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PubMed2005

Impaired fatty acid metabolism in type 2 diabetic skeletal muscle cells is reversed by PPARgamma agonists.

The impact of type 2 diabetes on the ability of muscle to accumulate and dispose of fatty acids and triglycerides was evaluated in cultured muscle cells from nondiabetic (ND) and type 2 diabetic (T2D) subjects. In the presence of 5 microM palmitate, T2D muscle cells accumulated less lipid than ND cells (11.5 +/- 1.2 vs. 15.1 +/- 1.4 nmol/mg protein, P < 0.05). Chronic treatment (4 days) with the peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist troglitazone increased palmitate accumulation, normalizing uptake in T2D cells. There were no significant differences between groups with regard to the relative incorporation of palmitate into neutral lipid species. This distribution was also unaffected by troglitazone treatment. beta-Oxidation of both long-chain (palmitate) and medium-chain (octanoate) fatty acids in T2D muscle cells was reduced by approximately 40% compared with ND cells. Palmitate oxidation occurred primarily in mitochondrial ( approximately 40-50% of total) and peroxisomal (20-30%) compartments. The diabetes-related defect in palmitate oxidation was localized to the mitochondrial component. Both palmitate and octanoate oxidation were stimulated by a series of thiazolidinediones. Oxidation in T2D muscle cells was normalized after treatment. Troglitazone increased the mitochondrial component of palmitate oxidation. Skeletal muscle cells from T2D subjects express defects in free fatty acid metabolism that are retained in vitro, most importantly defects in beta-oxidation. These defects can be corrected by treatment with PPARgamma agonists. Augmentation of fatty acid disposal in skeletal muscle, potentially reducing intramyocellular triglyceride content, may represent one mechanism for the lipid-lowering and insulin-sensitizing effects of thiazolidinediones.

Adult↗
PubMed2006

Tissue-specific expression and regulation of GSK-3 in human skeletal muscle and adipose tissue.

Glycogen synthase kinase-3 (GSK-3) is a ubiquitous kinase implicated in both insulin action and adipogenesis. To determine how these multiple roles may relate to insulin resistance, we studied the regulation of GSK-3 protein expression and phosphorylation in skeletal muscle and isolated adipocytes from nonobese healthy control (HC), obese control (OC), and obese type 2 diabetic (OT2D) subjects. At baseline there were no differences in the GSK-3 protein expression in adipocytes. OC subjects underwent a 6-mo caloric restriction resulting in a 7% decrease in body mass index (BMI) and a 21% improvement in insulin-stimulated whole body glucose disposal rate (GDR). GSK-3alpha and GSK-3beta expression decreased in adipocytes (P < 0.05), whereas GSK-3alpha protein expression increased in skeletal muscle (P < 0.05). OT2D subjects were treated with troglitazone or metformin for 3-4 mo. After troglitazone treatment GDR improved (P < 0.05) despite an increase in BMI (P < 0.05), whereas metformin had no significant effect on GDR. There was no significant change in GSK-3 expression in adipocytes following troglitazone, whereas both GSK-3alpha and -beta were decreased in skeletal muscle (P < 0.05). Metformin treatment had no significant impact on GSK-3 protein expression in either adipocytes or skeletal muscle. Neither treatment influenced GSK-3 serine phosphorylation in skeletal muscle or adipocytes. These results suggest that there is tissue specificity for the regulation of GSK-3 in humans. In skeletal muscle GSK-3 plays a role in control of metabolism and insulin action, whereas the function in adipose tissue is less clear.

Adult↗
PubMed2002

Glitazones regulate glutamine metabolism by inducing a cellular acidosis in MDCK cells.

We studied the effect of the antihyperglycemic glitazones, ciglitazone, troglitazone, and rosiglitazone, on glutamine metabolism in renal tubule-derived Madin-Darby canine kidney (MDCK) cells. Troglitazone (25 microM) enhanced glucose uptake and lactate production by 108 and 92% (both P < 0.001). Glutamine utilization was not inhibited, but alanine formation decreased and ammonium formation increased (both P < 0.005). The decrease in net alanine formation occurred with a change in alanine aminotransferase (ALT) reactants, from close to equilibrium to away from equilibrium, consistent with inhibition of ALT activity. A shift of glutamine's amino nitrogen from alanine into ammonium was confirmed by using L-[2-(15)N]glutamine and measuring the [(15)N]alanine and [(15)N]ammonium production. The glitazone-induced shift from alanine to ammonium in glutamate metabolism was dose dependent, with troglitazone being twofold more potent than rosiglitazone and ciglitazone. All three glitazones induced a spontaneous cellular acidosis, reflecting impaired acid extrusion in responding to both an exogenous (NH) and an endogenous (lactic acid) load. Our findings are consistent with glitazones inducing a spontaneous cellular acidosis associated with a shift in glutamine amino nitrogen metabolism from predominantly anabolic into a catabolic pathway.

Acidosis↗
PubMed2001

Peroxisome proliferator-activated receptor-gamma activity is associated with renal microvasculature.

Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a nuclear transcription factor and the pharmacological target for antidiabetic thiazolidinediones (TZDs). TZDs ameliorate diabetic nephropathy and have direct effects on cultured mesangial cells (MCs); however, in situ hybridization failed to detect expression of PPAR gamma in glomeruli in vivo. The purpose of this study was to determine whether PPAR gamma is expressed in renal glomeruli. Two rabbit PPAR gamma isoforms were cloned. Nuclease protection assays demonstrate that both PPAR gamma isoforms are expressed in freshly isolated glomeruli. Treatment of rabbits with the TZD troglitazone selectively induced expression of an endogenous PPAR gamma target gene, adipocyte fatty acid-binding protein (A-FABP), in renal glomerular cells and renal medullary microvascular endothelial cells, demonstrated by both in situ hybridization and immunostain. Troglitazone also dramatically increased A-FABP expression in cultured MCs. Constitutive PPAR gamma expression was detected in cultured rabbit MCs. Endogenous MC PPAR gamma can also drive PPAR gamma reporter. Troglitazone and 15-deoxy-Delta 12,14 prostaglandin J(2) at low concentrations reduced mesangial cell [(3)H]thymidine incorporation without affecting viability. These data suggest that constitutive PPAR gamma activity exists in renal glomeruli in vivo and could provide a pharmacological target to directly modulate glomerular injury.

Amino Acid Sequence↗
PubMed1999

Thiazolidinedione induces apoptosis and monocytic differentiation in the promyelocytic leukemia cell line HL60.

Thiazolidinedione (TZD) is known to be a potent activator of peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor that constitutes a heterodimer with retinoid X receptor (RXR). Since a considerable amount of PPARgamma is expressed in various hematopoietic cells, the present study was undertaken to examine the effect of TZD in the absence or presence of LG100268, an RXR-selective ligand, on a cultured promyelocytic leukemia cell line, HL60. Treatment with TZD (25-50 microM troglitazone or pioglitazone) markedly suppressed cell proliferation of HL60. A cell cycle analysis revealed that the suppressive effect of troglitazone on HL60 cell proliferations was caused by G0/G1 cell cycle arrest as well as by an apoptotic effect. Treatment with the same concentration of troglitazone also induced the monocytic differentiation of HL60 cells. The apoptotic or the differentiating effect of TZD on HL60 cells was synergistically enhanced by the combined treatment with 1 microM LG100268, while LG100268 alone neither had an apoptotic nor a differentiating effect on HL60 cells. These results suggest that these actions are mediated through the nuclear receptor system constituted by the PPARgamma: RXR heterodimer.

Antineoplastic Agents↗
PubMed2004

Peroxisome proliferator-activated receptor gamma ligands inhibit Rho/Rho kinase pathway by inducing protein tyrosine phosphatase SHP-2.

Although peroxisome proliferator-activated receptor gamma (PPARgamma) ligands have an antihypertensive effect in vivo, the precise mechanism has not been fully elucidated. We examined their effects on Rho/Rho kinase pathway, a key regulator of vascular tone. In cultured rat aortic smooth muscle cells (RASMC), Rho kinase stimulated by angiotensin II was suppressed by the pretreatment with pioglitazone and troglitazone, and these effects were explained by the inhibition of the Rho translocation to the cell membrane. We evaluated the role of Vav, a GTP/GDP exchange factor upregulating Rho kinase activity, and Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2), a protein tyrosine phosphatase that dephosphorylated Vav and subsequently inactivated Rho kinase. Both pioglitazone and troglitazone upregulated SHP-2, particularly in the cytosolic fraction, and the SHP-2-bound Vav, and reduced the phosphorylation of Vav. Furthermore, 4-week treatment with pioglitazone lowered systolic blood pressure in spontaneously hypertensive rats (SHR) and suppressed the Rho/Rho kinase activity in aortic tissues isolated from SHR. Consistently, the expression of SHP-2 was upregulated in vascular tissues from pioglitazone-treated SHR. The phosphorylated Vav was increased in SHR, compared with that in normotensive Wistar-Kyoto rats (WKY), which was mitigated by pioglitazone. Finally, both basal and angiotensin II-stimulated levels of Rho kinase activity were greater in RASMC from SHR than those from WKY, and the enhanced Rho kinase activity was blocked by pioglitazone or troglitazone in both strains. Collectively, PPARgamma ligands inhibit the Rho/Rho kinase pathway through upregulation of cytosolic SHP-2 expression and inactivation of Vav, and may contribute to the hemodynamic, in addition to metabolic, action in hypertensive metabolic syndrome. The full text of this article is available online at http://circres.ahajournals.org.

Angiotensin II↗
PubMed1999

Thiazolidinediones inhibit osteoclast-like cell formation and bone resorption in vitro.

Osteoblasts and adipocytes are derived from common bone marrow stromal cells that play crucial roles in the generation of osteoclasts. Activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) induces adipogenic differentiation of stromal cells; however, whether this would affect osteoblast/osteoclast differentiation is unknown. Thus, we examined the effects of the thiazolidinedione (TZD) class of antidiabetic agents that activate PPARgamma on osteoblast/osteoclast differentiation using mouse whole bone marrow cell culture. As reported, all TZDs we tested (troglitazone, pioglitazone, and BRL 49653) markedly increased the number of Oil Red O-positive adipocytes and the expression of adipsin and PPARgamma 2. 1alpha,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] did not affect adipogenic differentiation induced by TZDs. TZDs did not affect alkaline phosphatase activity, an early marker of osteoblastic differentiation, despite their marked adipogenic effects. TZDs decreased the number of tartrate-resistant acid phosphatase-positive multinucleated osteoclast-like cells induced by 1,25-(OH)2D3 or PTH. Troglitazone dose dependently inhibited basal and 1,25-(OH)2D3- and PTH-induced bone resorption as assessed by pit formation assay. Interleukin-11 blocked the induction by troglitazone of adipogenesis, but had no effect on the inhibition of osteoclast-like cell formation. These results indicate that TZDs are potent inhibitors of bone resorption in vitro. Inhibitory effects of TZDs on osteoclastic bone resorption was not osteotropic factor specific and did not appear to be related to their adipogenic effects. Thus, TZDs may suppress bone resorption in diabetic patients and prevent bone loss.

Acid Phosphatase↗
PubMed2002

Ligands for the peroxisomal proliferator-activated receptor gamma and the retinoid X receptor inhibit aromatase cytochrome P450 (CYP19) expression mediated by promoter II in human breast adipose.

Local estrogen biosynthesis in breast adipose tissue, catalyzed by P450 aromatase, contributes to the growth of breast carcinomas. Aromatase expression is regulated by a number of alternative promoters, and in normal adipose tissue it is primarily regulated via the distal promoter I.4. However, in breast adipose containing a tumor, aromatase expression is regulated by the proximal promoter II in response to tumor-derived factors. Previously we have shown that peroxisomal proliferator-activated receptor gamma (PPARgamma) ligands inhibit aromatase expression in normal breast adipose tissue mediated by promoter I.4. In the present study, we investigated the effects of the PPARgamma ligand troglitazone and the retinoid X receptor (RXR) ligand LG101305 on aromatase expression mediated by promoter II. In cultured human breast adipose stromal cells, troglitazone or LG101305 alone inhibited aromatase activity and expression stimulated by inducers of promoter II, in a concentration-dependent manner, and this inhibition was greater in the presence of both ligands. Reporter gene assays showed that troglitazone and LG101305 inhibit transcription from promoter II of the CYP19 gene. However, EMSAs showed that PPARgamma and RXRalpha do not bind to promoter II of the CYP19 gene, indicating that PPARgamma- and RXR-mediated inhibition of aromatase expression via promoter II occurs through an indirect mechanism of action. Because ligands for PPARgamma and RXR inhibit aromatase expression in healthy breast adipose (via promoter I.4), as well as expression induced by tumor-derived factors (via promoter II), such compounds could find utility in the treatment of estrogen-dependent breast cancers.

Adipose Tissue↗
PubMed2004

Pharmacological treatment of insulin resistance at two different stages in the evolution of type 2 diabetes: impact on glucose tolerance and beta-cell function.

The purpose of this study was to compare the impact of treating insulin resistance with a thiazolidinedione drug before vs. at the onset of diabetes on glucose levels and beta-cell function. Nondiabetic Hispanic women of Mexican or Central American descent with prior gestational diabetes mellitus (GDM) were randomized to troglitazone (early intervention), 400 mg/d, or placebo (later intervention). Women who developed diabetes were placed on open-label troglitazone. Glucose tolerance, insulin resistance, and beta-cell function were measured at randomization, at the diagnosis of diabetes, and 8 months post trial to determine the long-term impact of the two treatment strategies on glucose levels and beta-cell function. During a mean follow-up of 4.3 yr between baseline and posttrial tests, glucose tolerance (oral glucose tolerance test glucose area, P = 0.04) and insulin resistance (MINMOD SI, P = 0.02) worsened more in women randomized to late intervention (n = 69) than to early intervention (n = 57). Insulin secretion (acute insulin response in the iv glucose tolerance test, P = 0.09) and beta-cell compensation for insulin resistance (disposition index, P = 0.07) also tended to worsen more in the late intervention group. Among women in the late intervention group who developed diabetes, oral glucose tolerance test glucose area (P = 0.0001) and beta-cell function (P < or = 0.04) deteriorated significantly during development of diabetes on placebo and then did not change significantly (P > 0.50) during treatment with troglitazone and posttreatment washout. In high-risk Hispanic women, amelioration of insulin resistance can stabilize glycemia at the time diabetes develops. These findings highlight the role of insulin resistance in the genesis of progressive beta-cell dysfunction during the evolution of type 2 diabetes.

Adult↗
PubMed2004

Effect of thiazolidinedione treatment on progression of subclinical atherosclerosis in premenopausal women at high risk for type 2 diabetes.

We tested the effects of treatment with a thiazolidinedione drug on rates of progression of carotid intima-media thickness (CIMT) and some putative determinants of CIMT in young women at high risk for type 2 diabetes. A total of 266 nondiabetic, Hispanic women with recent gestational diabetes were randomized to placebo or troglitazone. CIMT measurements were made at baseline, annually, and at study end, together with measurements of obesity, serum lipids, and glucose and insulin levels during oral glucose tolerance tests. Insulin sensitivity (minimal model analysis) was measured at baseline and 3 months later. Data were analyzed to compare CIMT progression rates between treatment groups and investigate potential determinants of differences in CIMT progression. One hundred ninety-two women had a CIMT measurement at baseline and at least one follow-up visit. The mean rate of CIMT change was 31% lower in women assigned to troglitazone (P = 0.048). This intergroup difference was not explained by baseline or on-trial differences in obesity, lipids, glucose, or insulin. The reduction in CIMT progression developed gradually, occurred only in women who had an increase in insulin sensitivity, and was unrelated to the presence of the metabolic syndrome at baseline. Troglitazone reduced the progression of subclinical atherosclerosis via a mechanism that involved unmeasured mediators of atherosclerosis, either in the circulation or directly in the arterial wall.

Adult↗
PubMed1997

Leptin concentrations in the polycystic ovary syndrome.

The polycystic ovary syndrome (PCOS) is characterized by menstrual disturbances, chronic anovulation and hyperandrogenism and is associated with insulin resistance and hyperinsulinemia. Leptin, the product of the ob gene, is an adipocyte-secreted molecule that signals the magnitude of energy stores to the brain and has been recently shown to have important effects on the reproductive axis of rodents. To assess the potential contribution of leptin to the pathogenesis of PCOS, we measured leptin levels in 24 obese women with PCOS and 12 weight- and age-matched controls and determined whether alterations in hyperinsulinemia produced by administration of the insulin-sensitizing agent troglitazone had an effect on serum leptin levels. Leptin concentrations at baseline were not different in women with PCOS (38.1 +/- 2.15 ng/mL) and controls (33.12 +/- 2.39 ng/mL). Moreover, leptin concentrations remained unchanged after treatment with troglitazone (38.1 +/- 2.15 vs. 39.21 +/- 2.65 ng/mL). Baseline leptin correlated strongly with body mass index in both controls (r = 0.59; P < 0.05) and women with PCOS (r = 0.70; P = 0.0004). Leptin levels were not associated with baseline insulin, testosterone, non-sex hormone-binding globulin (SHBG)-bound testosterone, dehydroepiandrosterone sulfate, estradiol, or SHBG. Finally, despite significantly reduced insulin, non-SHBG-bound testosterone, and estradiol levels after troglitazone treatment of women with PCOS, their leptin levels remained unchanged. We conclude that circulating leptin levels in patients with PCOS do not differ from those in age- and weight-matched controls. Furthermore, increased circulating insulin due to insulin resistance does not appear to alter circulating leptin levels in women with PCOS.

Adult↗
PubMed2000

Peroxisome proliferator-activated receptor-gamma modulates differentiation of human trophoblast in a ligand-specific manner.

The ligand-dependent nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates the differentiation of several tissues and cell types. PPARgamma was recently determined to be essential for murine placental development and differentiation. We therefore assessed the influence of PPARgamma on differentiation of human placental trophoblasts. We initially used immunohistochemistry to examine term human placentas for PPARgamma expression and found that PPARgamma is present in syncytiotrophoblasts and cytotrophoblasts in placental villi. We correlated the expression of PPARgamma with differentiation of primary human trophoblasts and found that 8-bromo-cAMP, a known enhancer of trophoblast differentiation, stimulates PPARgamma activity, but has no effect on PPARgamma expression. We demonstrated that the PPARgamma ligand 15-deoxy-delta12,14-prostaglandin J2 (15deltaPGJ2) and the thiazolidinedione troglitazone stimulate PPARgamma activity in the trophoblast cell line BeWo. Importantly, whereas exposure of cultured primary trophoblasts to troglitazone enhances biochemical and morphological trophoblast differentiation, 15deltaPGJ2 diminishes trophoblast differentiation. Furthermore, 15deltaPGJ2, but not troglitazone, up-regulates p53 expression and promotes trophoblast apoptosis. These data indicate that PPARgamma is expressed in human placental trophoblasts, and that ligand-specific activation of PPARgamma results in opposing effects on trophoblast differentiation. Our results suggest that PPARgamma plays an important role in placental differentiation during human pregnancy.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2004

Pharmacologic prevention or delay of type 2 diabetes mellitus.

OBJECTIVE: To evaluate the current data on pharmacologic interventions intended to prevent or delay the onset of type 2 diabetes mellitus. DATA SOURCES: Searches of MEDLINE (1966-July 2002) and an extensive manual review of journals were performed using the key search terms diabetes mellitus, metformin, acarbose, troglitazone, orlistat, nateglinide, risk reduction, and prevention. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated, and all information deemed relevant was included for this review. Randomized controlled trials and meta-analyses were included if the primary outcome measure was prevention of diabetes and/or change in the rate of progression to diabetes. DATA SYNTHESIS: Type 2 diabetes mellitus is a growing epidemic. Major risk factors include obesity, impaired glucose tolerance, and impaired fasting glucose. Complications of diabetes result in significant morbidity and mortality and are a substantial public health issue. Four randomized, blinded, controlled trials have assessed the efficacy of different medications, including metformin, troglitazone, acarbose, and orlistat, at decreasing the risk of progression to diabetes in patients at risk for developing diabetes. All of these agents decreased the risk of progression to diabetes. CONCLUSIONS: Metformin, troglitazone, acarbose, and orlistat have been shown to decrease the risk of progression to diabetes in patients at risk for developing diabetes. Other questions that address issues such as identifying target populations, cost-effectiveness, and screening strategies must be answered to more fully define the place of pharmacologic therapy to prevent or delay diabetes.

Acarbose↗
PubMed1997

Thiazolidinediones downregulate stearoyl-CoA desaturase 1 gene expression in 3T3-L1 adipocytes.

Thiazolidinediones (TZDs) are known to have potent increases of insulin sensitivity. Because peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a receptor for TZDs, is mainly expressed in adipocytes, we tried to search the TZD-targeted genes in mouse 3T3-L1 adipocytes. By the mRNA differential display method, one band repressed by troglitazone was obtained, which corresponded to the partial sequences of the stearoyl-CoA desaturase 1 (SCD1) gene. Troglitazone dramatically decreased SCD1 mRNA levels in 3T3-L1 adipocytes in a dose-dependent manner. Pioglitazone also repressed the SCD1 mRNA expression, whereas WY-14,643 had no apparent effect. Both troglitazone and pioglitazone raised the composition (weight percentage) of myristic acid (C14:0), palmitic acid (C16:0), and stearic acid (C18:0), but lowered the composition of the delta9-cis desaturated fatty acids such as myristoleic acid (C14:1, delta9), palmitoleic acid (C16:1, delta9), oleic acid (C18:1, delta9), and linoleic acid (C18:2, delta9,12). These results indicate that TZDs repress SCD1 activity in 3T3-L1 adipocytes via downregulating SCD1 enzyme gene expression.

3T3 Cells↗
PubMedDate not supplied

Comparison of effects of thiazolidinediones on cardiovascular risk factors: observations from a clinical practice.

OBJECTIVE: To compare short-term glycosylated hemoglobin (HbA(1c)), lipid, weight, tolerability, and hepatic effects after switching patients with type 2 diabetes from troglitazone to either pioglitazone or rosiglitazone treatment. METHODS: This study compared the effects of conversion from maintenance troglitazone therapy to pioglitazone versus rosiglitazone. HbA(1c), lipids, weights, adverse effects, and hepatic status were monitored, providing no other major therapeutic change had been made. Of 163 study candidates, 144 and 125 patients fulfilled the criteria for comparison of HbA(1c) and lipids, respectively. RESULTS: HbA(1c) decreased an absolute mean of 0.08% for each treatment group, after a mean 3.2-month observation. Mean cholesterol, triglyceride, and low-density lipoprotein (LDL) cholesterol levels decreased in the pioglitazone group by 4.7%, 11.3%, and 7.3% but increased 8.4%, 38.4%, and 8.1%, respectively, in the rosiglitazone group. Mean high-density lipoprotein (HDL) increased 2.6% with pioglitazone and decreased 6.3% with rosiglitazone therapy. Patients receiving a statin concomitantly when switched to rosiglitazone treatment had a 51.9% mean triglyceride increase versus a 25.7% increase for those not taking a statin, whereas the patients switched to pioglitazone therapy had respective decreases of 14.2% and 6.2%. Both drugs were generally well tolerated; patients in both groups had similar slight weight increases and no hepatic dysfunction. CONCLUSION: Patients switched from maintenance troglitazone treatment to either pioglitazone or rosiglitazone therapy had similar glycemic control. Conversion to pioglitazone therapy caused a trend toward improvement in all lipid variables, but switching to rosiglitazone therapy caused significantly increased levels of cholesterol, triglycerides, and LDL and a trend toward decreased HDL. Patients already receiving statins when switched to rosiglitazone therapy had particularly notable triglyceride worsening. Whether these effects will lead to changes in cardiovascular outcome or will be maintained over a longer period remains to be established.

Adult↗
PubMed1999

Human uterine leiomyomata express higher levels of peroxisome proliferator-activated receptor gamma, retinoid X receptor alpha, and all-trans retinoic acid than myometrium.

Uterine leiomyomata are the main indication for a hysterectomy in the United States and occur in 25% of women >35 years. Because uterine leiomyomata can form when ovariectomized guinea pigs are exposed to estradiol and retinoic acids, we tested whether human leiomyomata had high levels of retinoic acids and related nuclear receptors. Compared with normal human myometrium, leiomyomata had 3- to 5-fold higher levels of peroxisome proliferator-activated receptor gamma (PPARgamma), retinoid X receptor alpha proteins, and all-trans retinoic acid, but only during the follicular phase of the menstrual cycle. 9-cis Retinoic acid was undetectable in either leiomyomata or myometrium. PPARgamma mRNA levels were lower in leiomyomata than myometrium, but only during the luteal phase of the cycle. A PPARgamma agonist, troglitazone, was given to guinea pigs along with estradiol and all-trans retinoic acid and produced the largest leiomyomata seen to date in this model. By contrast, no tumors formed when troglitazone was given alone or with estradiol or when troglitazone was given with estradiol and 9-cis retinoic acid. New therapies for human leiomyomata may emerge by combining antagonists for PPARgamma and retinoid X receptor alpha with selective estrogen receptor modulators.

Alitretinoin↗
PubMed2000

The thiazolidinediones or "glitazones" a treatment option for type 2 diabetes mellitus.

The glitazones offer a promising alternative to patients not currently able to achieve target gylcemic control with current therapy. Glitazones have a synergistic effect when combined with sulfonlyureas and metformin and may have a favorable effect on the dyslipidemia experienced by patients with type 2 diabetes. The main concern with these agents is safety due to the hepatocellular injury experienced by several patients taking troglitazone. Although elevations in serum alanine amino transferase (ALT) concentrations more than three times normal occurred in 1.9% of patients on troglitazone in clinical trials, liver toxicity was not truly associated with this drug until post-marketing use by more than 600,000 people in the US. The onset of elevated ALT is typically delayed. In the clinical trials only one patient experienced an elevation in the first month, the majority occurred between the third and seventh month. The glitazones should be avoided in patients with liver disease or a history of alcohol abuse. The mechanism of action for troglitazone-induced liver disease is unknown; consequently, identifying a particular subset of people as being at an increased risk for developing liver failure is difficult. Therefore, monitoring liver function is of critical importance. The newer agents rosiglitazone and pioglitazone may provide a safer alternative, however this question will remain unanswered until clinicians have access to substantially more post marketing surveillance data. The two recent cases of hepatocellular injury associated with rosiglitazone therapy further supports a cautious approach to utilization of these agents.

Chromans↗
PubMed2001

Ligands for peroxisome proliferator-activated receptors alpha and gamma inhibit chemically induced colitis and formation of aberrant crypt foci in rats.

The biological role of the peroxisome proliferator-activated receptors (PPARs) in various diseases, including inflammation and cancer, has been highlighted recently. Although PPARgamma ligands have been found to inhibit mammary carcinogenesis in rodents, the effects on colon tumorigenesis are controversial. In the present study, three different experiments were conducted to investigate the modifying effects of PPARs ligands (PPARalpha and PPARgamma) on colitis and an early phase of colitis-related colon carcinogenesis in male F344 rats. In the first experiment, gastric gavage of troglitazone (PPARgamma ligand, 10 or 100 mg/kg body weight) or bezafibrate (PPARalpha ligand, 10 or 100 mg/kg body weight) inhibited colitis induced by dextran sodium sulfate (DSS) and lowered trefoil factor-2 content in colonic mucosa. In the second experiment, dietary administration (0.01 or 0.05% in diet) of troglitazone and bezafibrate for 4 weeks significantly reduced azoxymethane (AOM, two weekly s.c. injections, 20 mg/kg body weight)-induced formation of aberrant crypts foci, which are precursor lesions for colon carcinoma. In the third experiment, dietary administration (0.01% in diet for 6 weeks) of pioglitazone (PPARgamma ligand), troglitazone, and bezafibrate effectively suppressed DSS/AOM-induced ACF. Administration of both ligands significantly reduced cell proliferation activity in colonic mucosa exposed to DSS and AOM. Our results suggest that synthetic PPARs ligands (PPARalpha and PPARgamma) can inhibit the early stages of colon tumorigenesis with or without colitis.

Animals↗