Antidiabetic and hypolipidemic effects of a novel dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, E3030, in db/db mice and beagle dogs.

We investigated the antidiabetic effects of E3030, which is a potent dual activator of peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma, in an animal model of diabetes, C57BL/KsJ-db/db mice (db/db mice), and the lipidemic effects of E3030 in beagle dogs, whose PPARalpha and PPARgamma transactivation responses to E3030 were similar to those of humans. E3030 activated human PPARalpha, mouse PPARalpha, dog PPARalpha, human PPARgamma, mouse PPARgamma, and dog PPARgamma with EC(50) values of 65, 920, 87, 34, 73, and 34 nM, respectively, in the chimeric GAL4-PPAR receptor transactivation reporter assay. In db/db mice orally administered E3030 decreased blood glucose, triglyceride (TG), non-esterified fatty acids (NEFA), and insulin levels and increased blood adiponectin levels during a 14-day experimental period. Significant effects on blood glucose and adiponectin levels were observed at a dose of 3 mg/kg or greater. Furthermore, significant effects on blood TG, NEFA, and insulin levels were observed at doses of 1 mg/kg or more. An oral glucose tolerance test (OGTT) performed on Day 15 showed that E3030 at 3 mg/kg improved glucose tolerance in this model. Fourteen days of oral treatment with E3030 at a dose of 0.03 mg/kg or greater showed remarkable TG- and non high-density lipoprotein (non-HDL) cholesterol-lowering effects in beagle dogs. These results were similar to those observed for the PPARalpha agonist fenofibrate. E3030 also reduced apo C-III levels on Days 7 and 14, and elevated lipoprotein lipase (LPL) levels on Day 15. These results indicate that the TG- and non-HDL cholesterol-lowering actions of E3030 involve combined effects on reduction of apo C-III and elevation of LPL, resulting in increased lipolysis. The experimental results in animals suggest that E3030 has potential for use in the treatment of various aspects of metabolic dysfunction in type 2 diabetes, including dyslipidemia, hyperglycemia, hyperinsulinemia, and impaired glucose disposal.

[1]  Novel phthalazinone and benzoxazinone containing thiazolidinediones as antidiabetic and hypolipidemic agents. , 2001, European journal of medicinal chemistry.

[2]  Y. Terauchi,et al.  The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity , 2001, Nature Medicine.

[3]  G. Schonfeld,et al.  The effects of fibrates on lipoprotein and hemostatic coronary risk factors. , 1994, Atherosclerosis.

[4]  Y. Yamasaki,et al.  Pioglitazone (AD-4833) ameliorates insulin resistance in patients with NIDDM. AD-4833 Glucose Clamp Study Group, Japan. , 1997, The Tohoku journal of experimental medicine.

[5]  M. Laakso,et al.  Diabetes and atherosclerosis: an epidemiologic view. , 1987, Diabetes/metabolism reviews.

[6]  H. Brewer,et al.  New micromethod for measuring cholesterol in plasma lipoprotein fractions. , 1977, Clinical chemistry.

[7]  Masahiro Suzuki,et al.  Design, synthesis, and evaluation of substituted phenylpropanoic acid derivatives as human peroxisome proliferator activated receptor activators. Discovery of potent and human peroxisome proliferator activated receptor alpha subtype-selective activators. , 2003, Journal of medicinal chemistry.

[8]  Z. Varghese,et al.  PPARα agonist fenofibrate improves diabetic nephropathy in db/db mice. Commentary , 2006 .

[9]  T. Ide,et al.  Pharmacological characterization of a human-specific peroxisome proliferater-activated receptor alpha (PPARalpha) agonist in dogs. , 2004, Biochemical pharmacology.

[10]  D. Rader,et al.  Role of fibrates in the management of hypertriglyceridemia. , 1999, The American journal of cardiology.

[11]  J. Auwerx,et al.  Transcriptional control of triglyceride metabolism: fibrates and fatty acids change the expression of the LPL and apo C-III genes by activating the nuclear receptor PPAR. , 1996, Atherosclerosis.

[12]  S. Uchida,et al.  Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase , 2002, Nature Medicine.

[13]  R. A. Norman,et al.  The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. , 2002, Diabetes.

[14]  M. Matsuda,et al.  PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. , 2001, Diabetes.

[15]  S. O’Rahilly,et al.  Induction of Adipocyte Complement-related Protein of 30 Kilodaltons by Ppar␥ Agonists: a Potential Mechanism of Insulin Sensitization , 2022 .

[16]  A. Gotto,et al.  Consensus for the use of fibrates in the treatment of dyslipoproteinemia and coronary heart disease. Fibrate Consensus Group. , 1998, The American journal of cardiology.

[17]  T. Rabelink,et al.  Thiazolidinediones and Blood Lipids in Type 2 Diabetes , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[18]  T. Willson,et al.  The PPARs: From Orphan Receptors to Drug Discovery , 2000 .

[19]  John A. Wagner,et al.  Overview of Biomarkers and Surrogate Endpoints in Drug Development , 2002, Disease markers.

[20]  D. Doddrell,et al.  Effect of rosiglitazone on insulin sensitivity and body composition in type 2 diabetic patients [corrected]. , 2002, Obesity research.

[21]  J Auwerx,et al.  Mechanism of action of fibrates on lipid and lipoprotein metabolism. , 1998, Circulation.