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New oral therapies for type 2 diabetes.

Over the past few years, several oral agents for the treatment of type 2 diabetes have become available in the United States. Metformin, a biguanide that has been used for decades in other countries throughout the world, improves glycemic control without exacerbating hyperinsulinemia or promoting weight gain. This agent has recently been reintroduced in the United States. Acarbose is an alpha-glucosidase inhibitor that improves glycemic control by decreasing the intestinal absorption of glucose, thereby decreasing postprandial glucose elevations. The use of metformin and acarbose may be limited by their side effects and potential risks, especially the risk of lactic acidosis with metformin. The third newly available agent, troglitazone, has been shown to improve insulin sensitivity. Combinations of metformin, acarbose and troglitazone may facilitate improved glycemic control without the use of insulin, or they may allow sulfonylurea or insulin dosages to be reduced, in this way minimizing the adverse effects of hyperinsulinemia. Unfortunately, current oral therapies do not prevent the inevitable decline in glycemic control that occurs during the natural history of type 2 diabetes.

Acarbose↗

Rapid induction of peroxisome proliferator-activated receptor gamma expression in human monocytes by monosodium urate monohydrate crystals.

OBJECTIVE: Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a member of the nuclear hormone receptor superfamily and functions as a key regulator of lipid and glucose metabolism, atherosclerosis, and inflammatory responses. This study was undertaken to evaluate the biologic role of PPAR gamma in self-limiting episodes of acute gouty arthritis. To do this, we investigated PPAR gamma expression by monosodium urate monohydrate (MSU) crystal-stimulated monocytes, and we studied the effects of PPAR gamma ligands on crystal-induced acute inflammation. METHODS: PPAR gamma expression by MSU crystal-stimulated human peripheral blood mononuclear cells was determined by reverse transcription-polymerase chain reaction and immunostaining. Expression of CD36 on monocytes was detected by flow cytometric analysis. The effects of PPAR gamma ligands on in vitro crystal-induced cytokine production and on in vivo cellular infiltration during crystal-induced acute inflammation were also investigated. RESULTS: MSU crystals rapidly and selectively induced PPAR gamma expression by monocytes. Gene expression was detected as early as 2 hours, and maximum expression was observed at 4 hours after stimulation. The induced PPAR gamma was functional, since a PPAR gamma ligand was able to up-regulate CD36 expression on monocytes. A natural ligand of PPAR gamma, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15deoxy-PGJ(2)), significantly reduced the crystal-induced production of cytokines by monocytes. Indomethacin inhibited cytokine production only at high concentrations, and an antidiabetic thiazolidinedione (troglitazone) failed to exert significant effects. Administration of troglitazone and 15deoxy-PGJ(2) significantly prevented cellular accumulation in a mouse air-pouch model of MSU crystal-induced acute inflammation. CONCLUSION: Rapid induction of PPAR gamma expression on monocytes by MSU crystals may contribute, at least in part, to the spontaneous resolution of acute attacks of gout.

Acute Disease↗

Stimulation by eicosapentaenoic acids of leptin mRNA expression and its secretion in mouse 3T3-L1 adipocytes in vitro.

Recent evidence indicates that both leptin and eicosapentaenoic acids (EPA) improve insulin sensitivity. In the present study, we examined the effect of EPA on endogenous leptin expression in 3T3-L1 adipocytes to clarify whether the EPA's effect is exerted through leptin expression. EPA caused a time- and dose-dependent increase of leptin mRNA levels in 3T3-L1 adipocytes. Leptin mRNA expression was significantly increased up to 309.4 +/- 17.0% of the control by 24 h (P < 0.01; n = 6). Leptin secretion was also significantly increased up to 193.3 +/- 12.1% of the control by 24 h (P < 0.01; n = 6). EPA is a ligand for peroxisome proliferator-activated receptors (PPARs) with the highest affinity to PPARalpha. We examined the effect on leptin expression of clofibrate, a ligand for PPARalpha, bezafibrate, for PPARbeta, or troglitazone, for PPARgamma, to clarify whether these ligands for PPARs could mimic EPA-induced stimulation of leptin expression. Neither clofibrate nor bezafibrate affected leptin mRNA expression, whereas troglitazone significantly suppressed leptin mRNA expression. On the other hand, inhibition by 6-diazo-5-oxo-l-norleucine of the rate-limiting enzyme in hexosamine biosynthesis blunted EPA-induced stimulation of leptin mRNA expression and its secretion. These data suggest that EPA up-regulates leptin gene expression and its secretion probably through a hexosamine biosynthetic pathway.

3T3 Cells↗

Down regulation of peroxisome proliferator-activated receptorgamma expression by inflammatory cytokines and its reversal by thiazolidinediones.

AIMS/HYPOTHESIS: Previous studies show that inflammatory cytokines play a part in the development of insulin resistance. Thiazolidinediones were developed as insulin-sensitizing drugs and are ligands for the peroxisome proliferator-activated receptory (PPARgamma). We hypothesized that the anti-diabetic mechanism of thiazolidinediones depends on the quantity of PPARgamma in the insulin resistant state in which inflammatory cytokines play a part. METHODS: We isolated rat PPARgamma1 and gamma2 cDNAs and examined effects of various cytokines and thiazolidinediones on PPARgamma mRNA expression in rat mature adipocytes. RESULTS: Various inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha), interleukin-1alpha (IL-1alpha), IL-1beta, IL-6 and leukaemia inhibitory factor decreased PPARgamma mRNA expression. In addition, hydrogen peroxide, lysophosphatidylcholine or phorbol 12-myristate 13-acetate also decreased the expression of PPARgamma. The suppression of PPARgamma mRNA expression caused by 10 nmol/l of TNF-alpha was reversed 60% and 55% by treatment with 10(-4) mol/l of troglitazone and 10(-4) mol/l of pioglitazone, respectively. The suppression of glucose transporter 4 mRNA expression caused by TNF-alpha was also reversed by thiazolidinediones. Associated with the change of PPARgamma mRNA expression, troglitazone improved glucose uptake suppressed by TNF-alpha. CONCLUSION/INTERPRETATION: Our study suggests that inflammatory cytokines could be factors that regulate PPARgamma expression for possible modulation of insulin resistance. In addition, we speculate that the regulation of PPARgamma mRNA expression may contribute to the anti-diabetic mechanism of thiazolidinediones.

Adipocytes↗

Antiproliferative effect of fluvastatin and thiazolidinedione in mesangial cells of diabetic rats.

Treatment with hydroxymethylglutaryl coenzyme A reductase inhibitors and thiazolidinedione derivatives may prevent the development of diabetic nephropathy. The precise mechanisms of the beneficial effects of these agents in mesangial cells are uncertain. We cultured mesangial cells from Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model for human type 2 diabetes mellitus. The effects of fluvastatin and/or troglitazone on DNA synthesis were determined. Fluvastatin in combination with troglitazone markedly inhibited DNA synthesis and induced apoptosis in mesangial cells from OLETF rats. Combined therapy with fluvastatin and thiazolidinedione derivatives may be effective for suppression of mesangial cell proliferation in the early phase of diabetes, thereby possibly slowing the evolution of diabetic glomerulopathy.

Animals↗

Impact of thiazolidenediones on serum lipoprotein levels.

The thiazolidinediones, acting through peroxisome proliferator-activated receptor chi (PPARchi), affect multiple areas of metabolism. Of increasing importance is the recognition that these agents affect lipoprotein metabolism and cause changes in serum lipid and lipoprotein levels. All three thiazolidinediones, including troglitazone (which was withdrawn in the year 2000), rosiglitazone, and pioglitazone, tend to increase high-density lipoprotein (HDL) cholesterol, increase the size/decrease the density of low-density lipoprotein (LDL) particles, and raise the level of lipoprotein(a). In addition, troglitazone and pioglitazone, but not rosiglitazone, lower triglyceride levels modestly, thereby further contributing to increases in LDL and HDL size. The mechanism for these effects is still being clarified, but may involve enhancement of triglyceride clearance (in the case of pioglitazone), alteration of apolipoprotein C-III levels, reduction of hepatic lipase, and increase in ATP binding cassette A1 (ABCA1) activity. The clinical implications of these effects need further exploration.

Clinical Trials as Topic↗

Identification and regulation of novel PPAR-gamma splice variants in human THP-1 macrophages.

We have previously identified four novel isoforms of PPAR-gamma transcripts in monkey macrophages (J. Zhou, K.M. Wilson, J.D. Medh, Genetic analysis of four novel peroxisome proliferator receptor-gamma splice variants in monkey macrophages. Biochem. Biophys. Res. Commun., 293 (2002) 274-283). The purpose of this study was to ascertain that these isoforms are also present in humans. Specific primers were designed to amplify individual isoform transcripts. The presence of PPAR-gamma4, PPAR-gamma5, and PPAR-gamma7 transcripts in human THP-1 macrophages was confirmed by RT-PCR and sequencing. A transcript corresponding to PPAR-gamma6 was not detected. The presence of novel full-length transcripts and protein was also ascertained by Northern and Western blot analysis. Treatment of THP-1 cells with 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) resulted in more than 20% induction in the expression of PPAR-gamma5 and PPAR-gamma7 transcripts by both Northern blot analysis and RT-PCR. Another PPAR-gamma ligand, troglitazone, induced expression of only PPAR-gamma5. Both ligands inhibited the expression of PPAR-gamma1 and PPAR-gamma2. Additionally, 15d-PGJ2 and troglitazone increased the level of apolipoprotein E transcript by 60% but decreased lipoprotein lipase expression by 15% in THP-1 cells. The differential regulation of PPAR-gamma transcripts suggests that each transcript isoform may contribute to macrophage function.

Alternative Splicing↗

Suppression of prostaglandin E2 receptor subtype EP2 by PPARgamma ligands inhibits human lung carcinoma cell growth.

Prostaglandin E(2) (PGE(2)), a major cyclooxygenase (COX-2) metabolite, plays important roles in tumor biology and its functions are mediated through one or more of its receptors EP1, EP2, EP3, and EP4. We have shown that the matrix glycoprotein fibronectin stimulates lung carcinoma cell proliferation via induction of COX-2 expression with subsequent PGE(2) protein biosynthesis. Ligands of peroxisome proliferator-activated receptor gamma (PPARgamma) inhibited this effect and induced cellular apoptosis. Here, we explore the role of the PGE(2) receptor EP2 in this process and whether the inhibition observed with PPARgamma ligands is related to effects on this receptor. We found that human non-small cell lung carcinoma cell lines (H1838 and H2106) express EP2 receptors, and that the inhibition of cell growth by PPARgamma ligands (GW1929, PGJ2, ciglitazone, troglitazone, and rosiglitazone [also known as BRL49653]) was associated with a significant decrease in EP2 mRNA and protein levels. The inhibitory effects of BRL49653 and ciglitazone, but not PGJ2, were reversed by a specific PPARgamma antagonist GW9662, suggesting the involvement of PPARgamma-dependent and -independent mechanisms. PPARgamma ligand treatment was associated with phosphorylation of extracellular regulated kinase (Erk), and inhibition of EP2 receptor expression by PPARgamma ligands was prevented by PD98095, an inhibitor of the MEK-1/Erk pathway. Butaprost, an EP2 agonist, like exogenous PGE(2) (dmPGE(2)), increased lung carcinoma cell growth, however, GW1929 and troglitazone blocked their effects. Our studies reveal a novel role for EP2 in mediating the proliferative effects of PGE(2) on lung carcinoma cells. PPARgamma ligands inhibit human lung carcinoma cell growth by decreasing the expression of EP2 receptors through Erk signaling and PPARgamma-dependent and -independent pathways.

Base Sequence↗

Up-regulation of ADRP in fatty liver in human and liver steatosis in mice fed with high fat diet.

The present study was performed to examine a role of adipose differentiation-related protein (ADRP) in the process of liver steatosis. Immunohistochemical findings indicated that ADRP expression is increased in the hepatocytes in patients with fatty liver when compared with normal liver. ADRP expression is localized in the surface of lipid droplets in the hepatocytes. Increased expression of ADRP mRNA and protein was similarly observed in fatty liver in ob/ob mice and the liver steatosis induced by high fat diet in mice. The up-regulation of ADRP mRNA and protein in the liver by high fat diet was identified in the surface of lipid droplets in a time-dependent manner. Recent studies demonstrated that up-regulation of PPARgamma in the hepatocytes is deeply involved in liver steatosis. To clarify whether ADRP expression is increased by PPARgamma activation in hepatocytes, we examined the effect of a PPARgamma ligand, troglitazone, on ADRP mRNA expression in HepG2 cells. ADRP mRNA expression was increased by troglitazone in dose- and time-dependent manners. All these results suggest that ADRP is up-regulated in liver steatosis in human and mice, and that high fat diet increases expression of ADRP through PPARgamma activation, followed by induction of liver steatosis.

Animals↗

Regulatory effects of synthetic liver X receptor- and peroxisome-proliferator activated receptor agonists on sterol transport pathways in polarized cerebrovascular endothelial cells.

The blood-brain barrier contributes to maintain brain cholesterol metabolism and protects this uniquely balanced system from exchange with plasma lipoprotein cholesterol. Brain capillary endothelial cells, representing a physiological barrier to the central nervous system, express apolipoprotein A-I (apoA-I, the major high-density lipoprotein (HDL)-associated apolipoprotein), ATP-binding cassette transporter A1 (ABCA1), and scavenger receptor, class B, type I (SR-BI), proteins that promote cellular cholesterol mobilization. Liver X receptors (LXRs) and peroxisome-proliferator activated receptors (PPARs) are regulators of cholesterol transport, and activation of LXRs and PPARs has potential therapeutic implications for lipid-related neurodegenerative diseases. To clarify the functional impact of LXR/PPAR activation, sterol transport along the: (i) ABCA1/apoA-I and (ii) SR-BI/HDL pathway was investigated in primary, polarized brain capillary endothelial cells, an in vitro model of the blood-brain barrier. Activation of LXR (24(S)OH-cholesterol, TO901317), PPARalpha (bezafibrate, fenofibrate), and PPARgamma (troglitazone, pioglitazone) modulated expression of apoA-I, ABCA1, and SR-BI on mRNA and/or protein levels without compromising transendothelial electrical resistance or tight junction protein expression. LXR-agonists and troglitazone enhanced basolateral-to-apical cholesterol mobilization in the absence of exogenous sterol acceptors. Along with the induction of cell surface-located ABCA1, several agonists enhanced cholesterol mobilization in the presence of exogenous apoA-I, while efflux of 24(S)OH-cholesterol (the major brain cholesterol metabolite) in the presence of exogenous HDL remained unaffected. Summarizing, in cerebrovascular endothelial cells apoA-I, ABCA1, and SR-BI represent drug targets for LXR and PPAR-agonists to interfere with cholesterol homeostasis at the periphery of the central nervous system.

ATP Binding Cassette Transporter 1↗

Peroxisome proliferator activated receptor-gamma (PPARgamma) represses thyroid hormone signaling in growth plate chondrocytes.

Peroxisome proliferator activated receptors (PPARs) are DNA-binding nuclear hormone receptors that are upregulated in response to high fat diets. PPARs are structurally related to the type II nuclear receptors, including the thyroid hormone receptors (TRs). To investigate if PPARs modulate TR-mediated terminal differentiation of growth plate chondrocytes, primary cultures of epiphyseal chondrocytes transiently transfected with TRalpha and PPARgamma expression vectors were treated with the PPAR ligands ciglitazone or troglitazone. Forced overexpression of PPARgamma decreased TRalpha1-mediated transcriptional activity and suppressed T3-induced increases in alkaline phosphatase activity and type X collagen expression. Similar effects were observed when the cells were treated with the PPARgamma activator ciglitazone or troglitazone. Overexpression of retinoid X receptor-alpha (RXRalpha) partially restored not only the inhibition of transcriptional activation by PPARgamma but also T3-induced hypertrophic differentiation. These data demonstrate that activation of PPARgamma signaling by either addition of PPARgamma ligands or overexpression of PPARgamma in growth plate chondrocytes inhibits TR-mediated gene transcription and inhibits the biological effects of thyroid hormone on terminal differentiation. The molecular mechanism involved in this inhibition appears to be competition between PPARgamma and TRalpha for limiting amounts of the heterodimeric partner RXR.

Animals↗

Capsaicin inhibits the production of tumor necrosis factor alpha by LPS-stimulated murine macrophages, RAW 264.7: a PPARgamma ligand-like action as a novel mechanism.

Capsaicin, a major ingredient of hot pepper, is considered to exhibit anti-inflammatory properties. Our previous study demonstrated that capsaicin inhibited the production of pro-inflammatory mediators through NF-kappaB inactivation in LPS-stimulated macrophages. In order to further clarify the mechanism underlying the anti-inflammatory action of capsaicin, we investigated whether capsaicin alters PPARgamma activity, which regulates the production of the pro-inflammatory cytokine TNFalpha. Capsaicin significantly inhibited the production of TNFalpha by macrophages in a dose-dependent manner. Simultaneous exposure of the cells to capsaicin and PPARgamma agonist troglitazone or RXR agonist LG100268 resulted in stronger inhibition of TNFalpha production compared to the cells treated with either capsaicin, troglitazone, or LG100268 alone. Luciferase reporter assay revealed that capsaicin induced GAL4/PPARgamma chimera and full length PPARgamma (PPRE) transactivations in a dose-dependent manner. Furthermore, a specific PPARgamma antagonist T0070907 abrogated the inhibitory action of capsaicin on LPS-induced TNFalpha production by RAW 264.7 cells, indicating that capsaicin acts like a ligand for PPARgamma. Our data demonstrate for the first time that the anti-inflammatory action of capsaicin may be mediated by PPARgamma activation in LPS-stimulated RAW 264.7 cells.

Animals↗

15-Deoxy-delta(12,14)-prostaglandin J(2) inhibits IL-1beta-induced IKK enzymatic activity and IkappaBalpha degradation in rat chondrocytes through a PPARgamma-independent pathway.

Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands have been shown to inhibit the effects of proinflammatory cytokines such as interleukin-1beta (IL-1beta). This cytokine plays a key role in articular pathophysiologies by inducing the production of inflammatory mediators such as nitric oxide (NO) and prostaglandin E(2) (PGE(2)). We previously demonstrated that 15d-PGJ(2) was more potent than troglitazone to counteract IL-1beta effects on chondrocytes. Here, we studied the action of 15d-PGJ(2) on intracellular targets in nuclear factor-kappaB (NF-kappaB) signalling pathway in IL-1beta treated rat chondrocytes. We found that 15d-PGJ(2) decreased inhibitor kappaBalpha (IkappaBalpha) degradation but not its phosphorylation by specifically inhibiting IkappaB kinase beta (IKKbeta), but not IKKalpha, enzymatic activity. We further evaluated the involvement of PPARgamma in the anti-inflammatory action of its ligands. In chondrocytes overexpressing functional PPARgamma protein, 15d-PGJ(2) pre-treatment inhibited inducible NO synthase and COX-2 mRNA expression, nitrite and PGE(2) production, p65 translocation and NF-kappaB activation. Troglitazone or rosiglitazone pre-treatment had no effect. 15d-PGJ(2) exhibited the same effect in chondrocytes overexpressing mutated PPARgamma protein. These results suggest that 15d-PGJ(2) exerts its anti-inflammatory effect in rat chondrocytes by a PPARgamma-independent mechanism, which can be conferred to a partial inhibition of IkappaBalpha degradation.

Animals↗

Basic fibroblast growth factor enhances PPARgamma ligand-induced adipogenesis of mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are capable of differentiating into a variety of lineages, including bone, cartilage, or fat, depending on the inducing stimuli and specific growth and differentiation factors. It is widely acknowledged that basic fibroblast growth factor (bFGF) modulates chondrogenic and osteogenic differentiation of MSCs, but thorough investigations of its effects on adipogenic differentiation are lacking. In this study, we demonstrate on the cellular and molecular level that supplementation of bFGF in different phases of cell culture leads to a strong enhancement of adipogenesis of MSCs, as induced by an adipogenic hormonal cocktail. In cultures receiving bFGF, mRNA expression of peroxisome proliferator-activated receptor gamma2 (PPARgamma2), a key transcription factor in adipogenesis, was upregulated even prior to adipogenic induction. In order to investigate the effects of bFGF on PPARgamma ligand-induced adipogenic differentiation, the thiazolidinedione troglitazone was administered as a single adipogenic inducer. Basic FGF was demonstrated to also strongly increase adipogenesis induced by troglitazone, that is, bFGF clearly increased the responsiveness of MSCs to a PPARgamma ligand.

Adipocytes↗

Heat-shock protein 27 is a major methylglyoxal-modified protein in endothelial cells.

In endothelial cells cultured under high glucose conditions, methylglyoxal is the major intracellular precursor in the formation of advanced glycation endproducts. We found that endothelial cells incubated with 30 mM d-glucose produced approximately 2-fold higher levels of methylglyoxal but not 3-deoxyglucosone and glyoxal, as compared to 5 mM d-glucose. Under hyperglycaemic conditions, the methylglyoxal-arginine adduct argpyrimidine as detected with a specific antibody, but not N(e)-(carboxymethyl)lysine and N(e)-(carboxyethyl)lysine, was significantly elevated. The glyoxylase I inhibitor HCCG and the PPARgamma ligand troglitazone also increased argpyrimidine levels. Increased levels of argpyrimidine by glucose, HCCG and troglitazone are accompanied by a decrease in proliferation of endothelial cells. A 27 kDa protein was detected as a major argpyrimidine-modified protein. With in-gel digestion and mass spectrometric analysis, we identified this major protein as heat-shock protein 27 (Hsp27). This argpyrimidine modification of Hsp27 may contribute to changes in endothelial cell function associated to diabetes.

Cells, Cultured↗

Antihyperglycemic activity of Tarralin, an ethanolic extract of Artemisia dracunculus L.

The studies reported here were undertaken to examine the antihyperglycemic activity of an ethanolic extract of Artemisia dracunculus L., called Tarralin in diabetic and non-diabetic animals. In genetically diabetic KK-A(gamma) mice, Tarralin treatment by gavage (500 mg/kg body wt./day for 7 days) lowered elevated blood glucose levels by 24% from 479+/-25 to 352+/-16 mg/dl relative to control animals. In comparison, treatment with the known antidiabetic drugs, troglitazone (30 mg/kg body wt./day) and metformin (300 mg/kg body wt./day), decreased blood glucose concentrations by 28% and 41%, respectively. Blood insulin concentrations were reduced in the KK-A(gamma) mice by 33% with Tarralin, 48% with troglitazone and 52% with metformin. In (STZ)-induced diabetic mice, Tarralin treatment, (500 mg/kg body wt./day for 7 days), also significantly lowered blood glucose concentrations, by 20%, from 429+/-41 to 376+/-58 mg/dl relative to control. As a possible mechanism, Tarralin was shown to significantly decrease phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression by 28% in STZ-induced diabetic rats. In non-diabetic animals, treatment with Tarralin did not significantly alter PEPCK expression, blood glucose or insulin concentrations. The extract was also shown to increase the binding of glucagon-like peptide (GLP-1) to its receptor in vitro. These results indicate that Tarralin has antihyperglycemic activity and a potential role in the management of diabetic states.

Animals↗

Viability assessment in sandwich-cultured rat hepatocytes after xenobiotic exposure.

Troglitazone, bosentan and glibenclamide inhibit the bile salt export pump (Bsep) which transports taurocholate into bile. Sandwich-cultured rat hepatocytes maintain functional sodium taurocholate co-transporting polypeptide and Bsep transport proteins, and may be useful to study inhibition of transport by xenobiotics at concentrations below the lowest observable adverse effect level (LOAEL). The purpose of this study was to compare viability assessments determined with the neutral red, lactate dehydrogenase (LDH), alamar blue, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and propidium iodide assays in sandwich-cultured rat hepatocytes following exposure to xenobiotics known to inhibit Bsep, and to define the LOAEL for these xenobiotics in this system. The neutral red assay was not amenable to use in this model due to crystal formation on the collagen. Troglitazone decreased viability in every assay examined, with a LOAEL approximately 100 microM. Bosentan also decreased viability as measured by the LDH, MTT and propidium iodide assays, with a LOAEL approximately 200 microM; however, a significant decrease in viability was not observed with the alamar blue assay. Glibenclamide did not decrease viability with any assay at the xenobiotic concentrations examined in this study. Based on the results of this study, the LDH or propidium iodide assays would be the methods of choice to assess viability in sandwich-cultured rat hepatocytes after xenobiotic exposure.

Animals↗

Cardiovascular risk continuum: implications of insulin resistance and diabetes.

Although low-density lipoprotein (LDL) cholesterol is a critically important factor in the development of atherosclerosis, nearly half the patients with coronary artery disease have LDL cholesterol levels within the National Cholesterol Education Program (NCEP) guidelines. Therefore, attention has focused on other modifiable risk factors that could strongly impact the development of coronary artery disease. Type 2 diabetics have a 3-fold increased risk of coronary artery disease; prediabetics, without chronic hyperglycemia, have a 2-fold increased risk compared with normal subjects. Insulin resistance has also been implicated as the cause of atherosclerosis. Insulin resistance is associated with hyperinsulinemia and a constellation of other factors, some of which are themselves independent risk factors for coronary artery disease. These include reduced levels of high-density lipoprotein (HDL) cholesterol, hypertriglyceridemia, increased small dense LDL particles, hypertension, visceral obesity, and increased levels of plasminogen activator inhibitor-1 (PAI-1). Hyperinsulinemia and insulin resistance at the vascular level also may contribute to vascular injury and the atherosclerotic process. Current studies suggest that controlling hyperglycemia, LDL cholesterol, and blood pressure are important to protect the diabetic from atherosclerosis. A key question, particularly in type 2 diabetes, is to define the best regimen for glucose control that will protect the vasculature. Sulfonylureas, metformin, and troglitazone have direct vascular actions. Metformin lowers LDL cholesterol and triglycerides, while troglitazone reverses many of the components associated with the insulin resistance syndrome. Clinical trials focusing on coronary artery disease outcomes are now warranted to prevent coronary artery disease, the major vascular complication and cause of mortality in diabetes.

Arteriosclerosis↗