SKF 99085 a novel hypocholesterolemic agent with multiple anti-atherosclerotic properties, suppresses HMG-CoA reductase and induces LDL receptor activity by a novel mechanism

Poster abstractPeer reviewe

Perturbation of hormone storage and release induced by cyproheptadine in rat pancreatic islets in vitro

The effects of cyproheptadine (CPH) added in vitro were studied in rat pancreatic islets maintained in culture medium. CPH added over 6 days resulted in either an increase (5 X 10(-7) M CPH) or a marked, but reversible decrease (5 X 10(-5 M) in insulin content of islets when related to that of controls. At both concentrations, however, total recoverable insulin from islets, cells detached from islets, and medium was decreased relative to control cultures. The increased insulin content observed after 6 days with 5 X 10(-7) M CPH may be explained by the partial inhibition of insulin release, preventing the normally occurring early drop in insulin content of control islets. The decreased total recoverable insulin in the culture system with 5 X 10(-5) M CPH (17% of the initial insulin content of the islets placed into the CPH-containing culture medium) was not acounted for by the combined effects of insulin degradation in the culture medium and inhibition of insulin biosynthesis. Together and by exclusion these data suggest increased insulin degradation within beta-cells as a result of exposure to 5 X 10(-5) M CPH. Since increased intracellular insulin degradation was not found at 5 X 10(-7) M CPH, the data suggest that only severe inhibition of insulin release (5 X 10(-5) M CPH) increases intracellular insulin degradation. CPH added in vitro irreversibly decreased islet glucagon content; the data suggest that these effects are due to alterations in the physical properties of the peripheral cell layers of isolated islets. Studies with 5 X 10(-5) M CPH on the biosynthesis of insulin immunoreactive material failed to link the appearance of flocculent material in dilated cisternae of the rough endoplasmic reticulum (observed by electron microscopy) with accumulation of an immunoreactive biosynthetic precursor for insulin

Effects of Niacin Extended-Release and Fenofibrate on Endothelial Function

Aim: Niacin and fenofibrate are to date the most effective available HDL-C raising therapies. We examined the effects of niacin extended-release (ER) and fenofibrate treatment on endothelial function. Methods: In a multicenter, randomized, open-label, cross-over study, dyslipidemic subjects were included; 24 with low HDL-C (<40 mg/dL) and 42 with normal HDL-C (40-59 mg/dL) at baseline, received 6 weeks\u2019 treatment with niacin ER (0.5 g/d then 1 g/d) and fenofibrate (160 mg/d) with 4 weeks\u2019 wash-out between treatments. Lipoprotein composition and particle size distribution were determined using NMR. Endothelial function was assessed by ultrasound brachial flow mediated dilatation (FMD) at start and end of the 6 week treatment periods. Between treatment effects were compared using ANCOVA. In slope analyses within treatments, each of the lipids and lipoproteins were correlated with %FMD, both at baseline and at end of treatment Results: Complete FMD datasets of 19 niacin ER and 17 fenofibrate treatments were available. There was no difference in FMD between treatments (p>0.2). The slope analyses, however, showed correlations between lipids and FMD, the strongest correlations occurred in the niacin ER group. In particular HDL-C (p=0.032), HDL particle size (p=0.009) and LDL sizes correlated with FMD upon niacin ER treatment. Conclusions: There were no differential effects between niacin ER and fenofibrate on endothelial function, however slope analyses revealed lipid modification by niacin ER and (to a lesser extent) fenofibrate can favorably improve endothelial function

Establishment of rat pancreatic endocrine cell lines by infection with simian virus 40.

The feasibility of infection and transformation by SV40 (simian virus 40) of primary cell cultures derived from newborn-rat pancreas was investigated. As judged by the presence of intranuclear SV40 T-antigen, exposure to the virus resulted specifically in infection and transformation of epithelioid (predominantly endocrine) cells. The transformed cells were subcultured (more than 64 passages) and cloned. Culture medium and acid/ethanol extracts of the cells did not contain detectable amounts of immunoreactive insulin after the third subculture. However, inoculation of such SV40-transformed pancreatic cells into immunodeficient rats results in tumours in which insulin production was partially restored through the passage in vivo, since the tumour cells contained and synthesized small amounts of immunoreactive insulin which co-migrated with an insulin marker on gel chromatography. Interestingly, the transformed cells maintained under tissue-culture conditions produced a protein immunologically related to insulin, soluble in aqueous buffer but insoluble in acid/ethanol. This 3000-dalton protein is too large to be a translation product of the rat preproinsulin 9S mRNA. SV40-transformed pancreatic cells might prove useful in the investigation of the factors controlling and maintaining insulin biosynthesis

Effects of niacin extended-release and fenofibrate on endothelial function

Aim: Niacin and fenofibrate are to date the most effective available HDL-C raising therapies. We examined the effects of niacin extended-release (ER) and fenofibrate treatment on endothelial function. Methods: In a multicenter, randomized, open-label, cross-over study, dyslipidemic subjects were included; 24 with low HDL-C (<40 mg/dL) and 42 with normal HDL-C (40-59 mg/dL) at baseline, received 6 weeks\u2019 treatment with niacin ER (0.5 g/d then 1 g/d) and fenofibrate (160 mg/d) with 4 weeks\u2019 wash-out between treatments. Lipoprotein composition and particle size distribution were determined using NMR. Endothelial function was assessed by ultrasound brachial flow mediated dilatation (FMD) at start and end of the 6 week treatment periods. Between treatment effects were compared using ANCOVA. In slope analyses within treatments, each of the lipids and lipoproteins were correlated with %FMD, both at baseline and at end of treatment Results: Complete FMD datasets of 19 niacin ER and 17 fenofibrate treatments were available. There was no difference in FMD between treatments (p>0.2). The slope analyses, however, showed correlations between lipids and FMD, the strongest correlations occurred in the niacin ER group. In particular HDL-C (p=0.032), HDL particle size (p=0.009) and LDL sizes correlated with FMD upon niacin ER treatment. Conclusions: There were no differential effects between niacin ER and fenofibrate on endothelial function, however slope analyses revealed lipid modification by niacin ER and (to a lesser extent) fenofibrate can favorably improve endothelial function

A new selective peroxisome proliferator-activated receptor gamma antagonist with antiobesity and antidiabetic activity.

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) plays a key role in adipocyte differentiation and insulin sensitivity. Its synthetic ligands, the thiazolidinediones (TZD), are used as insulin sensitizers in the treatment of type 2 diabetes. These compounds induce both adipocyte differentiation in cell culture models and promote weight gain in rodents and humans. Here, we report on the identification of a new synthetic PPARgamma antagonist, the phosphonophosphate SR-202, which inhibits both TZD-stimulated recruitment of the coactivator steroid receptor coactivator-1 and TZD-induced transcriptional activity of the receptor. In cell culture, SR-202 efficiently antagonizes hormone- and TZD-induced adipocyte differentiation. In vivo, decreasing PPARgamma activity, either by treatment with SR-202 or by invalidation of one allele of the PPARgamma gene, leads to a reduction of both high fat diet-induced adipocyte hypertrophy and insulin resistance. These effects are accompanied by a smaller size of the adipocytes and a reduction of TNFalpha and leptin secretion. Treatment with SR-202 also dramatically improves insulin sensitivity in the diabetic ob/ob mice. Thus, although we cannot exclude that its actions involve additional signaling mechanisms, SR-202 represents a new selective PPARgamma antagonist that is effective both in vitro and in vivo. Because it yields both antiobesity and antidiabetic effects, SR-202 may be a lead for new compounds to be used in the treatment of obesity and type 2 diabetes

Fenofibrate and extended-release niacin improve the endothelial protective effects of HDL in patients with metabolic syndrome

Background: Fibrates and niacin are at present the most effective therapies to increase plasma levels of high density lipoprotein-cholesterol (HDL-C); to date, limited data are available on their effects on HDL protective functions. Methods and results: Within a multicenter, randomized, open-label, cross-over study, 37 patients with metabolic syndrome received 6 weeks' treatment with fenofibrate or extended-release niacin (ER niacin), with a 4 weeks' wash-out period. HDL ability to preserve endothelial cell homeostasis was assessed by incubating cultured endothelial cells with HDL isolated from patients at baseline and after each treatment. HDL isolated from patients at baseline were as effective as control HDL in inhibiting vascular cell adhesion molecule-1 (VCAM-1) expression, but less efficient in promoting endothelial cell nitric oxide (NO) release. Both fenofibrate and ER niacin increased HDL ability to inhibit TNF\u3b1-induced VCAM-1 expression (+. 7% and +. 11%, respectively). Fenofibrate and ER niacin also improved the impaired HDL ability to induce the expression of endothelial nitric oxide synthase and NO production (+. 10% and +. 8%, respectively). Interestingly, HDL isolated after treatment showed an ability to promote endothelial NO release similar to HDL isolated from controls. No differences were observed between the two drugs. With both drugs, HDL function was improved irrespective of baseline HDL-C levels. Conclusion: Treatment with fenofibrate or ER niacin in patients with metabolic syndrome not only increased HDL-C levels but also improved the endothelial protective effects of HDL

Differential effects of fenofibrate and extended-release niacin on high-density lipoprotein particle size distribution and cholesterol efflux capacity in dyslipidemic patients

BACKGROUND: The effectiveness of therapies that raise high-density lipoprotein cholesterol (HDL-C) to lower cardiovascular disease risk is currently under debate, and further research into the relationship between HDL-C and function is required. OBJECTIVE: o investigate whether 2 established HDL-C-raising therapies had differential effects on parameters of high-density lipoprotein (HDL) quality and function, such as HDL particle profile and cholesterol efflux capacity (CEC), in patients with dyslipidemia. METHODS AND RESULTS: Sixty-six patients with dyslipidemia, 24 with low HDL-C levels (<40 mg/dL) and 42 with normal HDL-C levels (40-59 mg/dL), were treated for 6 weeks with fenofibrate (160 mg/d) or extended-release (ER) niacin (0.5 g/d for 3 weeks, then 1 g/d) with 4 weeks of washout between treatments. Lipoprotein particle size distribution was determined using nuclear magnetic resonance, and pathway-specific serum CECs were assessed in J774 macrophages, hepatoma, and Chinese hamster ovary-human adenosine triphosphate-binding cassette transporter G1 cells. Comparable increases in HDL-C and apolipoprotein A-I levels were seen with fenofibrate and ER niacin. There was a shift toward larger HDL, predominantly to medium-size HDL particles for fenofibrate (+209%) and to large HDL particles for ER niacin (+221%). Minor changes in serum CECs were observed with fenofibrate and ER niacin for all the efflux pathways measured. Small increases in plasma cholesteryl ester transfer protein and lecithin: cholesterol acyltransferase concentrations, and decreases in cholesteryl ester transfer protein activity were seen with both drugs. CONCLUSIONS: Fenofibrate and ER niacin increased plasma HDL-C level similarly, but modulated HDL particle size distribution differently; however, these changes did not result in differential effects on serum CECs