Metabolism of plasma low density lipoproteins in familial combined hyperlipidaemia: effect of acipimox therapy.

Ten male patients with familial combined hyperlipidaemia (FCHL) were studied with regard to LDL metabolism and composition. The FCHL patients had higher LDL levels than healthy controls (5.4 +/- 1.4 vs. 3.7 +/- 0.7 mmol l-1; P < 0.005) and a higher rate of production of the lipoprotein (15.8 +/- 3.1 mg kg-1 d-1 in FCHL vs. 13.1 +/- 1.8 mg kg-1 d-1 in the normals; P < 0.005). The fractional catabolic rate of LDL was low-normal in the FCHL patients, with a high level of interindividual variation. The actual individual LDL cholesterol level within the FCHL patient group appeared to be more closely associated with the LDL apoB FCR value than the rate of production of the particle. Analysis of the LDL particles from FCHL patients revealed a relative enrichment in triglycerides, while the cholesterol content of the lipoprotein was normal. Institution of acipimox therapy in 8 patients reversed the high rate of synthesis of LDL (15.2 +/- 3.5 mg kg-1 d-1) to a more normal level (13.9 +/- 4.0 mg kg-1 d-1; P = 0.08), while the FCR did not change significantly. In conclusion, patients with FCHL show an apparent overproduction of LDL apoB, while the actual degree of LDL elevation appears to be dependent on the clearance capacity of the lipoprotein, measured as LDL apoB FCR. The overproduction defect of LDL apoB can, at least in part, be managed by treatment with the nicotinic acid analogue acipimox.     

Effects of intensive insulin therapy alone and in combination with pioglitazone on body weight, composition, distribution and liver fat content in patients with type 2 diabetes

Aim: To evaluate the effects of intensive insulin therapy alone and with added pioglitazone on body weight, fat distribution, lean body mass (LBM) and liver fat in type 2 diabetic patients. Methods: Twenty‐five insulin‐treated, obese patients with type 2 diabetes were randomized to addition of pioglitazone 45 mg (n = 12) or placebo (n = 13) and treated intensively for 12–16 weeks. Dual‐energy X‐ray absorptiometry/abdominal computed tomography scans were performed before/after treatment. LBM, visceral/subcutaneous adipose tissue (VAT/SAT) and liver/spleen (L/S) attenuation ratios were measured pre‐/posttreatment (a ratio <1 represents fatty liver). Results: Intensive insulin alone and insulin + pioglitazone significantly improved glycaemic control (7.8 ± 0.3 to 7.2 ± 0.3% and 7.6 ± 0.3 to 7.1 ± 0.4%, respectively). Body weight gain was greater with insulin + pioglitazone (4.9 ± 4.5 kg) versus insulin therapy alone (1.7 ± 0.7 kg). SAT increased significantly with pioglitazone + insulin therapy (393.9 ± 48.5 to 443.2 ± 56.7 cm², p < 0.01) compared to a non‐significant increase with insulin therapy alone (412.9 ± 42.5 to 420.8 ± 43.8 cm²). VAT decreased non‐significantly in both groups (240.3 ± 41.7 to 223.8 ± 38.1 cm² with insulin + pioglitazone and 266.6 ± 27.4 to 250.5 ± 22.2 cm² with insulin therapy). LBM increased significantly by 1.92 ± 0.74 kg with insulin + pioglitazone treatment. The L/S attenuation ratio in the placebo + insulin group decreased from 1.08 ± 0.1 to 1.04 ± 0.1 (p = ns) and increased from 1.00 ± 0.1 to 1.08 ± 0.05 (p = 0.06) in the pioglitazone + insulin group. Conclusions: Intensification of insulin therapy in type 2 diabetic patients causes modest weight gain and no change in body fat distribution, LBM or liver fat. In contrast, the addition of pioglitazone, at equivalent glycaemia, increases weight gain, fat mass and SAT; increases LBM and tends to decrease liver fat. These changes in fat distribution may contribute to the beneficial effects of pioglitazone, despite greater weight gain.     

Both cerivastatin and fenofibrate improve arterial vasoreactivity in patients with combined hyperlipidaemia

OBJECTIVES: The aim of this study was to compare the effects of cerivastatin and fenofibrate on endothelium dependent and independent arterial dilation. DESIGN: In a prospective, double blind study, 38 overweight, nonsmoking, males aged between 40 and 60 years with combined hyperlipidaemia were randomized and, after 6 weeks run-in phase with American Heart Association step I diet treatment, submitted to 12 weeks' treatment either with fenofibrate (250 mg daily) or cerivastatin. Cerivastatin was given in a daily dose of 0.2 mg for 6 weeks and was increased to 0.4 mg daily, if the LDL-C did not decrease below 3.0 mmol x L(-1). Flow-mediated (endothelium-dependent) dilation (FMD) and nitroglycerin-induced (endothelium-independent) [gliceryltrinitrate (GTN)] dilation of brachial artery were measured using high resolution ultrasound. RESULTS: The FMD increased from 3.4 +/- 3.3 to 9.3 +/- 2.4% (P < 0.001) in the cerivastatin group, and from 3.3 +/- 2.8 to 6.5 +/- 3.1% (P < 0.001) in the fenofibrate group, the improvement being significantly better after cerivastatin (P=0.006). GTN increased from 11.5 +/- 4.1 to 16.2 +/- 3.5% (P < 0.01) and from 11.1 +/- 2.5 to 16.0 +/- 2.9% (P < 0.01), respectively, with no difference between the groups. Cerivastatin reduced total cholesterol by 24%, LDL-cholesterol by 31%, triglycerides by 24%, ox-LDL by 29% and increased HDL-cholesterol by 5%, whilst, after fenofibrate, these changes were -15, -13, -41, -17 and 18%, respectively. Only the decrease of LDL-C turned out to be an independent predictor the FMD improvement. The improvement in GTN-induced dilation did not correlate with the changes in blood lipids. CONCLUSIONS: Both cerivastatin and fenofibrate lead to an improvement of endothelium-dependent and endothelium-independent dilation of brachial artery in overweight patients with combined hyperlipidaemia and no other atherosclerotic risk factors. The effects on FMD were greater in subjects receiving cerivastatin than in subjects receiving fenofibrate, but the effects on GTN were equal in both groups.     

Cardiovascular risk factors and testing of relatives amongst patients with familial hyperlipidaemia one decade after a clinical trial

OBJECTIVES: We examined the cardiovascular disease risk factor status of men and women with familial hyperlipidaemia (FH) 10-11 years after a clinical trial and asked whether first-degree relatives had undergone lipid testing. DESIGN SETTING AND SUBJECTS: Subjects started lipid-lowering drugs in 1987-88. Of 60 subjects, 12 had died, one emigrated and 35 men and 12 women took part in a follow-up clinical examination in 1998. RESULTS: Total cholesterol level was reduced by 41% and high-density lipoprotein (HDL) cholesterol level increased by 13% compared with baseline (diet alone). Low-density lipoprotein (LDL) cholesterol level was lower at the end of the trial than at follow-up (3.6 +/- 1.5 vs. 4.6 +/- 2.2 mmol L-1; P = 0.01) and was higher in the group taking a low dose of a statin alone compared with other drug groups. Thus, two-thirds of the subjects required adjustment of lipid-lowering drugs to reach target lipid levels. One-fifth consumed at least two food groups rich in saturated fat regularly. Body mass index (BMI) increased from 25.6 +/- 2.9 to 26.8 +/- 3.3 kg m-2 (P < 0.001). Five subjects compared with one at baseline had type II diabetes or glucose intolerance; 12 compared with four at baseline had a blood pressure of >/= 160 mmHg systolic or >/= 95 mmHg diastolic. Plasma total homocysteine was higher in subjects with coronary artery disease than in subjects without disease (11.7 +/- 3.9 vs. 9.0 +/- 2.3 micromol L-1; P = 0.01). Barriers to testing for lipids amongst children or siblings included family feuds, fear of increased insurance and psychiatric disease. CONCLUSION: The majority of subjects were undertreated. Increases in BMI, blood pressure and glucose levels and the diet posed challenges to risk reduction. Plasma homocysteine levels should be considered in this group. Testing of all first-degree relatives may not be achievable because of psychological barriers.     

Effects of pioglitazone and rosiglitazone combined with metformin on body weight in people with diabetes

Currently, pioglitazone and rosiglitazone are the thiazolidinediones available for clinical use. In the literature, there are different studies concerning the efficacy, safety and tolerability of thiazolidinediones as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin alone. Metformin and thiazolidinediones are both antihyperglycaemic drugs, both lower blood glucose concentrations in type 2 diabetes without causing overt hypoglycaemia and both require the presence of insulin to generate their therapeutic effects, but act without stimulating insulin secretion. Some authors reported that the improved glycaemic control obtained with thiazolidinediones is associated with an increase in body weight with an estimated 2–3 kg weight gain for every 1% decrease in HbA_1c which could negate some of the benefits of the improved metabolic control. Some other authors, instead, reported that thiazolidinediones give a better improvement in the glycaemic control compared with metformin alone without giving weight gain. The emerging discrepancies from these studies could be because of the study design, the patient selection, the degree of glycaemic control and/or the methods to measure body weight. We have undertaken a thorough literature search on Medline and Embase to evaluate the effects of thiazolidinediones plus metformin combination in people with diabetes on the body weight.     

Long-term treatment experience in a subject with Dunnigan-type familial partial lipodystrophy: efficacy of rosiglitazone.

Dunnigan-type familial partial lipodystrophy (FPLD) is caused by mutations in LMNA, the gene that encodes nuclear lamins A and C. FPLD is characterized by peripheral fat loss, excess central adiposity, insulin resistance, and hyperlipidaemia, which are difficult to treat. We present our 2 years' experience of treatment with rosiglitazone in a subject with FPLD. Insulin requirement decreased significantly from 240 IU/day to 76 IU/day (range 20-240 IU/day) and serum triglyceride concentration was lowered from 13.7 +/- 14.4 mmol/l to 4.5 +/- 4.3 mmol/l and remained stable. Mean HbA(1c) prior to rosiglitazone therapy was 9.4 +/- 1.32% and decreased to 7.4 +/- 0.6% during therapy with rosiglitazone. This case demonstrates the benefits of PPARgamma-agonists on glycaemic control and dyslipidaemia in a patient with FPLD. This in turn implies that PPARgamma may play a pathophysiological role in FPLD.     

Glycaemic control and familial factors determine hyperlipidaemia in early childhood diabetes. Oxford Regional Prospective Study of Childhood Diabetes.

AIMS: To determine whether abnormal lipid levels in children with Type 1 diabetes mellitus are the result of poor metabolic control or may in part be determined by genetic factors. METHODS: Non-fasting lipid levels were measured in 141 children with Type 1 diabetes (age range 7.7-19 years) 3 years after diagnosis, and in 192 of their parents. Glycosylated haemoglobin and the urinary albumin-creatinine ratio (three urine samples) were estimated in each child annually. RESULTS: The children had a mean total cholesterol of 4.46 +/- 1.25 mmol/l (+/- SD) and a median triacylglycerol of 1.18 mmol/l (range 0.32-4.7). A total of 15.3% of the population had a total cholesterol > 5.2 mmol/l and 17.9% had a triacylglycerol > 1.7 mmol/l; in 5.6% both total cholesterol and triacylglycerol were greater than these cut-off points. Total cholesterol, triacylglycerol and very low density lipoprotein-cholesterol were significantly correlated to glycaemic control. However, total cholesterol was also significantly related to parental total cholesterol either as analysed separately or as mean parental total cholesterol (r = 0.37, P = 0.0001). In stepwise multiple regression analysis both mean parental total cholesterol (P = 0.001) and HbA1c (P = 0.015) were significant determinants of the child's total cholesterol. The children studied were being followed prospectively for the development of microalbuminuria and there was a weak association across tertiles of total cholesterol, linking higher levels to the development of microalbuminuria (P < 0.05). CONCLUSIONS: We conclude that both glycaemic control and familial factors may be important determinants of lipid levels in young people with diabetes. Both may contribute to the subsequent risk of cardiovascular disease and possibly the development of incipient diabetic nephropathy.     

吡格列酮和胰岛素对内皮祖细胞增殖和凋亡及分泌一氧化氮的影响

目的观察吡格列酮和胰岛素对大鼠骨髓内皮祖细胞(EPCs)的增殖能力、凋亡及分泌NO能力的影响,并探讨其机制。方法取正常SD大鼠32只,随机分为吡格列酮组和非吡格列酮组,各16只,分别给予吡格列酮和生理盐水灌胃预处理。喂养10天后,断颈处死,密度梯度离心法取骨髓单个核细胞,在M199培养液中培养扩增EPCs并进行鉴定。贴壁细胞培养4天后,将吡格列酮组EPCs消化后进一步分为两组,分别给予胰岛素(1nmol/L)或空白干预,非吡格列酮组EPCs处理同吡格列酮组EPCs。24h后检测NO水平,3天后检测凋亡情况,7天后检测细胞增殖能力。结果吡格列酮预处理能提高EPCs数量(P<0.01),吡格列酮预处理和(或)体外给予胰岛素干预组EPCs与未处理组细胞相比EPCs增殖能力提高(P<0.01),凋亡程度降低(P<0.05),培养上清中NO浓度增加(P<0.05)。结论体内吡格列酮预处理与体外胰岛素干预均能促进EPCs增殖,抑制EPCs凋亡,并促进EPCs分泌NO,且两种药物联合应用具有协同作用。     

血浆apoB100水平升高不宜作为家族性混合型高脂血症与家族性高胆固醇血症鉴别诊断的指标

目的 探讨家族性混合型高脂血症与家族性高胆固醇血症血浆载脂蛋白A1（apoA1)、载脂蛋白B100（apoB100)水平的异同。方法 病例－对照／家系设计,家族性混合型高脂血症家系15个（93人）;家族性高胆固醇血症家系11个（94人）;对照家系12个（67人）。比较家系间及家系内受累组与未受累组血浆apoA1与apoB100水平。结果 两种高脂血症家系间及两种家系内受累组间血浆apoA1与apoB100水平未见统计学显著性差异;与对照家系相比,两种高脂血症家系血浆apoB100水平均显著升高（P＜0．01）,同时,家系内受累组血浆apoB100水平显著高于未受累组（P＜0．01）。结论 两种高脂血症家系受累组血浆apoB100水平均显著升高,故血浆apoB100水平升高不宜作为家族性混合型高脂血症与家族性高胆固醇血症鉴别诊断的指标。     

Rosiglitazone and pioglitazone similarly improve insulin sensitivity and secretion, glucose tolerance and adipocytokines in type 2 diabetic patients

Objective: We examined the effects of rosiglitazone treatment on profiles of adipocytokines levels, postprandial insulin and glucose excursion, lipids levels, comparing with those of pioglitazone treatment in patients with type 2 diabetes mellitus (T2DM). Methods: Changes in body weight, haemoglobin A_1c (HbA_1c), glucose/insulin/C‐peptide/free fatty acid (FFA) during 75 g oral glucose tolerance test (OGTT), HDL‐/LDL‐cholesterol, triglyceride (TG) and adipocytokines [tumour necrosis factor (TNF)‐α, leptin and adiponectin] were measured in T2DM patients treated with rosiglitazone, 8 mg/day (n = 35), or pioglitazone, 45 mg/day (n = 21), for 3 months. Results: After rosiglitazone or pioglitazone treatment, HbA_1c (8.6–7.2 vs. 8.3–6.9%, rosiglitazone vs. pioglitazone), fasting plasma glucose (190–144 vs. 178–140 mg/dl), fasting FFA (729–595 vs. 641–526 μEq/l), mean plasma glucose‐OGTT (292–229 vs. 285–233 mg/dl) and mean FFA‐OGTT (580–430 vs. 488–377 μEq/l) decreased similarly and all were statistically significant (p < 0.01). The insulinogenic index (ΔI_0–120/ΔG_0–120) (0.19–0.30 vs. 0.17–0.26) and Matsuda index of insulin sensitivity (2.0–3.1 and 2.7–4.3) increased (p < 0.01) similarly, despite increase in body weight (85–88 vs. 81–84 kg). TNF‐α (3.8–3.4 vs. 5.2–4.5 pg/ml) decreased (p < 0.05) and adiponectin (6.3–17.8 vs. 7.1–16.4 μg/ml) increased (p < 0.01), while leptin did not change following either treatment. After rosiglitazone treatment, plasma HDL‐cholesterol (34–38 mg/dl) and LDL‐cholesterol (103–120 mg/dl) increased (p < 0.01), while TGs (177–167 mg/dl) did not change significantly. After pioglitazone treatment, plasma HDL‐cholesterol (34–37 mg/dl) increased (p < 0.05), while LDL‐cholesterol (104–105 mg/dl) did not change and TGs (153–106 mg/dl) decreased (p < 0.01). Conclusions: Rosiglitazone and pioglitazone have similar beneficial effects on glycaemic control insulin sensitivity, insulin secretion and plasma adipocytokine levels. However, pioglitazone has a more beneficial effect on the plasma lipid profile than rosiglitazone.     

Statin therapy and risk of diabetes in patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia

Objective

Controversial findings exist regarding potential influence of statin therapy on diabetic incidence. Aim of this study was to investigate the role of long duration statin treatment on diabetes mellitus (DM) incidence of Heterozygous Familial Hypercholesterolemia (hFH) and Familial Combined Hyperlipidemia (FCH) patients.

Methods

Study population consisted of 212 hFH and 147 FCH patients that visited Lipid Outpatient Department (mean follow up of 11 and 10 years respectively). Several clinical data such as history of DM, cardiovascular disease, thyroid function, metabolic syndrome, glucose levels, lipid profile and lifestyle data were obtained. In order to compare the effects of different doses of different types of statins, a “statin treatment intensity product” was used.

Results

14% of FCH and only 1% of hFH patients developed DM during follow up. Although univariate analysis showed a statistical trend (p = 0.06) in the association between new onset DM and statin treatment intensity (STI) in the FCH subgroup of patients with normal baseline glucose levels, this was no longer significant after adjusting for several confounders. Furthermore, the type of statins used did not seem to play a role in the development of DM either in hFH or FCH patients.

Conclusion

Long duration of high STI does not seem to be associated with diabetic risk in hFH patients. High STI used in the FCH population is not associated with increased risk of new onset DM compared to low STI. Further studies are required in order to clarify the potential diabetogenic effects of statins in these high risk populations.     

Effects of intensive insulin therapy alone and with added pioglitazone on renal salt/water balance and fluid compartment shifts in type 2 diabetes

Objective: To evaluate the effects of intensive insulin therapy alone or with added pioglitazone on renal salt/water balance and body fluid compartment shifts in type 2 diabetes. Methods: A total of 25 insulin‐treated, obese patients with type 2 diabetes were randomized to pioglitazone 45 mg (n = 12) or placebo (n = 13) and treated intensively for 12–16 weeks to achieve equivalent glycaemic control. We measured total body water (TBW) and extracellular/intracellular fluid by bioimpedance analysis; plasma/RBC volume with I¹³¹albumin; sodium handling by fractional excretion of sodium/lithium (FeNa/FeLi) and other renal/hormonal parameters. Results: Intensification of insulin therapy and the addition of pioglitazone significantly improved glycaemia (HbA1C 7.8–7.2% and 7.6–7.1%) and increased body weight (1.7 and 4.9 kg) respectively. TBW increased 1.7 l with insulin alone (65% intracellular) and 1.6 l with added pioglitazone (75% extracellular) (p = 0.06 and 0.09 respectively). Plasma volume increased 0.2 ± 0.1 l with insulin alone (p = 0.05) and 0.4 ± 0.1 l with added pioglitazone (p < 0.05). Extravascular, extracellular (interstitial) fluid increased significantly and more with added pioglitazone (0.8 ± 0.2 l, p < 0.01) than with insulin alone (0.4 ± 0.2 l, p = ns). At steady‐state, FeLi (marker of proximal‐tubular sodium delivery to the distal nephron) increased significantly with added pioglitazone (12.4 ± 1.3 to 18.0 ± 3.2%) vs. no significant change with insulin alone (15.4 ± 1.2 to 14.5 ± 2.3%). There were no significant changes in the other parameters. Conclusion: In intensively insulin‐treated obese type 2 diabetic patients, at equivalent glycaemic control, the addition of pioglitazone causes greater weight gain, but a similar increase in body water that is mainly extracellular and interstitial compared with intracellular increase with insulin therapy alone. Pioglitazone also increases the filtered load of sodium reabsorbed at the distal nephron with no net change in FeNa.     

家族性混合型高脂血症与脂蛋白脂酶基因的连锁分析

目的 探讨脂蛋白脂酶基因与家族性混合型高脂血症是否连锁，以期发现家族性混合型高脂血症遗传易感位点。方法 从北京地区搜集12个（81人）家族性混合型高脂血症家系选择脂蛋白脂酶基因及其附近的微卫星遗传标记（LPLGZ14／15与D8S282）进行连锁分析。结果 CENEHUNTER软件包多点连锁分析显示微卫星遗传标记最大LOD score(HLOD)值如下：HLODLPLGZ14／15＝－8．9及HLODD8S282＝－10．5。结论 中国北京地区家族性混合型高脂血症家系提示，脂蛋白脂酶基因不是影响家族性混合型高脂血症表型的遗传易感基因。     

吡格列酮对胰岛素抵抗HepG2细胞胰岛素受体底物表达的影响

目的探讨毗格列酮对胰岛索抵抗（IR）HepG2细胞胰岛素受体底物（IRS）蛋白表达的影响。方法胰岛素抵抗HepG2细胞模型建立后,培养液中加入吡格列酮共同孵育,观察吡格列酮对模型细胞葡萄糖掺入率的影响;应用免疫细胞化学染色法观察吡格列酮对IR HepG2细胞IRS-1、IRS-2表达的影响。结果与模型细胞组比较,1×10^-5mol／L吡格列酮显著提高了HepG2细胞的葡萄糖掺入率（P〈0．01）,使IRHepG2细胞IRS-1、IRS-2蛋白的表达显著增加（P〈0．05）。结论吡格列酮的胰岛素增敏作用可能与胰岛素信号转导分子IRS-1、IRS-2蛋白的表达增强有关。     

吡格列酮对非酒精性脂肪肝的疗效观察

目的寻找一安全有效的治疗非酒精性脂肪性肝病的方法。方法将非酒精性脂肪性肝病患者43例随机分组,吡格列酮组22例(n=22),对照组21例(n=21),比较两组疗效(观察ALT,GGT,TG,HOMA-IR,BMI等指标)。结果3个月时,两组的观察指标均有改善,虽治疗组更明显,但无显著差异(P>0.05),6个月时,ALT,GGT,TG,HOMA-IR及疗效,治疗组与对比组比较,疗效有显著差异(19/22,11/21,P<0.05)。结论胰岛素增敏剂(吡格列酮)治疗NAFLD,安全、有效,值得临床推广应用。