title: AZ 242, a novel PPARalpha/gamma agonist with beneficial effects on insulin resistance and carbohydrate and lipid metabolism in ob/ob mice and obese Zucker rats.
abstract: Abnormalities in fatty acid (FA) metabolism underlie the development of insulin resistance and alterations in glucose metabolism, features characteristic of the metabolic syndrome and type 2 diabetes that can result in an increased risk of cardiovascular disease. We present pharmacodynamic effects of AZ 242, a novel peroxisome proliferator activated receptor (PPAR)alpha/gamma agonist. AZ 242 dose-dependently reduced the hypertriglyceridemia, hyperinsulinemia, and hyperglycemia of ob/ob diabetic mice. Euglycemic hyperinsulinemic clamp studies showed that treatment with AZ 242 (1 micromol/kg/d) restored insulin sensitivity of obese Zucker rats and decreased insulin secretion. In vitro, in reporter gene assays, AZ 242 activated human PPARalpha and PPARgamma with EC(50) in the micro molar range. It also induced differentiation in 3T3-L1 cells, an established PPARgamma effect, and caused up-regulation of liver fatty acid binding protein in HepG-2 cells, a PPARalpha-mediated effect. PPARalpha-mediated effects of AZ 242 in vivo were documented by induction of hepatic cytochrome P 450-4A in mice. The results indicate that the dual PPARalpha/gamma agonism of AZ 242 reduces insulin resistance and has beneficial effects on FA and glucose metabolism. This effect profile could provide a suitable therapeutic approach to the treatment of type 2 diabetes, metabolic syndrome, and associated vascular risk factors.
authors.affiliation: AstraZeneca R&D, Research Area CV/GI, Mölndal S 431 83 Mölndal, Sweden. bengt.ljung@astrazeneca.com
authors.forename: Bengt
authors.initials: B
authors.lastname: Ljung
authors.forename: Krister
authors.initials: K
authors.lastname: Bamberg
authors.forename: Björn
authors.initials: B
authors.lastname: Dahllöf
authors.forename: Ann
authors.initials: A
authors.lastname: Kjellstedt
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Oakes
authors.forename: Jörgen
authors.initials: J
authors.lastname: Ostling
authors.forename: Lennart
authors.initials: L
authors.lastname: Svensson
authors.forename: Germán
authors.initials: G
authors.lastname: Camejo
mesh_terms: D000476:Alkanesulfonates; D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology; D050260:Carbohydrate Metabolism; D002934:Cinnamates / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008820:Mice, Obese; D015394:Molecular Structure; D009765:Obesity; D010666:Phenylpropionates; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000476:Alkanesulfonates; D002934:Cinnamates; D005227:Fatty Acids; D010666:Phenylpropionates; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C501413:tesaglitazar; D005947:Glucose; D001629:Bezafibrate