cellular cholesterol synthesis: a comparison between hypertriglyceridaemic diabetic and non-diabetic patients.

The present investigation was undertaken to examine the relationship between serum triglyceride and composition of lipoprotein. Six groups of patients were examined, three with Type 2 (non-insulin-dependent) diabetes and three without diabetes. The groups were further categorized on the basis of their serum cholesterol and triglyceride levels into normocholesterolaemic (serum cholesterol less than 6.5 mmol l-1) and hypercholesterolaemic (serum cholesterol greater than 6.5 mmol l-1) with and without hypertriglyceridaemia (serum triglyceride greater than or less than 3.5 mmol l-1). Low density lipoprotein (LDL) composition was determined and regulation of cholesterol synthesis by LDL was assessed by measuring its effect on [14C]-acetate incorporation into mononuclear leucocyte cholesterol. LDL from the hypercholesterolaemic diabetic patients had a significantly higher esterified cholesterol content when the patients were normotriglyceridaemic (1.14 +/- 0.04 vs 0.76 +/- 0.04 g g-1; p less than 0.01). The ability of LDL to suppress cholesterol synthesis (percent inhibition) was significantly less using LDL from the normocholesterolaemic diabetic patients or hypercholesterolaemic non-diabetic or diabetic patients compared with LDL from the normocholesterolaemic non-diabetic control subjects (47.4 +/- 3.9%, 39.1 +/- 5.1% and 35.2 +/- 4.1% vs 59.5 +/- 1.2%, p less than 0.01). However, hypertriglyceridaemia had no effect on LDL suppression of cholesterol synthesis. We conclude that hypertriglyceridaemia alters LDL composition but the alteration is not associated with the ability of LDL to regulate cholesterol synthesis.     

宁波地区冠心病病人低密度脂蛋白胆固醇基础水平及调脂疗效

目的观察经冠状动脉造影确诊为冠心病的住院病人血脂基础水平及经药物治疗病人的血脂水平,了解宁波地区冠心病病人的血脂状态及达标水平,并对其常规调脂药使用后疗效进行分析。方法经选择性冠状动脉造影确诊为冠心病者180例,观察使用日剂量阿托伐他汀10mg、辛伐他汀20mg、氟伐他汀40mg治疗3个月对调脂的疗效。结果他汀类治疗3月后,冠心病病人低密度脂蛋白胆固醇为(2.0±0.7)mmol/L,与治疗前比较,下降幅度差异有统计学意义(P<0.001)。与其他他汀类比较,阿托伐他汀组低密度脂蛋白胆固醇下降幅度最明显(P<0.05),而辛伐他汀组和氟伐他汀组低密度脂蛋白胆固醇相比,差异无统计学意义(P>0.05)。结论宁波地区冠心病病人低密度脂蛋白胆固醇水平偏低,常规剂量他汀类药物即可达强化调脂目的。     

The effect of long-term glycaemic control on serum lipoprotein(a) levels in patients with Type 2 diabetes mellitus.

AIMS: To examine whether long-term glycaemic control affects lipoprotein(a) (Lp(a)) levels in patients with Type 2 diabetes mellitus. METHODS: Eighty-nine Type 2 diabetic patients (38 men, 51 women) were recruited from the diabetes clinic. Based on HbA1c concentrations at baseline, patients were divided into two groups: those with HbA1c < 8.0% (n =45) and those with HbA1c > or = 8.0% (n=44). Comparisons of Lp(a) levels were made between both groups. The effect of long-term glycaemic control on Lp(a) levels was investigated in a subgroup of 20 patients, selected from those with baseline HbA1c > or = 8%. All these patients were treated with a goal of HbA1c <7%. RESULTS: Lp(a) levels were not significantly different between those with HbA1c< 8.0% and those with HbA1c, > or = 8.0%. No correlation between Lp(a) and HbA1c or fasting blood glucose levels was noted in diabetic patients as a whole. After 2 years of intensive glycaemic control, all patients exhibited remarkable improvement of therapy: their average HbA1c levels were 6.5 +/- 0.7%, being < 7% in 70% of patients. However, no change in Lp(a) levels were observed after 2 years (19.5 +/- 14.8-21.4 +/- 13.4 mg/dl, P = 0.390). CONCLUSION: These results indicate that improvement of glycaemic control does not affect serum Lp(a) levels in patients with Type 2 diabetes mellitus.     

Low high‐density lipoprotein cholesterol level is a significant risk factor for development of type 2 diabetes: Data from the Hawaii–Los Angeles–Hiroshima study

Aims/Introduction

A low level of high‐density lipoprotein cholesterol (HDLC) is a common feature of metabolic syndrome. We have reported that Japanese–Americans who share a virtually identical genetic makeup with native Japanese, but who have lived Westernized lifestyles for decades, have lower HDLC levels and a high prevalence of type 2 diabetes compared with native Japanese. However, the impact of low HDLC level on type 2 diabetes is unclear. The aims of the present study were to evaluate whether serum HDLC level was associated with development of type 2 diabetes and if the effect might be modified by lifestyle.

Materials and Methods

We examined 1,133 non‐diabetic Japanese–Americans and 1,072 non‐diabetic Japanese, who underwent the 75‐g oral glucose tolerance test (OGTT) and were followed for an average of 8.8 and 7.0 years, respectively. We analyzed whether serum HDLC level is a risk factor for development of type 2 diabetes based on the Cox proportional hazards model.

Results

After adjustment for age and sex, hazard ratios for development of type 2 diabetes per unit of serum HDLC level (mmol/L) were 0.292 (95% confidence interval [CI] 0.186–0.458, P < 0.0001) among Japanese–Americans and 0.551 (95% CI 0.375–0.88, P = 0.0023) among native Japanese. Comparable hazard ratios after further adjustment for category of OGTT and body mass index were 0.981 (95% CI 0.970–0.993, P = 0.0018) and 0.991 (95% CI 0.980–1.002, P = 0.112), respectively.

Conclusions

HDLC level was associated with development of type 2 diabetes in both Japanese–Americans and native Japanese. However, these results suggest that the impact of high‐density lipoprotein on glucose metabolism might be affected by lifestyle.     

低密度脂蛋白胆固醇异常在2型糖尿病家系中的家族聚集性及相关因素分析

目的探讨低密度脂蛋白胆固醇(LDL-C)异常在北京地区2型糖尿病(T2DM)家系一级亲属中是否存在遗传倾向以及相关因素。方法收集北京地区具有两个或以上T2DM患者的家系295个,共978例,将每一家系中先证者按LDL-C<2.6 mmol/L和≥2.6 mmol/L分为正常LDL-C组131例和高LDL-C组163例,比较两组患者T2DM和非T2DM一级亲属的LDL-C水平,用多因素逐步回归分析了解其相关因素。结果高LDL-C组的T2DM一级亲属的年龄、空腹血糖(FPG)、糖化血红蛋白(HbA1c)、总胆固醇(TCHO)和LDL-C高于正常LDL-C组(P<0.05)。多因素逐步回归分析显示,T2DM一级亲属的LDL-C与先证者LDL-C、HbA1c及年龄独立相关。高LDL-C组的非T2DM一级亲属的TCHO和LDL-C高于正常LDL-C组(P<0.05)。多因素逐步回归分析显示,非T2DM一级亲属的LDL-C与先证者LDL-C、HbA1c及年龄独立相关。结论在中国北京地区T2DM家系中LDL-C异常存在家族聚集现象,且LDL-C与HbA1c和年龄独立相关。     

Effects of plant stanol esters on serum cholesterol concentrations, relative markers of cholesterol metabolism and endothelial function in type 1 diabetes

We investigated the effect of plant stanol esters (STAEST) on serum total and LDL cholesterol concentrations and endothelial function in subjects with type 1 diabetes (T1D). In addition, the changes in the relative serum markers of cholesterol metabolism were recorded. In a parallel, randomized, double-blind study the intervention group (n = 11) consumed STAEST spread (2 g/day stanols) and the control group (n = 8) the same spread containing no added stanols for 12 weeks. At baseline, brachial artery diameter was negatively correlated with serum HDL cholesterol concentration (r = −0.476, P < 0.05), but not with total or LDL cholesterol concentrations or serum non-cholesterol sterol ratios to cholesterol. Flow-mediated dilatation was positively associated with serum absorption marker ratios to cholesterol, significantly so with the sitosterol ratio (r = 0.467, P < 0.05). During the intervention, serum total and LDL cholesterol concentrations were reduced by 4.9 and 6.9% from baseline in the STAEST group, and by 10.8 and 16.1% from controls, respectively (P < 0.05 for all). No significant changes in HDL cholesterol and serum triglyceride concentrations were found. The STAEST consumption reduced serum campesterol and sitosterol ratios by 17–21% (P < 0.05) from baseline, but the relative serum synthesis markers were not changed. Brachial artery diameter and flow-mediated dilatation did not change during the investigation. In conclusion, STAEST significantly reduced serum total and LDL cholesterol concentrations and serum plant sterol ratios without affecting HDL and triglyceride concentrations in subjects with T1D. STAEST had no effect on endothelial function.     

血脂康和辛伐他汀对高胆固醇血症调脂作用的比较

目的研究血脂康对高胆固醇血症患者的调脂作用并与辛伐他汀比较。方法２８例高胆固醇血症患者随机分为两组，服药前及服药后４、８周测定血脂。结果（１）服药后４周ＴＣ分别降低了２０７％和２２５％（Ｐ值均＜０００１）；血脂康降低血清低密度脂蛋白胆固醇（ＬＤＬＣ）作用与辛伐他汀相似，ＬＤＬＣ水平分别降低了２８２％和３３％（Ｐ值均＜００１）；（２）血脂康明显降低１７４％的血清ＴＧ水平（Ｐ＜００５）；（３）服血脂康和辛伐他汀４周后，载脂蛋白（Ａｐｏ）Ａ１却分别增加了１２７％和１３６％（Ｐ值均＜００１）；ＡｐｏＢ水平均下降了８％左右（Ｐ＜００５）；分别使脂蛋白（ａ）［Ｌｐ（ａ）］水平降低了３１３％（Ｐ＜００１）和２７８％（Ｐ＜００５）；（４）除了治疗８周后Ｌｐ（ａ）水平进一步下降外，两种药物治疗８周后的调脂作用与４周比较无明显差异。结论血脂康能显著降低Ⅱａ和Ⅱｂ型高胆固醇血症患者血清ＴＣ和ＬＤＬＣ，其作用与辛伐他汀相等；血脂康降低ＴＧ作用优于辛伐他汀     

Impact of low-density lipoprotein cholesterol on cardiovascular outcomes in people with type 2 diabetes: A meta-analysis of prospective cohort studies

Aims

To estimate the prospective association of low-density lipoprotein (LDL) cholesterol on cardiovascular disease (CVD) risk among people with type 2 diabetes.

Methods

We used extensive literature searching strategies to locate prospective cohort studies that reported LDL cholesterol levels as a risk factor for cardiovascular events. We conducted meta-analytic procedures for two outcomes: incident CVD and CVD mortality.

Results

A total of 16 studies were included in this analysis with a mean follow-up range of 4.8–11 years. The pooled relative risk associated with a 1 mmol/L increase in LDL cholesterol in people with type 2 diabetes was 1.30 (95% confidence interval [CI], 1.19–1.43) for incident CVD, and 1.50 (95% CI, 1.25–1.80) for CVD mortality, respectively. Subgroup analyses showed that for incident CVD, the pooled relative risk was 1.28 (95% CI, 1.17–1.41) for 7 studies adjusted for blood pressure and/or glucose concentration (or insulin concentration, glycated hemoglobin) and 1.40 (95% CI, 1.05–1.86) for 3 studies that did not adjust for these variables.

Conclusions

Our study demonstrates that LDL cholesterol was associated with an increased risk for cardiovascular outcomes in people with type 2 diabetes, independent of other conventional risk factor.     

Effects of patient‐tailored atorvastatin therapy on ameliorating the levels of atherogenic lipids and inflammation beyond lowering low‐density lipoprotein cholesterol in patients with type 2 diabetes

Aims/Introduction

Recently, patient‐tailored statin therapy was proven effective for achieving target low‐density lipoprotein (LDL) cholesterol levels. It is unclear, however, whether this therapeutic modality would be effective for atherogenic lipid profiles and inflammation in patients with type 2 diabetes.

Materials and Methods

The present study was an 8‐week, multicenter, single‐step titration trial of patient‐tailored atorvastatin therapy (10, 20 and 40 mg) according to baseline LDL cholesterol levels in 440 patients with type 2 diabetes. We measured the LDL particle size by polyacrylamide gel electrophoresis, and used high‐sensitivity C‐reactive protein (hsCRP) and adiponectin as surrogate markers of inflammation.

Results

In the intention‐to‐treat analysis, 91% of the patients achieved their LDL cholesterol targets (<2.6 mmol/L) at week 8. There were significant reductions at week 8 in total cholesterol, triglycerides, non‐high‐density lipoprotein cholesterol (HDL) cholesterol, and the total cholesterol:HDL cholesterol ratio compared with the baseline values for all of the doses. The mean LDL particle size was significantly increased, and the small, dense LDL cholesterol levels were decreased in a dose‐dependent manner over the study period. In addition, the hsCRP levels were decreased in those high‐risk patients with baseline hsCRP levels over 3 mg/L (P < 0.001), and the adiponectin levels tended to increase with all of the doses (P = 0.004) at 8 weeks.

Conclusions

Patient‐tailored atorvastatin therapy based on LDL cholesterol at baseline was effective in ameliorating atherogenic LDL particle size and inflammation, in addition to achieving the target LDL cholesterol level without an undesirable effect on glycemic control in patients with type 2 diabetes. This trial was registered with ClinicalTrials.gov (no. NCT01239849).     

Relationship between postheparin plasma lipases and high-density lipoprotein cholesterol in different types of diabetes

Summary We measured serum lipids, lipoproteins and postheparin plasma lipases, lipoprotein lipase and hepatic lipase, in 12 female patients with Type 1 (insulin-dependent) diabetes (postglucagon C-peptide undetectable), in 11 female insulin-treated patients with Type 2 (non-insulin-dependent) diabetes (postglucagon C-peptide >0.60 nmol/l) and in 16 non-diabetic female control subjects. These three groups of subjects were similar with respect to age and obesity. Insulin dose was similar in patients with Type 1 and with Type 2 diabetes. HDL and HDL₂ cholesterol were lower in patients with Type 2 diabetes than in non-diabetic control subjects (p<0.05) but did not differ between patients with Type 1 diabetes and non-diabetic control subjects. No difference in lipoprotein lipase activity was seen between the groups. The highest levels of lipoprotein lipase and hepatic lipase activities were observed in patients with Type 2 diabetes. Lipoprotein lipase activity correlated significantly with HDL cholesterol in patients with Type 1 diabetes (p<0.01) and in patients with Type 2 diabetes (p<0.001) but not in control subjects. Hepatic lipase activity did not correlate significantly with HDL cholesterol in any of the groups. In conclusion, postheparin plasma lipoprotein lipase and hepatic lipase activities do not seem to explain the difference in HDL cholesterol concentration between patients with Type 1 and Type 2 diabetes.     

Are the binding and degradation of low density lipoprotein altered in type 2 (non-insulin-dependent) diabetes mellitus?

Summary Studies in vitro have shown that glycosylation of low density lipoprotein (LDL) will decrease its ability to bind to its receptor. We have evaluated the possibility that such an event might occur in vivo in diabetes by comparing the binding and degradation by normal fibroblasts and mouse peritoneal macrophages of LDL obtained from normal control subjects and patients with Type 2 (non-insulin-dependent) diabetes mellitus. When compared with control subjects, Type 2 diabetic patients had elevated fasting glucose (increased by 160%), haemoglobin A_1c (increased by 75%), triglyceride (increased by 550%), and cholesterol (increased by 48%) levels. LDL from Type 2 diabetic patients displayed populations of particles with more heterogeneous hydrated densities than LDL from control subjects, with enrichment in the triglyceride content of the lighter population. ¹²⁵I-LDL from normal and Type 2 diabetic subjects bound to fibroblasts with similar binding affinities and binding capacities. The kinetics of degradation of LDL from normal and Type 2 diabetic subjects by fibroblasts were also similar. Furthermore, all populations of LDL particles from Type 2 diabetic patients were bound and degraded by normal fibroblasts in identical fashions. In addition, ¹²⁵I-LDL from normal and Type 2 diabetic subjects were not bound or degraded by mouse peritoneal macrophages. It is concluded that the LDL of patients with Type 2 diabetes with moderate hyperglycaemia are not modified sufficiently to alter their normal binding and degradation by human fibroblasts or to cause their uptake by mouse peritoneal macrophages.     

维生素E、维生素C对糖尿病患者心血管保护作用的研究

本文测定了57例2型糖尿病患者(2-DM组)和57例健康人(对照组)血浆内维生素E、维生素C的水平与低密度脂蛋白和高密度脂蛋白的变化情况，结果发现两组维生素E的水平无显著差异；维生素C水平2-DM组低于对照组。认为补充维生素E及维生素C可增强机体的抗氧化能力，调节脂质代谢，从而降低了高血压、冠心病、心肌梗死的发病率。     

Alternate-day dosing of atorvastatin: effects in treating type 2 diabetic patients with dyslipidaemia

Abstract An analysis is made of the effect of alternateday dosing of atorvastatin and standard once-daily dosing, based on mean low-density lipoprotein (LDL) reduction from baseline in type 2 diabetics. Forty-four type 2 diabetics were enrolled in the study. In compliance with American Diabetes Association (ADA) and National Cholesterol Education Program Expert Panel (NCEP-III) guidelines, LDL-C<100 mg/dl was chosen as the treatment target. Patients were assigned to 10 mg atorvastatin as an initial dose every day. The atorvastatin dose was doubled every 6 weeks if the patients failed to reach the treatment target. After achieving LDL<100 mg/dl, the patients were assigned to the corresponding atorvastatin dose every other day for 12 weeks. Thirty-three patients correctly completed the study. LDL-C decreased 39% after the every-day period and 23% after the alternate-day atorvastatin dosing period (p<0.05). The target LDL-C concentration of <100 mg/dl was maintained in 19 patients (57.6%) in the alternate-day period. None of the 33 patients showed elevations in liver enzymes or creatine kinase during the alternate-day dosing period. Alternate-day dosing of atorvastatin could be an effective and safe alternative to daily-dosing in some type 2 diabetic patients.     

依泽替米贝通过上调甾醇调控元件结合蛋白2、低密度脂蛋白受体促进肝细胞摄取低密度脂蛋白胆固醇

目的探讨依泽替米贝对肝脏低密度脂蛋白胆固醇(LDLC)摄取的影响及其机制。方法使用5 mg/(kg·d)依泽替米贝灌胃高脂模型小鼠,4个月后测定其血液中总胆固醇(TC)、LDLC和高密度脂蛋白胆固醇(HDLC)的含量;HE染色观察肝脏组织形态。依泽替米贝(30μmol/L)与低密度脂蛋白(25 mg/L)共同孵育肝脏Hep G2细胞24 h,油红O染色观察细胞的脂滴分布情况;酶学方法检测细胞内TC、游离胆固醇(FC)和胆固醇酯(CE)的含量;采用Di I-LDL检测细胞对LDLC的摄取情况;实时荧光定量PCR和Western blot分别检测甾醇调控元件结合蛋白2(SREBP-2)和低密度脂蛋白受体(LDLR)在mRNA及蛋白水平的表达;流式细胞术检测肝细胞膜上LDLR含量。结果依泽替米贝降低小鼠血浆中TC和LDLC的含量,升高HDLC含量,减少肝脏脂质沉积;提升Hep G2细胞摄取LDLC的能力,促进FC向CE转化;上调Hep G2细胞中SREBP-2和LDLR的表达水平,并增加LDLR在细胞膜上的分布。结论依泽替米贝通过上调SREBP-2、LDLR促进肝细胞摄取LDLC。     

Short-term Acipimox decreases the ability of plasma from Type 2 diabetic patients and healthy subjects to stimulate cellular cholesterol efflux: a potentially adverse effect on reverse cholesterol transport.

AIMS: To evaluate the effect of short-term administration of the anti-lipolytic agent, Acipimox, on the ability of plasma to stimulate cellular cholesterol removal, which represents one of the first steps in the anti-atherogenic process of reverse cholesterol transport. METHODS: Eight male Type 2 diabetic patients and eight healthy subjects were studied after a 12-h fast at baseline, after 24 h of Acipimox administration, 250 mg every 4 h, and again after 1 week (recovery). Plasma lipids, apolipoprotein AI, phospholipid transfer protein (PLTP) activity, pre-beta high-density lipoproteins (HDL) in incubated plasma and efflux of radiolabelled cholesterol from Fu5AH rat hepatoma cells to plasma were measured at each time point. RESULTS: Acipimox lowered plasma triglycerides in diabetic patients (P = 0.001) and healthy subjects (P = 0.002), whereas plasma non-esterified fatty acids were decreased in diabetic patients (P = 0.001) compared with the averaged values at baseline and recovery. Acipimox decreased HDL cholesterol in healthy subjects (P = 0.007) and plasma apolipoprotein AI in both groups (P = 0.001 for diabetic patients; P = 0.008 for healthy subjects). Not only plasma PLTP activity (P = 0.001 for diabetic patients; P = 0.01 for healthy subjects), but also pre-beta HDL in incubated plasma (P = 0.001 for diabetic patients; P = 0.03 for healthy subjects) and cellular cholesterol efflux to plasma (P = 0.04 for diabetic patients; P = 0.005 for healthy subjects) were lowered by Acipimox in both groups. CONCLUSIONS: Short-term Acipimox administration impairs the ability of plasma from Type 2 diabetic patients and healthy subjects to stimulate cellular cholesterol efflux, in conjunction with alterations in HDL parameters and in PLTP activity. If the impairment of cellular cholesterol efflux to plasma is sustained with long-term treatment, this potentially adverse effect should be considered when treating diabetic dyslipidaemia with Acipimox. Diabet. Med. 18, 509-513 (2001)     

The role of dietary cholesterol in the regulation of postprandial apolipoprotein B48 levels in diabetes

The atherogenicity of intestinally derived postprandial lipoproteins has been confirmed in a number of recent studies. We have shown abnormalities in postprandial lipoprotein metabolism in diabetic patients, a group with an increased susceptibility to atherosclerosis. This study examined the relationship between dietary cholesterol and the postprandial, intestinally derived, apolipoprotein B48 and apolipoprotein B100 from the liver. We compared 10 non-insulin-dependent (Type 2, NIDDM) diabetic patients and 10 age-matched non-diabetic control subjects. Fasting blood was taken and subjects were fed a cholesterol-free, high fat meal. Blood samples were repeated at 2 h, 4 h, 6 h, and 8 h postprandial. The following week fasting blood was collected and subjects were given the same meal with 1g of added cholesterol. Blood was collected at the same time points. Chylomicrons and very low density lipoprotein were isolated by sequential ultracentrifugation and their lipoprotein composition determined. Apolipoproteins B48 and B100 were separated by gradient gel electrophoresis and quantified by densitometric scanning using a low density lipoprotein apolipoprotein B100 standard. Post prandial chylomicron cholesterol and triglyceride increased after the high cholesterol meal in both groups (p < 0.001). The postprandial chylomicron apolipoprotein B48 response of both diabetic and control subjects to the cholesterol meal was less than to the cholesterol-free meal (p < 0.001). Fasting very low density lipoprotein apolipoprotein B48 was higher in diabetic patients compared to control subjects and their postprandial increase following the cholesterol-free meal was significantly greater (p < 0.001). There was a 10-fold increase in the incremental postprandial VLDL apolipoprotein B48 area under the curve after the cholesterol-rich meal in the diabetic patients compared to a 3-fold increase in control subjects. The postprandial very low density lipoprotein apolipoprotein B100 was similar in the two groups with both meals. The study demonstrates a very significant increase in the amount of intestinally derived small apolipoprotein B48-associated particles in the very low density lipoprotein fraction following a cholesterol-rich meal in diabetic patients. Synthesis rather than clearance may be the major cause of the increase in these atherogenic postprandial particles. © 1997 John Wiley & Sons, Ltd.