DOCSLIB.ORG

Combination Treatment with Pioglitazone and Fenofibrate

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Combination Treatment with Pioglitazone and Fenofibrate 179 Combination treatment with pioglitazone and fenofibrate attenuates pioglitazone-mediated acceleration of bone loss in ovariectomized rats Rana Samadfam, Malaika Awori, Agnes Be´nardeau1, Frieder Bauss2, Elena Sebokova1, Matthew Wright1 and Susan Y Smith Charles River Laboratories, 22022 Transcanadienne, Senneville, Montre´al, Que´bec, Canada H9X 3R3 1F. Hoffmann-La Roche AG, Basel, CH-4070 Switzerland 2Roche Diagnostics GmbH, Penzberg, DE-82377 Germany (Correspondence should be addressed to S Y Smith; Email: [email protected]) Abstract Peroxisome proliferator-activated receptor (PPAR) g ago- mineral content (w45%) and bone mineral density (BMD; nists, such as pioglitazone (Pio), improve glycemia and lipid w60%) at the lumbar spine. Similar effects of treatments were profile but are associated with bone loss and fracture risk. Data observed at the femur, most notably at sites rich in trabecular regarding bone effects of PPARa agonists (including bone. At the proximal tibial metaphysis, concomitant fenofibrate (Feno)) are limited, although animal studies treatment with PioCFeno prevented Pio exacerbation of suggest that Feno may increase bone mass. This study ovariectomy-induced loss of trabecular bone, resulting in investigated the effects of a 13-week oral combination BMD values in the PioCFeno group comparable to OVX treatment with Pio (10 mg/kg per day)CFeno (25 mg/kg controls. Discontinuation of Pio or Feno treatment of per day) on body composition and bone mass parameters OVX rats was associated with partial reversal of effects on compared with Pio or Feno alone in adult ovariectomized bone loss or bone mass gain, respectively, while values in the (OVX) rats, with a 4-week bone depletion period, followed PioCFeno group remained comparable to OVX controls. by a 6-week treatment-free period. Treatment of OVX rats These data suggest that concurrent/dual agonism of PPARg with PioCFeno resulted in w50% lower fat mass gain and PPARa may reduce the negative effects of PPARg compared with Pio treatment alone. Combination treatment agonism on bone mass. with PioCFeno partially prevented Pio-induced loss of bone Journal of Endocrinology (2012) 212, 179–186 Introduction selectivity/agonistic effects on PPAR subtypes. Thiazolidine- diones (TZDs) work predominantly through the activation of Bone is a highly specialized and dynamic tissue that undergoes PPARg and have been shown to improve insulin sensitivity constant remodeling by balancing bone formation and and glucose homeostasis in type 2 diabetes mellitus resorption (Clarke 2008, Eriksen 2010), processes that are (Spiegelman 1998, Lalloyer & Staels 2010), while fibrates regulated by osteoblasts and osteoclasts respectively (Clarke activate PPARa, with the primary effect of improving plasma 2008, Eriksen 2010). Osteoblastogenesis, osteoclastogenesis, lipids (Sierra et al. 2007, Lalloyer & Staels 2010). Accumulating and activity of the resultant cell types are controlled by a evidence from animal studies as well as clinical trials indicates variety of hormonal and humoral factors such as estrogen that activation of PPARg results in loss of bone mass and/or (Manolagas et al. 2002), thyroid hormones (Eriksen 2010), strength (Kahn et al. 2006, Glintborg et al. 2008, Schwartz growth factors (Eriksen 2010), and cytokines (Clarke 2008, 2008) via effects on bone formation and resorption (Sottile Eriksen 2010), the actions of which are mediated via specific et al. 2004, Grey et al. 2007), underlying the increased risk of receptors, including nuclear receptors (Boyce et al. 2009, fractures observed clinically with these agents (Kahn et al. Eriksen 2010). 2006, Glintborg et al. 2008). The role of PPARa (and the third The peroxisome proliferator-activated receptors (PPARs) member of the PPAR family, PPARd) in regulating bone are a group of ligand-activated nuclear receptors that play a key health is much less understood although, recently,fibrates were role in the regulation of lipid and carbohydrate metabolism, as reported to increase bone mass and strength in normal rats well as inflammation, immunomodulation, and cellular (Syversen et al. 2009) and in an animal model of osteoporosis, differentiation (Karpe & Ehrenborg 2009, Lalloyer & Staels the ovariectomized (OVX) rat (Stunes et al. 2011). 2010). PPAR agonists are a diverse group of compounds Combined (dual) activation of PPARa and PPARg has and, although often grouped together, exhibit different been pursued for over a decade due to the expectation of Journal of Endocrinology (2012) 212, 179–186 DOI: 10.1530/JOE-11-0356 0022–0795/12/0212–179 q 2012 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/25/2021 09:19:03AM via free access 180 R SAMADFAM and others . Effects of PPARa and g activation on bone mass better control of cardiovascular risk factors vs solo activation was discontinued in the remaining ten animals from each of one of the PPARs, as both diabetic dyslipidemia and of these groups for 6 weeks (i.e. end of the study at week 19). glucose control/insulin sensitivity are targeted (Lalloyer & Body weight and food consumption were measured Staels 2010). Several combined (dual) PPARa/g agonists weekly, starting from the last week of the acclimation period have reached phase III trials – muraglitazar (Kendall et al. and extending through the treatment and treatment-free 2006), tesaglitazar (Bays et al. 2007), and aleglitazar (Henry periods. In addition, body weight was measured at et al. 2009) – and although the development of muraglitazar randomization and on the day of termination (as an overnight and tesaglitazar was terminated because of safety concerns, the fasted body weight). therapeutic potential of PPARa/g agonists remains of high clinical interest. To our knowledge, the effect of combined Laboratory analysis activation of PPARg and PPARa on bone biology has not been investigated previously. At the end of the bone depletion period, blood was collected The objective of this study was to investigate the effects of from overnight fasted animals at weeks 5 or 6 and 12 or 13 of combination treatment with an agonist of PPARa (fenofi- the treatment period and at week 19 (i.e. end of the brate (Feno)) and PPARg (pioglitazone (Pio)) on bone mass, treatment-free period). Plasma was analyzed for assessment of bone density, and markers of bone turnover compared with triglyceride (TG), insulin, and biomarkers of bone turnover the effect of Pio and Feno alone in OVX rats. In addition, the (serum osteocalcin (bone formation) and urinary effect of discontinuation of treatment was investigated to C-telopeptide of type I collagen (CTx; bone resorption)). evaluate the reversibility of observed effects. TG was measured by an enzymatic colorimetric assay (GPO-PAP, Roche Diagnostics GmbH), while insulin and osteocalcin were measured using rat RIA kits (LINCO Research, Billerica, MA, USA and Biomedical Technologies, Materials and Methods Inc., Stoughton, MA, USA respectively). CTx was assessed with a rat ELISA (Immunodiagnostic Systems, Tyneand Wear, Animals UK). Adiponectin was measured by a colorimetric ELISA The study was conducted in accordance with Standard assay (B-Bridge International, Inc., Cupertino, CA, USA). Operating Procedures of Charles River Laboratories, Montreal, and F. Hoffmann-La Roche AG and the protocol Bone densitometry measurements was approved by the Institutional Animal Care and Use Committee. Animals were appropriately housed and experi- Bone densitometry was evaluated by dual-energy X-ray mental procedures were performed in accordance with absorptiometry (DXA) and peripheral quantitative computed guidelines of the Association for the Assessment and tomography (pQCT). Animals were anesthetized using iso- Accreditation of Laboratory and Animal Care and appropriate flurane and were maintained under the effect during the scans. federal, state, or local guidelines. Scans were acquired once prior to surgery,at the end of the bone At the beginning of treatment, animals were w7 months of depletion period, during weeks 5/6 and 12/13 of the treatment age and ranged in weight from 318 to 454 g. Animals had free period, and at the end of the treatment-free period at week 19. access to purified water and standard laboratory diet (PMI Certified rodent 5002, PMI Nutrition International, Inc., Dual-energy X-ray absorptiometry Saint Paul, MN, USA) throughout the study, except where indicated. The overall average temperature and relative DXA was used to measure area (cm2), bone mineral content humidity during the study were 21.9 8C and 50% respectively. (BMC (g)), and bone mineral density (BMD (g/cm2)) using a After a minimum acclimation period of 3 weeks, animals Hologic Discovery A densitometer (Hologic, Inc., Bedford, underwent surgical procedure (sham operation or ovari- MA, USA) with small animal hi-res software version 12.3. ectomy). Prior to surgery, baseline bone densitometry and The percent coefficient of variation for rat BMD at the spine body weight measurements were obtained from all animals. and femur was 1.1–1.5%. In addition, lean mass and fat mass Using a randomization procedure stratified according to body were reported from whole-body DXA scans. Bone densito- weight, animals were assigned to one of the following metry measurements of the whole body, lumbar spine (L1– treatment groups: 1) sham vehicle control, 2) OVX vehicle L4), and whole and regionalized right femur were acquired control, 3) OVX Pio (10 mg/kg per day),
Load more

Recommended publications
  • Insulin Aspart Sanofi, If It Is Coloured Or It Has Solid Pieces in It
    ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Insulin aspart Sanofi 100 units/ml solution for injection in vial Insulin aspart Sanofi 100 units/ml solution for injection in cartridge Insulin aspart Sanofi 100 units/ml solution for injection in pre-filled pen 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One ml solution contains 100 units insulin aspart* (equivalent to 3.5 mg). Insulin aspart Sanofi 100 units/ml solution for injection in vial Each vial contains 10 ml equivalent to 1,000 units insulin aspart. Insulin aspart Sanofi 100 units/ml solution for injection in cartridge Each cartridge contains 3 ml equivalent to 300 units insulin aspart. Insulin aspart Sanofi 100 units/ml solution for injection in pre-filled pen Each pre-filled pen contains 3 ml equivalent to 300 units insulin aspart. Each pre-filled pen delivers 1-80 units in steps of 1 unit. *produced in Escherichia coli by recombinant DNA technology. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection (injection). Clear, colourless, aqueous solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Insulin aspart Sanofi is indicated for the treatment of diabetes mellitus in adults, adolescents and children aged 1 year and above. 4.2 Posology and method of administration Posology The potency of insulin analogues, including insulin aspart, is expressed in units, whereas the potency of human insulin is expressed in international units.
    [Show full text]
  • Dualism of Peroxisome Proliferator-Activated Receptor Α/Γ: a Potent Clincher in Insulin Resistance
    AEGAEUM JOURNAL ISSN NO: 0776-3808 Dualism of Peroxisome Proliferator-Activated Receptor α/γ: A Potent Clincher in Insulin Resistance Mr. Ravikumar R. Thakar1 and Dr. Nilesh J. Patel1* 1Faculty of Pharmacy, Shree S. K. Patel College of Pharmaceutical Education & Research, Ganpat University, Gujarat, India. [email protected] Abstract: Diabetes mellitus is clinical syndrome which is signalised by augmenting level of sugar in blood stream, which produced through lacking of insulin level and defective insulin activity or both. As per worldwide epidemiology data suggested that the numbers of people with T2DM living in developing countries is increasing with 80% of people with T2DM. Peroxisome proliferator-activated receptors are a family of ligand-activated transcription factors; modulate the expression of many genes. PPARs have three isoforms namely PPARα, PPARβ/δ and PPARγ that play a central role in regulating glucose, lipid and cholesterol metabolism where imbalance can lead to obesity, T2DM and CV ailments. It have pathogenic role in diabetes. PPARα is regulates the metabolism of lipids, carbohydrates, and amino acids, activated by ligands such as polyunsaturated fatty acids, and drugs used as Lipid lowering agents. PPAR β/δ could envision as a therapeutic option for the correction of diabetes and a variety of inflammatory conditions. PPARγ is well categorized, an element of the PPARs, also pharmacological effective as an insulin resistance lowering agents, are used as a remedy for insulin resistance integrated with type- 2 diabetes mellitus. There are mechanistic role of PPARα, PPARβ/δ and PPARγ in diabetes mellitus and insulin resistance. From mechanistic way, it revealed that dual PPAR-α/γ agonist play important role in regulating both lipids as well as glycemic levels with essential safety issues.
    [Show full text]
  • Comparative Transcriptional Network Modeling of Three PPAR-A/C Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes
    Comparative Transcriptional Network Modeling of Three PPAR-a/c Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes Rene´e Deehan1, Pia Maerz-Weiss2, Natalie L. Catlett1, Guido Steiner2, Ben Wong1, Matthew B. Wright2*, Gil Blander1¤a, Keith O. Elliston1¤b, William Ladd1, Maria Bobadilla2, Jacques Mizrahi2, Carolina Haefliger2, Alan Edgar{2 1 Selventa, Cambridge, Massachusetts, United States of America, 2 F. Hoffmann-La Roche AG, Basel, Switzerland Abstract Aims: To compare the molecular and biologic signatures of a balanced dual peroxisome proliferator-activated receptor (PPAR)-a/c agonist, aleglitazar, with tesaglitazar (a dual PPAR-a/c agonist) or a combination of pioglitazone (Pio; PPAR-c agonist) and fenofibrate (Feno; PPAR-a agonist) in human hepatocytes. Methods and Results: Gene expression microarray profiles were obtained from primary human hepatocytes treated with EC50-aligned low, medium and high concentrations of the three treatments. A systems biology approach, Causal Network Modeling, was used to model the data to infer upstream molecular mechanisms that may explain the observed changes in gene expression. Aleglitazar, tesaglitazar and Pio/Feno each induced unique transcriptional signatures, despite comparable core PPAR signaling. Although all treatments inferred qualitatively similar PPAR-a signaling, aleglitazar was inferred to have greater effects on high- and low-density lipoprotein cholesterol levels than tesaglitazar and Pio/Feno, due to a greater number of gene expression changes in pathways related to high-density and low-density lipoprotein metabolism. Distinct transcriptional and biologic signatures were also inferred for stress responses, which appeared to be less affected by aleglitazar than the comparators. In particular, Pio/Feno was inferred to increase NFE2L2 activity, a key component of the stress response pathway, while aleglitazar had no significant effect.
    [Show full text]
  • Lobeglitazone
    2013 International Conference on Diabetes and Metabolism Lobeglitazone, A Novel PPAR-γ agonist with balanced efficacy and safety Kim, Sin Gon. MD, PhD. Professor, Division of Endocrinology and Metabolism Department of Internal Medicine, Korea University College of Medicine. Disclosure of Financial Relationships This symposium is sponsored by Chong Kun Dang Pharmaceutical Corp. I have received lecture and consultation fees from Chong Kun Dang. Pros & Cons of PPAR-γ agonist Pros Cons • Good glucose lowering • Adverse effects • Durability (ADOPT) (edema, weight gain, • Insulin sensitizing CHF, fracture or rare effects (especially in MS, macular edema etc) NAFLD, PCOS etc) • Possible safety issues • Prevention of new- (risk of MI? – Rosi or onset diabetes (DREAM, bladder cancer? - Pio) ACT-NOW) • LessSo, hypoglycemiathere is a need to develop PPAR-γ • Few GI troubles agonist• Outcome with data balanced efficacy and safety (PROactive) Insulin Sensitizers : Several Issues Rosi, Peak sale ($3.3 billion) DREAM Dr. Nissen Dr. Nissen ADOPT META analysis BARI-2D (5,8) Rosi, lipid profiles RECORD 1994 1997 1999 2000 2002 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Tro out d/t FDA, All diabetes hepatotoxicity drug CV safety Rosi (5) FDA, Black box Rosi, Rosi , CV safety warning - REMS in USA = no evidence - Europe out Pio (7) PIO, bladder cancer CKD 501 Lobeglitazone 2000.6-2004.6 2004.11-2007.1 2007.3-2008.10 2009.11-2011.04 Discovery& Preclinical study Phase I Phase II Phase III Developmental Strategy Efficacy • PPAR activity Discovery & Preclinical study • In vitro & vivo efficacy • Potent efficacy 2000.06 - 2004.06 Phase I 2004.11 - 2007.01 • In vitro screening • Repeated dose toxicity • Metabolites • Geno toxicity • Phase II CYP 450 • Reproductive toxicity 2007.03 - 2008.10 • DDI • Carcinogenic toxicity ADME Phase III Safety 2009.11 - 2011.04 CV Safety / (Bladder) Cancer / Liver Toxicity / Bone loss Lobeglitazone (Duvie) 1.
    [Show full text]
  • Title: Combination of Pparg Agonist Pioglitazone and Trabectedin Induce Adipocyte Differentiation to Overcome Trabectedin Resistance in Myxoid Liposarcomas
    Author Manuscript Published OnlineFirst on September 3, 2019; DOI: 10.1158/1078-0432.CCR-19-0976 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Title: Combination of PPARg agonist pioglitazone and trabectedin induce adipocyte differentiation to overcome trabectedin resistance in myxoid liposarcomas Roberta Frapolli1, Ezia Bello1, Marianna Ponzo1, Ilaria Craparotta2, Laura Mannarino2, Sara Ballabio2, Sergio Marchini2, Laura Carrassa3, Paolo Ubezio4, Luca Porcu5, Silvia Brich6, Roberta Sanfilippo7, Paolo Giovanni Casali7, Alessandro Gronchi8, Silvana Pilotti6, and Maurizio D’Incalci9*. 1 Unit of Preclinical Experimental Therapeutics, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy. 2 Unit of Translational Genomic, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy. 3Unit of DNA repair, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy. 4 Unit of Biophysics, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy. 5 Unit of Methodological Research, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy. 6Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. 7 Medical Oncology Unit 2, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. 8 Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. 9 Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy. Running title: Pioglitazone - trabectedin in myxoid liposarcomas. Keywords: Myxoid liposarcoma, trabectedin resistance, PPAR agonist, and patient-derived xenograft. Additional information: Financial support: This work was supported by the Italian Association for Cancer Research grant to M.D.
    [Show full text]
  • OSENI Safely and Effectively
    HIGHLIGHTS OF PRESCRIBING INFORMATION -----------------------WARNINGS AND PRECAUTIONS---------------------- These highlights do not include all the information needed to use Congestive heart failure: Fluid retention may occur and can OSENI safely and effectively. See full prescribing information for exacerbate or lead to congestive heart failure. Combination use OSENI. with insulin and use in congestive heart failure NYHA Class I and OSENI (alogliptin and pioglitazone) tablets II may increase risk. Monitor patients for signs and symptoms. Initial U.S. Approval: 2013 (5.1) Acute pancreatitis: There have been postmarketing reports of WARNING: CONGESTIVE HEART FAILURE acute pancreatitis. If pancreatitis is suspected, promptly See full prescribing information for complete boxed warning discontinue OSENI. (5.2) Thiazolidinediones, including pioglitazone, cause or Hypersensitivity: There have been postmarketing reports of exacerbate congestive heart failure in some patients. (5.1) serious hypersensitivity reactions in patients treated with alogliptin After initiation of OSENI and after dose increases, monitor such as anaphylaxis, angioedema and severe cutaneous adverse patients carefully for signs and symptoms of heart failure reactions. In such cases, promptly discontinue OSENI, assess for (e.g., excessive, rapid weight gain, dyspnea, and/or other potential causes, institute appropriate monitoring and edema). If heart failure develops, it should be managed treatment, and initiate alternative treatment for diabetes. (5.3) according to current standards of care and Hepatic effects: Postmarketing reports of hepatic failure, discontinuation or dose reduction of pioglitazone in OSENI sometimes fatal. Causality cannot be excluded. If liver injury is must be considered. detected, promptly interrupt OSENI and assess patient for OSENI is not recommended in patients with symptomatic probable cause, then treat cause if possible, to resolution or heart failure.
    [Show full text]
  • NPY1R-Targeted Peptide-Mediated Delivery of a Dual PPAR&Alpha
    Original Article NPY1R-targeted peptide-mediated delivery of a dual PPARa/g agonist to adipocytes enhances adipogenesis and prevents diabetes progression Stefanie Wittrisch 1, Nora Klöting 2,**, Karin Mörl 1, Rima Chakaroun 2,3, Matthias Blüher 2,3,***, Annette G. Beck-Sickinger 1,* ABSTRACT Objective: PPARa/g dual agonists have been in clinical development for the treatment of metabolic diseases including type 2 diabetes and dyslipidemia. However, severe adverse side effects led to complications in clinical trials. As most of the beneficial effects rely on the compound activity in adipocytes, the selective targeting of this cell type is a cutting-edge strategy to develop safe anti-diabetic drugs. The goal of this study was to strengthen the adipocyte-specific uptake of the PPARa/g agonist tesaglitazar via NPY1R-mediated internalization. 7 34 Methods: NPY1R-preferring peptide tesaglitazar-[F ,P ]-NPY (tesa-NPY) was synthesized by a combination of automated SPPS and manual couplings. Following molecular and functional analyses for proof of concept, cell culture experiments were conducted to monitor the effects on adipogenesis. Mice treated with peptide drug conjugates or vehicle either by gavage or intraperitoneal injection were characterized phenotypically and metabolically. Histological analysis and transcriptional profiling of the adipose tissue were performed. 7 34 Results: In vitro studies revealed that the tesaglitazar-[F ,P ]-NPY conjugate selectively activates PPARg in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells. In vivo studies using db/db mice demonstrated that the anti-diabetic activity of the peptide conjugate is as efficient as that of systemically administered tesaglitazar.
    [Show full text]
  • Muraglitazar Bristol-Myers Squibb/Merck Daniella Barlocco
    Muraglitazar Bristol-Myers Squibb/Merck Daniella Barlocco Address Originator Bristol-Myers Squibb Co University of Milan . Istituto di Chimica Farmaceutica e Tossicologica Viale Abruzzi 42 Licensee Merck & Co Inc 20131 Milano . Italy Status Pre-registration Email: [email protected] . Indications Metabolic disorder, Non-insulin-dependent Current Opinion in Investigational Drugs 2005 6(4): diabetes © The Thomson Corporation ISSN 1472-4472 . Actions Antihyperlipidemic agent, Hypoglycemic agent, Bristol-Myers Squibb and Merck & Co are co-developing Insulin sensitizer, PPARα agonist, PPARγ agonist muraglitazar, a dual peroxisome proliferator-activated receptor-α/γ . agonist, for the potential treatment of type 2 diabetes and other Synonym BMS-298585 metabolic disorders. In November 2004, approval was anticipated as early as mid-2005. Registry No: 331741-94-7 Introduction [579218], [579221], [579457], [579459]. PPARγ is expressed in Type 2 diabetes is a complex metabolic disorder that is adipose tissue, lower intestine and cells involved in characterized by hyperglycemia, insulin resistance and immunity. Activation of PPARγ regulates glucose and lipid defects in insulin secretion. The disease is associated with homeostasis, and triggers insulin sensitization [579216], older age, obesity, a family history of diabetes and physical [579218], [579458], [579461]. PPARδ is expressed inactivity. The prevalence of type 2 diabetes is increasing ubiquitously and has been found to be effective in rapidly, and the World Health Organization warns that, controlling dyslipidemia and cardiovascular diseases unless appropriate action is taken, the number of sufferers [579216]. PPARα agonists are used as potent hypolipidemic will double to over 350 million individuals by the year compounds, increasing plasma high-density lipoprotein 2030. Worryingly, it is estimated that only half of sufferers (HDL)-cholesterol and reducing free fatty acids, are diagnosed with the condition [www.who.int].
    [Show full text]
  • Structural Basis for the Enhanced Anti-Diabetic Efficacy Of
    www.nature.com/scientificreports OPEN Structural Basis for the Enhanced Anti-Diabetic Efcacy of Lobeglitazone on PPARγ Received: 9 October 2017 Jun Young Jang 1, Hwan Bae2, Yong Jae Lee3, Young Il Choi3, Hyun-Jung Kim4, Accepted: 4 December 2017 Seung Bum Park 2, Se Won Suh2, Sang Wan Kim 5 & Byung Woo Han 1 Published: xx xx xxxx Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily. It functions as a ligand-activated transcription factor and plays important roles in the regulation of adipocyte diferentiation, insulin resistance, and infammation. Here, we report the crystal structures of PPARγ in complex with lobeglitazone, a novel PPARγ agonist, and with rosiglitazone for comparison. The thiazolidinedione (TZD) moiety of lobeglitazone occupies the canonical ligand-binding pocket near the activation function-2 (AF-2) helix (i.e., helix H12) in ligand-binding domain as the TZD moiety of rosiglitazone does. However, the elongated p-methoxyphenol moiety of lobeglitazone interacts with the hydrophobic pocket near the alternate binding site of PPARγ. The extended interaction of lobeglitazone with the hydrophobic pocket enhances its binding afnity and could afect the cyclin- dependent kinase 5 (Cdk5)-mediated phosphorylation of PPARγ at Ser245 (in PPARγ1 numbering; Ser273 in PPARγ2 numbering). Lobeglitazone inhibited the phosphorylation of PPARγ at Ser245 in a dose-dependent manner and exhibited a better inhibitory efect on Ser245 phosphorylation than rosiglitazone did. Our study provides new structural insights into the PPARγ regulation by TZD drugs and could be useful for the discovery of new PPARγ ligands as an anti-diabetic drug, minimizing known side efects.
    [Show full text]
  • Thiazolidinedione Drugs Down-Regulate CXCR4 Expression on Human Colorectal Cancer Cells in a Peroxisome Proliferator Activated Receptor Á-Dependent Manner
    1215-1222 26/3/07 18:16 Page 1215 INTERNATIONAL JOURNAL OF ONCOLOGY 30: 1215-1222, 2007 Thiazolidinedione drugs down-regulate CXCR4 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor Á-dependent manner CYNTHIA LEE RICHARD and JONATHAN BLAY Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 1X5, Canada Received October 26, 2006; Accepted December 4, 2006 Abstract. Peroxisome proliferator activated receptor (PPAR) Introduction Á is a nuclear receptor involved primarily in lipid and glucose metabolism. PPARÁ is also expressed in several cancer types, Peroxisome proliferator activated receptors (PPARs) are and has been suggested to play a role in tumor progression. nuclear hormone receptors that are involved primarily in PPARÁ agonists have been shown to reduce the growth of lipid and glucose metabolism (1). Upon ligand activation, colorectal carcinoma cells in culture and in xenograft models. these receptors interact with the retinoid X receptor (RXR) Furthermore, the PPARÁ agonist thiazolidinedione has been and bind to peroxisome proliferator response elements (PPREs), shown to reduce metastasis in a murine model of rectal cancer. leading to transcriptional regulation of target genes. Members Since the chemokine receptor CXCR4 has emerged as an of the thiazolidinedione class of antidiabetic drugs act as important player in tumorigenesis, particularly in the process ligands for PPARÁ (2), as does endogenously produced 15- 12,14 of metastasis, we sought to determine if PPARÁ agonists deoxy-¢ -prostaglandin J2 (15dPGJ2) (3). might act in part by reducing CXCR4 expression. We found In addition to regulation of glucose metabolism, PPARÁ that rosiglitazone, a thiazolidinedione PPARÁ agonist used appears also to be involved in tumorigenesis, although its primarily in the treatment of type 2 diabetes, significantly exact role has yet to be elucidated (4).
    [Show full text]
  • Alcoholic Fatty Liver Disease in Type 2 Diabetes: Its Efficacy and Predictive Factors Related to Responsiveness
    ORIGINAL ARTICLE Endocrinology, Nutrition & Metabolism https://doi.org/10.3346/jkms.2017.32.1.60 • J Korean Med Sci 2017; 32: 60-69 Lobeglitazone, a Novel Thiazolidinedione, Improves Non- Alcoholic Fatty Liver Disease in Type 2 Diabetes: Its Efficacy and Predictive Factors Related to Responsiveness Yong-ho Lee,1* Jae Hyeon Kim,2* Despite the rapidly increasing prevalence of non-alcoholic fatty liver disease (NAFLD) in So Ra Kim,1 Heung Yong Jin,3 type 2 diabetes (T2D), few treatment modalities are currently available. We investigated Eun-Jung Rhee,4 Young Min Cho,5 the hepatic effects of the novel thiazolidinedione (TZDs), lobeglitazone (Duvie) in T2D and Byung-Wan Lee1 patients with NAFLD. We recruited drug-naïve or metformin-treated T2D patients with NAFLD to conduct a multicenter, prospective, open-label, exploratory clinical trial. 1Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; 2Division of Transient liver elastography (Fibroscan®; Echosens, Paris, France) with controlled Endocrinology and Metabolism, Department of attenuation parameter (CAP) was used to non-invasively quantify hepatic fat contents. Medicine, Samsung Medical Center, Sungkyunkwan Fifty patients with CAP values above 250 dB/m were treated once daily with 0.5 mg University School of Medicine, Seoul, Korea; lobeglitazone for 24 weeks. The primary endpoint was a decline in CAP values, and 3Division of Endocrinology and Metabolism, Department of Internal Medicine, Research Institute secondary endpoints included changes in components of glycemic, lipid, and liver profiles. of Clinical Medicine, Chonbuk National University Lobeglitazone-treated patients showed significantly decreased CAP values (313.4 dB/m at Hospital, Chonbuk National University Medical baseline vs.
    [Show full text]
  • Pioglitazone (Actos®)
    VERDICT & SUMMARY Pioglitazone (Actos®) For the treatment of type 2 diabetes mellitus Committee’s Verdict: Category B (Q4) BNF: 6.1.2 Pioglitazone is suitable for use in primary care by a prescriber with a particular interest in type 2 diabetes who can identify patients likely to benefit from treatment, and monitor for side effects, e.g. heart failure. There is conflicting evidence whether pioglitazone is associated with long-term clinical benefits or harms on cardiovascular outcomes, which dictates caution in its use. Category B: suitable for restricted prescribing under defined conditions Q4 rating: One RCT and two meta-analyses evaluated the effect of pioglitazone treatment on cardiovascular mortality and morbidity compared Q2 Q1 higher place higher place with control treatment. All three studies found a higher risk of heart failure weaker evidence stronger evidence with pioglitazone, but the results were conflicting for other cardiovascular outcomes. Pioglitazone has been found to improve glycaemic control compared with placebo, as monotherapy or in combination with other Q4 Q3 antidiabetic agents, but it was not superior to other agents. Therefore, it is lower place lower place considered to have a relatively low place in therapy. weaker evidence stronger evidence The Q rating relates to the drug’s position on the effectiveness indicator grid. in primary carePlace therapy in The strength of the evidence is determined by the quality and quantity of studies Strength of evidence for efficacy that show significant efficacy of the drug compared with placebo or alternative therapy. Its place in therapy in primary care takes into account safety and practical aspects of using the drug in primary care, alternative options, relevant NICE guidance, and the need for secondary care input.
    [Show full text]