title: Comparison of the extrapancreatic action of BRX-220 and pioglitazone in the high-fat diet-induced insulin resistance.
abstract: A new Biorex molecule, BRX-220, has been shown to be effective in animal models of diabetic neuro- and retinopathy. Recent in vitro studies showed that it might also have an insulin-sensitizing action. Therefore, the effect of BRX-220 on insulin sensitivity was compared with the action of pioglitazone (PGZ) in high fat (HF) diet-induced insulin resistance (IR) of rats.
  
  
  METHODS
  Male Wistar rats were fed for 3 weeks a standard chow (PD) or the HF (70-cal%) diet. The HF-fed rats were also given daily BRX-220 (20 mg/kg BW) or PGZ (6 mg/kg BW) by gavage. In vivo insulin action was assessed by the euglycemic hyperinsulinemic clamp. Glucose, insulin, FFA, triglyceride (TG), and glycerol levels in blood were also measured, as well as tissue TG content.
  
  
  RESULTS
  Increased levels of fed TG in circulation after HF diet (PD: 2.0+/-0.2 vs. HF: 5.0+/-0.8 mmol/L) were partially corrected by BRX-220 (HF + BRX: 3.8+/-0.3) and normalized by PGZ (HF + PGZ: 2.6+/-0.3). Both molecules prevented the increase in fed serum FFA levels after HF diet (PD: 0.5+/-0.06; HF: 1.8+/-0.2 mmol/L), with a more pronounced effect of PGZ (HF + BRX: 1.2+/-0.1; HF + PGZ: 0.7+/-0.06). Tissue TG levels increased significantly in response to HF feeding in both liver (HF: 16+/-3.0; PD: 6.4+/-1.1 micromol/g) and skeletal muscle (HF: 7.7+/-1.2; PD: 2.4+/-0.4). This increase was completely normalized by both agents in the liver (HF + BRX: 8.8+/-0.8; HF + PGZ: 8.8+/-1.0), and only partially in the skeletal muscles. HF diet-induced in vivo IR (PD: 25.4+/-0.5; HF: 15.7+/-0.5 mg/kg/min) was significantly reduced by BRX-220 (HF + BRX: 18.7+/-0.3) and PGZ (HF + PGZ: 22.8+/-0.4) treatment.
  
  
  CONCLUSIONS
  (1) Subchronic administration of BRX-220 leads to an improvement of in vivo insulin action. (2) This insulin-sensitizing effect is, however, not as pronounced as that of PGZ. (3) It is accompanied by a decrease of circulating TG and FFA levels in the postprandial state and (4) by lower TG content in liver and skeletal muscle.
authors.affiliation: Diabetes and Nutrition Research Laboratory, Institute of Experimental Endocrinology, Slovak Academy of Sciences, SK-83306 Bratislava, Slovak Republic.
authors.forename: Elena
authors.initials: E
authors.lastname: Seböková
authors.forename: Maria
authors.initials: M
authors.lastname: Kürthy
authors.forename: T
authors.initials: T
authors.lastname: Mogyorosi
authors.forename: Karoly
authors.initials: K
authors.lastname: Nagy
authors.forename: Edita
authors.initials: E
authors.lastname: Demcáková
authors.forename: Jozef
authors.initials: J
authors.lastname: Ukropec
authors.forename: Laszlo
authors.initials: L
authors.lastname: Koranyi
authors.forename: Iwar
authors.initials: I
authors.lastname: Klimes
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage*; D006898:Hydroxylamines / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones
chemical_list: D004041:Dietary Fats; D006898:Hydroxylamines; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; C486387:arimoclomol; D000077205:Pioglitazone