A tailored therapy for the metabolic syndrome: the dual peroxisome proliferator-activated receptor-alpha/gamma agonist LY465608 ameliorates insulin resistance and diabetic hyperglycemia while improving cardiovascular risk factors in preclinical models.

@article{Etgen2002ATT,
  title={A tailored therapy for the metabolic syndrome: the dual peroxisome proliferator-activated receptor-alpha/gamma agonist LY465608 ameliorates insulin resistance and diabetic hyperglycemia while improving cardiovascular risk factors in preclinical models.},
  author={Garret J. Etgen and Brian A. Oldham and William Thomas Johnson and Carol L. Broderick and Chahrzad Montrose and Joseph T. Brozinick and Elizabeth A Misener and James S. Bean and William R. Bensch and Dawn A. Brooks and Anthony John Shuker and Christopher John Rito and James Ray Mccarthy and Robert John Ardecky and John S. Tyhonas and Sharon L. Dana and James M Bilakovics and James R. Paterniti and Kathleen M. Ogilvie and Shan Liu and Raymond F. Kauffman},
  journal={Diabetes},
  year={2002},
  volume={51 4},
  pages={
          1083-7
        }
}
A novel nonthiazolidinedione dual peroxisome proliferator- activated receptor (PPAR)-alpha/gamma agonist, LY465608, was designed to address the major metabolic disturbances of type 2 diabetes. LY465608 altered PPAR-responsive genes in liver and fat of db/db mice and dose-dependently lowered plasma glucose in hyperglycemic male Zucker diabetic fatty (ZDF) rats, with an ED(50) for glucose normalization of 3.8 mg small middle dot kg(-1) small middle dot day(-1). Metabolic improvements were… 

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References

SHOWING 1-10 OF 36 REFERENCES

Peroxisome Proliferator-activated Receptor α Activators Improve Insulin Sensitivity and Reduce Adiposity*

TLDR
Results indicate that compounds with a selective PPARα activation profile reduce insulin resistance without having adverse effects on body weight and adipose tissue mass in animal models of IR.

A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma: effect of PPAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats.

TLDR
The results suggest that PPAR-alpha agonism has a protective effect against abnormal lipid metabolism in liver of obese rats.

A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport

TLDR
The results suggest that PPARδ agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.

Fenofibrate and rosiglitazone lower serum triglycerides with opposing effects on body weight.

TLDR
The results serve to clearly differentiate the metabolic finality of two distinct classes of drugs, as well as their corresponding nuclear receptors, having similar effects on serum triglycerides.

Activation of PPARδ alters lipid metabolism in db/db mice

Efficacy of troglitazone on body fat distribution in type 2 diabetes.

TLDR
Weight gain during troglitazone treatment resulted in increased accumulation of SC fat without a change in visceral fat area and, consequently, in a significant decrease in the visceral-to-SC fat ratio.

Activation of human aortic smooth-muscle cells is inhibited by PPARα but not by PPARγ activators

TLDR
It is concluded that activators of PPARα inhibit the inflammatory response of aortic smooth-muscle cells and decrease the concentration of plasma acute-phase proteins, indicating that PPAR α in the vascular wall may influence the process of atherosclerosis and re-stenosis.

Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators.

TLDR
It is concluded that activators of PPAR alpha inhibit the inflammatory response of aortic smooth-muscle cells and decrease the concentration of plasma acute-phase proteins, indicating that PPARalpha in the vascular wall may influence the process of atherosclerosis and re-stenosis.

PPAR agonists as direct modulators of the vessel wall in cardiovascular disease

TLDR
Evidence suggesting that PPAR agonists may directly modulate vessel wall function is summarized, and it is suggested that these may parallel those effects reported recently for the statins.

Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ

TLDR
Evidence that PPARs serve as physiological sensors of lipid levels is provided and a molecular mechanism whereby dietary fatty acids can modulate lipid homeostasis is suggested.