Human Bone Marrow Endothelial Progenitor Cell Transplantation into Symptomatic ALS Mice Delays Disease Progression and Increases Motor Neuron Survival by Repairing Blood-Spinal Cord Barrier.

Convincing evidence demonstrated impairment of the blood-spinal cord barrier (BSCB) in Amyotrophic Lateral Sclerosis (ALS), mainly by endothelial cell (EC) alterations. Replacing damaged ECs by cell transplantation is a potential barrier repair strategy. Recently, we showed that intravenous (iv) administration of human bone marrow CD34+ (hBM34+) cells into symptomatic ALS mice benefits BSCB restoration and postpones disease progression. However, delayed effect on motor function and some severely damaged capillaries were noted. We hypothesized that hematopoietic cells from a restricted lineage would be more effective. This study aimed to establish the effects of human bone marrow-derived endothelial progenitor cells (hBMEPCs) systemically transplanted into G93A mice at symptomatic disease stage. Results showed that transplanted hBMEPCs significantly improved behavioral disease outcomes, engrafted widely into capillaries of the gray/white matter spinal cord and brain motor cortex/brainstem, substantially restored capillary ultrastructure, significantly decreased EB extravasation into spinal cord parenchyma, meaningfully re-established perivascular astrocyte end-feet, and enhanced spinal cord motor neuron survival. These results provide novel evidence that transplantation of hBMEPCs effectively repairs the BSCB, potentially preventing entry of detrimental peripheral factors, including immune/inflammatory cells, which contribute to motor neuron dysfunction. Transplanting EC progenitor cells may be a promising strategy for barrier repair therapy in this disease.

Reduction of microhemorrhages in the spinal cord of symptomatic ALS mice after intravenous human bone marrow stem cell transplantation accompanies repair of the blood-spinal cord barrier.

Blood-spinal cord barrier (BSCB) alterations, including capillary rupture, have been demonstrated in animal models of amyotrophic lateral sclerosis (ALS) and ALS patients. To date, treatment to restore BSCB in ALS is underexplored. Here, we evaluated whether intravenous transplantation of human bone marrow CD34+ (hBM34+) cells into symptomatic ALS mice leads to restoration of capillary integrity in the spinal cord as determined by detection of microhemorrhages. Three different doses of hBM34+ cells (5 × 104, 5 × 105 or 1 × 106) or media were intravenously injected into symptomatic G93A SOD1 mice at 13 weeks of age. Microhemorrhages were determined in the cervical and lumbar spinal cords of mice at 4 weeks post-treatment, as revealed by Perls' Prussian blue staining for ferric iron. Numerous microhemorrhages were observed in the gray and white matter of the spinal cords in media-treated mice, with a greater number of capillary ruptures within the ventral horn of both segments. In cell-treated mice, microhemorrhage numbers in the cervical and lumbar spinal cords were inversely related to administered cell doses. In particular, the pervasive microvascular ruptures determined in the spinal cords in late symptomatic ALS mice were significantly decreased by the highest cell dose, suggestive of BSCB repair by grafted hBM34+ cells. The study results provide translational outcomes supporting transplantation of hBM34+ cells at an optimal dose as a potential therapeutic strategy for BSCB repair in ALS patients.

Endothelial and Astrocytic Support by Human Bone Marrow Stem Cell Grafts into Symptomatic ALS Mice towards Blood-Spinal Cord Barrier Repair.

Vascular pathology, including blood-CNS barrier (B-CNS-B) damage via endothelial cell (EC) degeneration, is a recently recognized hallmark of Amyotrophic Lateral Sclerosis (ALS) pathogenesis. B-CNS-B repair may be a new therapeutic approach for ALS. This study aimed to determine effects of transplanted unmodified human bone marrow CD34+ (hBM34+) cells into symptomatic G93A mice towards blood-spinal cord barrier (BSCB) repair. Thirteen weeks old G93A mice intravenously received one of three different doses of hBM34+ cells. Cell-treated, media-treated, and control mice were euthanized at 17 weeks of age. Immunohistochemical (anti-human vWF, CD45, GFAP, and Iba-1) and motor neuron histological analyses were performed in cervical and lumbar spinal cords. EB levels in spinal cord parenchyma determined capillary permeability. Transplanted hBM34+ cells improved behavioral disease outcomes and enhanced motor neuron survival, mainly in high-cell-dose mice. Transplanted cells differentiated into ECs and engrafted within numerous capillaries. Reduced astrogliosis, microgliosis, and enhanced perivascular end-feet astrocytes were also determined in spinal cords, mostly in high-cell-dose mice. These mice also showed significantly decreased parenchymal EB levels. EC differentiation, capillary engraftment, reduced capillary permeability, and re-established perivascular end-feet astrocytes in symptomatic ALS mice may represent BSCB repair processes, supporting hBM34+ cell transplantation as a future therapeutic strategy for ALS patients.

Fenofibrate, HDL, and cardiovascular disease in Type-2 diabetes: The DAIS trial.

BACKGROUND: There are conflicting reports on the role of fibrates in CVD-risk. Several studies indicate beneficial effects of fibrates on CVD risk in type-2 diabetic patients. We tested how fenofibrate changes lipoprotein subfractions and glucose homeostasis in type-2 diabetic patients. STUDY DESIGN: Selected markers of lipid and glucose homeostasis and inflammation were measured in 204 diabetic patients who participated in the Diabetes Atherosclerosis Intervention Study (DAIS) and were randomly assigned to 200 mg fenofibrate or placebo. Percent changes from baseline until a minimum of 3 years (average 39.6 months) on therapy (end of study) were calculated for all study parameters. RESULTS: The concentrations of total LDL-C and small dense LDL-C (sdLDL-C) did not change on fenofibrate compared to placebo. Compared to placebo, fenofibrate significantly decreased concentrations of triglyceride and remnant-like particle cholesterol (RLP-C) and activity of lipoprotein-associated phospholipase A2 (Lp-PLA2), while significantly increased concentrations of HDL-C. In contrast to other lipid-modifying drugs (e.g. statins) which increase HDL-C by increasing large (α-1) HDL particles, fenofibrate increased HDL-C by increasing the smaller, less antiatherogenic HDL-C particles, α-3 and α-4. Furthermore, despite lowering TG levels by 20%, fenofibrate failed to decrease pre-ß1 levels. On fenofibrate, glycated serum-protein levels increased moderately, while insulin and adiponectin levels did not change. CONCLUSION: On fenofibrate, lipid homeostasis improved and Lp-PLA2 activity decreased while there was no improvement in glucose homeostasis. Despite increasing HDL-C and decreasing triglyceride levels, fenofibrate failed to improve the antiatherogenic properties of the HDL subpopulation profile.

Appropriate revascularization in stable angina: lessons from the BARI 2D trial.

BACKGROUND: The 2012 Guidelines for Diagnosis and Management of Patients with Stable Ischemic Heart Disease recommend intensive antianginal and risk factor treatment (optimal medical management [OMT]) before considering revascularization to relieve symptoms. The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial randomized patients with ischemic heart disease and anatomy suitable to revascularization to (1) initial OMT with revascularization if needed or (2) initial revascularization plus OMT and found no difference in major cardiovascular events. Ultimately, however, 37.9% of the OMT group was revascularized during the 5-year follow-up period. METHODS: Data from the 1192 patients randomized to OMT were analyzed to identify subgroups in which the incidence of revascularization was so high that direct revascularization without a trial period could be justified. Multivariate logistic analysis, Cox regression models of baseline data, and a landmark analysis of participants who did not undergo revascularization at 6 months were constructed. RESULTS: The models that used only data available at the time of study entry had limited predictive value for revascularization by 6 months or by 5 years; however, the model incorporating severity of angina during the first 6 months could better predict revascularization (C statistic = 0.789). CONCLUSIONS: With the possible exception of patients with severe angina and proximal left anterior descending artery disease, this analysis supports the recommendation of the 2012 guidelines for a trial of OMT before revascularization. Patients could not be identified at the time of catheterization, but a short period of close follow-up during OMT identified the nearly 40% of patients who underwent revascularization.

How can we improve the management of vascular risk in type 2 diabetes: insights from FIELD.

PURPOSE: Intensive multifactorial risk factor intervention, targeting blood glucose, blood pressure and low-density lipoprotein cholesterol, is central to therapeutic management of type 2 diabetes. This strategy reduces, but does not eliminate the risk for cardiovascular complications, and microvascular complications such as diabetic retinopathy and nephropathy still continue to develop or progress. Fibrates have been shown to be effective in managing mixed dyslipidemia characterized by elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C), typically associated with type 2 diabetes. METHODS: Data were reviewed from the largest fibrate study to date, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study which evaluated the effect of fenofibrate treatment in 9,795 patients with type 2 diabetes (about 80% without prior cardiovascular disease or microvascular complications). RESULTS: Although FIELD did not show a significant benefit with fenofibrate for major coronary events (the primary outcome), there was significant reduction in total cardiovascular events (relative risk reduction [RRR] 11%, p = 0.035 vs. placebo). The clinical benefits of fenofibrate treatment were greater in patients with marked mixed dyslipidemia (elevated triglycerides >or=200 mg/dL and low plasma levels of HDL-C), features of the metabolic syndrome commonly observed in patients with type 2 diabetes, with a RRR of 27%, p = 0.005. These data are consistent with evidence from other fibrate trials showing increased treatment benefits in patients with metabolic syndrome or type 2 diabetes and mixed dyslipidemia. The FIELD study also provided promising data for microvascular benefits with fenofibrate, specifically on the need for laser treatment for diabetic retinopathy, progression of albuminuria, and prevention of diabetes-related lower-limb amputation. CONCLUSIONS: Adding fenofibrate to primary statin therapy might be a useful strategy to address residual macrovascular and microvascular risk in type 2 diabetes.

Safety and tolerability of dalcetrapib.

Efficacy and safety data for dalcetrapib (RO4607381/JTT-705) are presented, following a report of increased mortality and cardiac events with another cholesteryl ester transfer protein inhibitor, torcetrapib, associated with off-target adverse effects (hypertension and the activation of the renin-angiotensin-aldosterone system). The efficacy and clinical safety of dalcetrapib 300, 600, and 900 mg or placebo were assessed (n = 838) in 4 pooled 4-week phase IIa trials (1 monotherapy, n = 193; 3 statin combination, n = 353) and 1 12-week phase IIb trial (with pravastatin, n = 292). Nonclinical safety, assessed by the induction of aldosterone production and aldosterone synthase (cytochrome P450 11B2) messenger ribonucleic acid, was measured in human adrenocarcinoma (H295R) cells exposed to dalcetrapib or torcetrapib. Dalcetrapib increased high-density lipoprotein cholesterol by up to 36% and apolipoprotein A-I by up to 16%. The incidence of adverse events (AEs) was similar between placebo (42%) and dalcetrapib 300 mg (50%) and 600 mg (42%), with more events with dalcetrapib 900 mg (58%) (p <0.05, pooled 4-week studies). Six serious AEs (3 with placebo, 1 with dalcetrapib 300 mg, and 2 with dalcetrapib 600 mg) were considered "unrelated" to treatment. Cardiovascular AEs were similar across treatment groups, with no dose-related trends and no clinically relevant changes in blood pressure or electrocardiographic results. Findings were similar in the 12-week study. In vitro, torcetrapib but not dalcetrapib increased aldosterone production and cytochrome P450 11B2 messenger ribonucleic acid levels. In conclusion, dalcetrapib alone or in combination with statins was effective at increasing high-density lipoprotein cholesterol and was well tolerated, without clinically relevant changes in blood pressure or cardiovascular AEs and no effects on aldosterone production as assessed nonclinically.

Lipid profiles in patients with rheumatoid arthritis: mechanisms and the impact of treatment.

OBJECTIVE: To describe the impact of rheumatoid arthritis (RA), and its treatment, on lipoprotein levels with potential implications for atherosclerosis. METHODS: A PubMed literature search was undertaken for studies published between 1990 and May 2007, using the search terms "rheumatoid arthritis" AND "lipid" OR "lipoprotein," and including all relevant drug treatment terms for glucocorticoids, disease-modifying antirheumatic drugs, and biologics. RESULTS: Patients with RA face an increased risk of developing premature cardiovascular disease and limited ability to modify risk factors, eg, through exercise. RA is associated with an abnormal lipoprotein pattern, principally low levels of high density lipoprotein (HDL) cholesterol. Most treatments for RA tend to improve the atherogenic index (total/HDL cholesterol ratio), with more evidence for biologics in this regard. The improvement in the lipoprotein profile in RA appears to be associated with suppression of inflammation. CONCLUSIONS: Lipid levels should be monitored and managed in patients with RA to minimize the long-term risk of cardiovascular disease. More research is needed to quantify the relationship between systemic inflammation and lipoprotein levels and to determine the impact of specific lipoprotein particles, eg, small dense low-density lipoprotein and subfractions of HDL on long-term risk. Control of inflammation may have an effect on modifying cardiovascular risk.

Fenofibrate for cardiovascular disease prevention in metabolic syndrome and type 2 diabetes mellitus.

Clinical guidelines highlight the importance of managing atherogenic mixed dyslipidemia to reduce the risk of premature cardiovascular disease in type 2 diabetes mellitus and metabolic syndrome. The lipid-modifying activity of fenofibrate, as demonstrated in clinical studies, indicates its effectiveness in treating dyslipidemia characteristic of these conditions. Fenofibrate also has a favorable impact on a number of nonlipid residual risk factors associated with type 2 diabetes and metabolic syndrome, mediated by peroxisome proliferator-activated receptor-alpha. In patients with type 2 diabetes, fenofibrate is effective in reducing the progression of coronary artery disease, as demonstrated by the Diabetes Atherosclerosis Intervention Study (DAIS). In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, the primary end point (major coronary events) was not significantly reduced by fenofibrate treatment. However, other findings from this study suggest that fenofibrate reduces cardiovascular risk. Both DAIS and the FIELD study also indicate that fenofibrate may offer additional vascular benefits, specifically affecting the progression of diabetes-related microvascular disease.

Lipid lowering in the patients with prediabetes/metabolic syndrome: what is the evidence?

PURPOSE OF REVIEW: Both the metabolic syndrome and prediabetes are associated with increased coronary risk. Lipoprotein abnormalities are among the many factors that may contribute to this. The present review focuses on these abnormalities and the evidence indicating that correcting them may reduce the risk. RECENT FINDINGS: Many drugs, both old and in development, may be able to correct lipoprotein abnormalities. No clinical trials are specifically designed to examine the effects of lipid intervention on coronary risk in the metabolic syndrome. Data from subgroup analyses and extrapolation from studies in those with and without diabetes have led to recommendations about the benefits and the targets for lipoprotein treatment. SUMMARY: The primary goal of lipoprotein treatment is to bring the LDL-C to target levels. Thereafter, if plasma triglycerides are high and HDL-C is low, these should be corrected.

In vivo regulation of phenylalanine hydroxylation to tyrosine, studied using enrichment in apoB-100.

Phenylalanine hydroxylation is necessary for the conversion of phenylalanine to tyrosine and disposal of excess phenylalanine. Studies of in vivo regulation of phenylalanine hydroxylation suffer from the lack of a method to determine intrahepatocyte enrichment of phenylalanine and tyrosine. apoB-100, a hepatic export protein, is synthesized from intrahepatocyte amino acids. We designed an in vivo multi-isotope study, [(15)N]phenylalanine and [2H2]tyrosine to determine rates of phenylalanine hydroxylation from plasma enrichments in free amino acids and apoB-100. For independent verification of apoB-100 as a reflection of enrichment in the intrahepatocyte pool, [1-(13)C]lysine was used as an indicator amino acid (IAA) to measure in vivo changes in protein synthesis in response to tyrosine supplementation. Adult men (n = 6) were fed an amino acid-based diet with low phenylalanine (9 mg.kg(-1).day(-1), 4.54 mumol.kg(-1).,h(-1)) and seven graded intakes of tyrosine from 2.5 (deficient) to 12.5 (excess) mg.kg(-1).day(-1). Gas chromatography-quadrupole mass spectrometry did not detect any tracer in apoB-100 tyrosine. A new and more sensitive method to measure label enrichment in proteins using isotope ratio mass spectrometry demonstrated that phenylalanine hydroxylation measured in apoB-100 decreased linearly in response to increasing tyrosine intake and reached a break point at 6.8 mg.kg(-1).day(-1). IAA oxidation decreased with increased tyrosine intake and reached a break point at 6.0 mg.kg(-1).day(-1). We conclude: apoB-100 is an accurate and useful measure of changes in phenylalanine hydroxylation; the synthesis of tyrosine via phenylalanine hydroxylation is regulated to meet the needs for protein synthesis; and that plasma phenylalanine does not reflect changes in protein synthesis.

Atherosclerosis in type 2 diabetes: a role for fibrate therapy?

Vascular complications associated with type 2 diabetes confer significant morbidity and mortality. Atherosclerosis develops much earlier and progresses more rapidly than in subjects without diabetes. The clustering of cardiovascular risk factors associated with type 2 diabetes is mainly responsible for accelerated atherosclerotic disease. While statins remain the primary lipid-modifying therapy, the pharmacological profile of the fibrates suggests potential as an alternative or additional treatment for reducing the risk of atherosclerotic vascular complications in type 2 diabetes.

Statement of the problem.

The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) study poses 2 questions. Of the options in treating the hyperglycemia of type 2 diabetes mellitus, which, if either, would be best for decreasing the likelihood of death or a serious cardiovascular disease event such as a heart attack: correcting the relative insulin deficiency or reducing insulin resistance? Do individuals with diabetes whose coronary disease can be managed medically have a better outcome with initial medical or interventional (percutaneous intervention or coronary artery bypass grafting) treatment? This article outlines the reasons for asking these questions.

A new perspective in the treatment of dyslipidemia : can fenofibrate offer unique benefits in the treatment of type 2 diabetes mellitus?

Patients with diabetes mellitus are at higher risk for cardiovascular events than those without diabetes. Furthermore, patients with diabetes have a characteristic 'lipid triad' of low high-density lipoprotein-cholesterol (HDL-C) levels, high triglyceride levels, and normal or slightly raised low-density lipoprotein-cholesterol (LDL-C) levels, with a preponderance of small, dense LDL-C particles. Current guidelines on preventing cardiovascular disease recognize the need not only to reduce LDL-C levels, but also to increase HDL-C and decrease triglyceride levels in diabetic patients. Some clinical trials of HMG-CoA reductase inhibitors (statins) have included large populations of diabetic patients. In some of these trials (such as 4S [Scandinavian Simvastatin Survival Study], CARE [Cholesterol and Recurrent Events] trial, and the HPS [Heart Protection Study]), HMG-CoA reductase inhibitor treatment significantly reduced cardiovascular events in diabetic patients, whereas in other trials (ALLHAT-LLT [Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial], ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial]) the reductions were not significant. In CARDS (Collaborative Atorvastatin Diabetes Study), the first large HMG-CoA reductase inhibitor study to enroll only patients with type 2 diabetes, atorvastatin reduced cardiovascular events by 37% (p=0.001) compared with placebo. Fibric acid derivatives (fibrates), which are agonists of peroxisome proliferator-activated alpha receptors, exert their effects by altering the transcription of genes encoding proteins that control lipoprotein metabolism. Fibric acid derivatives are a valuable tool in the treatment of dyslipidemia in patients with diabetes, as they reduce plasma triglyceride levels by 30--50%, increase HDL-C levels by 10--15%, and shift the distribution of LDL subfractions towards larger, less atherogenic particles. The DAIS (Diabetes Atherosclerosis Intervention Study), which was conducted exclusively in patients with type 2 diabetes, found that fenofibrate reduces the progression of angiographic coronary artery disease. The VA-HIT (Veterans Affairs Cooperative Studies Program HDL-C Intervention Trial) showed that gemfibrozil reduced cardiovascular events in subgroups of diabetic patients. A large clinical event study, FIELD (Fenofibrate Intervention and Event Lowering in Diabetes), which is currently being completed, will provide further information on the value of fenofibrate for the reduction of cardiovascular risk in patients with diabetes.

Fibrates and coronary risk reduction.

Many medications are currently available to correct lipoprotein abnormalities when lifestyle measures alone are not sufficient. No single agent or class of agents is able to correct all of the lipoprotein abnormalities. This paper reviews the role of one class, the fibrates, in the management of lipid disorders and summarizes the clinical trial information relating to their impact on coronary artery disease.

Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS).

BACKGROUND: Microalbuminuria is an early marker of diabetic nephropathy and an independent risk factor for cardiovascular disease. In the Diabetes Atherosclerosis Intervention Study (DAIS), treatment of people with type 2 diabetes with micronized fenofibrate for an average of 38 months reduced the progression of angiographically evaluated coronary artery disease and improved lipoprotein level abnormalities compared with placebo. The aim of this analysis is to study the influence of the treatment on changes in urinary albumin excretion. METHODS: Microalbuminuria was measured on 2 to 3 occasions by using timed overnight samples at baseline and yearly thereafter in 314 DAIS participants (77 women, 237 men; average age, 56 years); all except 3 participants had either a normal albumin excretion rate (<20 microg/min; n = 214) or microalbuminuria (albumin, 20 to 200 microg/min; n = 97) before randomization. Tabulated shifts (between normal, microalbuminuria, and macroalbuminuria) from baseline to last observed values were compared between treatment groups by means of chi-square or Fisher's exact test. RESULTS: Fenofibrate significantly reduced the worsening of albumin excretion (fenofibrate, 8% versus placebo, 18%; P < 0.05). This effect was caused mostly by reduced progression from normal albumin excretion to microalbuminuria: 3 of 101 participants in the fenofibrate group versus 20 of 113 participants in the placebo group (P < 0.001). Overall, changes in albumin excretion were independent of age or changes in lipid or creatinine levels, weight, or blood pressure. CONCLUSION: Improvement in lipid profiles with fenofibrate in patients with type 2 diabetes was associated with reduced progression from normal albumin excretion to microalbuminuria.

Response to micronized fenofibrate treatment is associated with the peroxisome-proliferator-activated receptors alpha G/C intron7 polymorphism in subjects with type 2 diabetes.

OBJECTIVE: The association between polymorphisms in candidate genes related to lipoprotein metabolism and the reduction in plasma triglyceride (TG) in response to fenofibrate treatment was evaluated in subjects with type 2 diabetes treated with micronized fenofibrate (200 mg/day) for at least 3 years in the Diabetes Atherosclerosis Intervention Study. METHODS: The cholesteryl ester transfer protein Taq1B, LPL S447X, hepatic lipase -514 C-->T, peroxisome-proliferator-activated receptors alpha (PPARA) L162V and G/C intron 7 polymorphisms and the apolipoprotein E2/E3/E4 alleles were genotyped using PCR and restriction enzyme digestion. Subjects were divided into high TG-responders (with > 30% TG relative reduction after treatment) and low TG-responders. RESULTS: The frequency of the PPARA intron 7 G/G genotype was higher in high TG-responders than in low TG-responders (85% vs. 69%, P < 0.05). There was no significant difference between the percentage of high TG-responders and low TG-responders for any of the other genetic polymorphisms examined. In stepwise logistic regression, baseline TG and only the PPARA intron 7 polymorphism among the others were selected in the model as significant predictors of TG-response (odds ratio: 3.10, 95% CI: 1.28-7.52, P = 0.012 for PPARA polymorphism). With age, gender, body mass index, smoking status and HbA1c as additional factors, baseline TG (P< 0.0001), intron 7 (P = 0.013), body mass index (P = 0.040) and LPL-S447X (P = 0.084) were significant predictors of TG-response. CONCLUSION: These results indicate that elevated baseline TG levels and PPARA gene intron 7 G/G genotype were associated with TG reduction > 30% after fenofibrate treatment in patients with type 2 diabetes.

Increased apoC-III production is a characteristic feature of patients with hypertriglyceridemia.

Apolipoprotein (apo) C-III plays an important role in regulating plasma triglyceride (TG) metabolism. In order to further investigate the plasma metabolism of apoC-III in hypertriglyceridemic subjects, we have studied the plasma kinetics of VLDL apoC-III, HDL apoC-III and total plasma apoC-III with a primed constant intravenous infusion of deuterated leucine in a group of male patients with mixed hyperlipidemia (type IIb hyperlipoproteinemia, HLP, n=6) and in a group with type III HLP (n=6). Compared to normolipidemic control subjects (n=5), patients with type IIb and type III HLP had significantly higher levels of plasma TG (0.89 +/- 0.15 mmol/l vs 2.56 +/- 0.40 mmol/l vs 8.76 +/- 1.39 mmol/l, respectively, P <0.01), plasma apoC-III (9.5 +/- 0.8 mg/dl vs 20.8 +/- 2.5 mg/dl vs 41.7 +/- 5.6 mg/dl, P <0.01) and VLDL apoC-III (3.6 +/- 0.8 mg/dl vs 14.6 +/- 2.2 mg/dl vs 35.4 +/- 5.1 mg/dl, P <0.01). VLDL apoC-III production rates were significantly elevated in type IIb and type III patients (1.35 +/- 0.23 mg kg(-1) day(-1) vs 3.53 +/- 0.43 mg kg(-1) day(-1) vs 5.60 +/- 0.78 mg kg(-1) day(-1), P <0.01), as were total plasma apoC-III production rates (1.80 +/- 0.22 mg kg(-1) day(-1) vs 4.16 +/- 0.44 mg kg(-1) day(-1) vs 7.26 +/- 0.74 mg kg(-1) day(-1), P <0.01). VLDL apoC-III but not total plasma apoC-III fractional catabolic rates were reduced in type IIb and type III patients. Together with our previous results showing an increase of apoC-III production in patients with type IV HLP, and in overweight subjects with reduced insulin sensitivity, our data suggest that increased apoC-III production is a characteristic feature of patients with hypertriglyceridemia.

Rate of production of plasma and very-low-density lipoprotein (VLDL) apolipoprotein C-III is strongly related to the concentration and level of production of VLDL triglyceride in male subjects with different body weights and levels of insulin sensitivity.

Overweight individuals with reduced insulin sensitivity often have mild to moderate hypertriglyceridemia. To investigate the role of apolipoprotein (apo)C-III metabolism in the etiology of hypertriglyceridemia in these individuals, we investigated 10 male subjects with different body weights (body mass index, 24-34 kg/m(2)) and insulin sensitivity (homeostasis model assessment, 4.7-35.0). Total plasma and very-low-density lipoprotein (VLDL) apoC-III kinetics, as well as VLDL triglyceride (TG) and VLDL apoB kinetics, were measured with iv injected stable isotopes. The apoC-III, TG, and apoB levels in VLDL ranged from 2.9-18.2 mg/dl, 0.49-2.89 mmol/liter, and 6.7-29.3 mg/dl, respectively. Mean production rates (PRs) were: VLDL apoC-III, 20.2 +/- 4.1 micromol/d (range, 8.0-44.8); VLDL TG, 26.9 +/- 4.6 mmol/d (range, 10.2-51.1); and VLDL apoB, 4.4 +/- 0.8 micromol/d (range, 1.5-9.1). VLDL apoC-III PRs were significantly correlated with body mass index, homeostasis model assessment, and plasma TG (r = 0.66, P < 0.05; r = 0.80, P < 0.01; r = 0.95, P < 0.001, respectively). Similar correlations were found for plasma apoC-III PRs (r = 0.70, P < 0.05; r = 0.67, P < 0.05; r = 0.80, P < 0.01, respectively). Fractional catabolic rates (FCRs) were not significantly related to metabolic variables. VLDL TG levels were strongly related to VLDL apoC-III levels (r = 0.99, P < 0.001) and VLDL apoC-III PRs (r = 0.94, P < 0.001). VLDL apoC-III levels were more strongly correlated with VLDL TG PRs (r = 0.81, P < 0.01) than with VLDL TG FCRs or VLDL apoB FCRs (r = -0.53, P = 0.12; r = -0.37, P = 0.29). These results suggest that increased hepatic production of VLDL apoC-III is characteristic of subjects with higher body weights and lower levels of insulin sensitivity and is strongly related to the plasma concentration and level of production of VLDL TG.

Fibrates in the metabolic syndrome and in diabetes.

There is increasing evidence that fibrates can reduce coronary artery disease. This finding seems to be particularly the case inpatients with the metabolic syndrome or with diabetes. Their beneficial effects can be explained partly by their effects on lipoproteins,but these effects may also result from some of their nonlipid pleotropic effects. Clinical trials are still needed to determine the potential role played by such pleotropic actions.