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This Article Full Text Full Text (PDF) All Versions of this Article: 292/5/E1358    most recent 00573.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Dhalla, A. K. Articles by Reaven, G. M. Search for Related Content PubMed PubMed Citation Articles by Dhalla, A. K. Articles by Reaven, G. M.

A₁ adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents

¹Department of Pharmacological Sciences, CV Therapeutics, Palo Alto, California; ²Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands; and ³Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California

Submitted 24 October 2006 ; accepted in final form 10 January 2007

There is substantial evidence in the literature that elevated plasma free fatty acids (FFA) play a role in the pathogenesis of type 2 diabetes. CVT-3619 is a selective partial A₁ adenosine receptor agonist that inhibits lipolysis and lowers circulating FFA. The present study was undertaken to determine the effect of CVT-3619 on insulin resistance induced by high-fat (HF) diet in rodents. HF diet feeding to rats for 2 wk caused a significant increase in insulin, FFA, and triglyceride (TG) concentrations compared with rats fed chow. CVT-3619 (1 mg/kg) caused a time-dependent decrease in fasting insulin, FFA, and TG concentrations. Acute administration of CVT-3619 significantly lowered the insulin response, whereas glucose response was not different with an oral glucose tolerance test. Treatment with CVT-3619 for 2 wk resulted in significant lowering of FFA, TG, and insulin concentrations in rats on HF diet. To determine the effect of CVT-3619 on insulin sensitivity, hyperinsulinemic euglycemic clamp studies were performed in C57BL/J6 mice fed HF diet for 12 wk. Glucose infusion rate was decreased significantly in HF mice compared with chow-fed mice. CVT-3619 treatment 15 min prior to the clamp study significantly (P < 0.01) increased glucose infusion rate to values similar to that for chow-fed mice. In conclusion, CVT-3619 treatment lowers FFA and TG concentrations and improves insulin sensitivity in rodent models of insulin resistance.

CVT-3619; antilipolytic; free fatty acids; triglycerides; oral glucose tolerance test

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