Antidiabetic and Hypolipidemic Effects of a Novel Dual Peroxisome Proliferator-Activated Receptor (PPAR) α/γ Agonist, E3030, in db/db Mice and Beagle Dogs

Abstract

Abstract. We investigated the antidiabetic effects of E3030, which is a potent dual activator of peroxisome proliferator-activated receptor (PPAR) α and PPARγ, in an animal model of diabetes, C57BL / KsJ-db/ db mice (db / db mice), and the lipidemic effects of E3030 in beagle dogs, whose PPARα and PPARγ transactivation responses to E3030 were similar to those of humans. E3030 activated human PPARα, mouse PPARα, dog PPARα, human PPARγ, mouse PPARγ, and dog PPARγ 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 PPARα 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.

Treatment of db/db diabetic mice with triptolide: a novel therapy for diabetic nephropathy

“…The improved metabolic disturbance by triptolide was characterized by decreased levels of Chol, TG and LDL and attenuated obesity. Previous studies showed that high HDL level in db/db diabetic mice [17] was markedly decreased after administration with peroxidase proliferator-activated receptor (PPARα/γ) agonist, rhein, simvastatin or benazepril [16,18,19]. The decreased HDL level was also one of characteristics of improved metabolic disturbance.…”

Fenofibrate Enhances Neovascularization in a Murine Ischemic Hindlimb Model

“…29 However, cotreatment with fenofibrate and L-NAME decreased the serum triglyceride levels without altering neovascularization, indicating that the effect of fenofibrate was independent of serum triglyceride level. The chosen dose of fenofibrate has been previously published in mouse studies, 30,31 and no harmful effects were observed in BP, appearance, or body weight. We believe that our study setting is appropriate to estimate the effect of fenofibrate in mice.…”

CompoundProtein Interaction Prediction Within Chemogenomics: Theoretical Concepts, Practical Usage, and Future Directions

“…Consider the context provided by a difference in cell type, such as a neuron and a blood cell, where a reference set of CPIs for glutamate receptors could rationally receive stronger weighting for the former cell type than the latter type. Experimentalists have been active in trying to find molecules that modulate "twonode" networks, such that ligands intentionally act on a pair of related targets such as for GPCRs, [87,88] subfamilies of related kinases, [89][90][91] multiple subfamilies of kinases, [92,93] and nuclear hormone receptors, [94,95] with most studies seeking to achieve therapeutic effects. A two-target mechanism is quite possibly the limit of rational design; such is distinct from the multi-target results being shown (and predicted).…”