Abstract
Reducing the availability and uptake of fatty acids is a plausible pharmaceutical target to ameliorate glucose intolerance and insulin resistance. CVT-3619 [2-{6-[((1R,2R)-2-hydroxycyclopentyl) amino]purin-9-yl(4S,5S,2R,3R)-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol] is a partial A1 adenosine receptor agonist with antilipolytic properties. Aims of the present study were to examine the acute effects of CVT-3619 on whole-body and cardiac glucose and fatty acid kinetics in vivo in normal and diet-induced insulin-resistant rats. Male Sprague-Dawley rats were fed either a chow (CH) or high-fat (HF) diet for 4 weeks. Catheters were then chronically implanted in the carotid artery and jugular vein for sampling and infusions, respectively. After 5 days of recovery, fasted animals (10 h) received either saline or CVT-3619 (0.4 mg/kg bolus + 1 mg/kg/h). Indices of glucose and fatty acid utilization were obtained by the administration of 2-deoxy[14C]glucose and [9,10-3H]-(R)-2-bromopalmitate. HF feeding resulted in elevated, fasting insulin and free fatty acid (FFA) levels compared with CH. CVT-3619 caused a 64 and 86% reduction of FFA and insulin in HF (p < 0.05) but less (N.S.) in CH diet-fed animals. In HF diet-fed rats, CVT-3619 increased whole-body glucose clearance with no change in fatty acid kinetics. Likewise, analysis of cardiac tissue metabolism showed that CVT-3619 caused an increased glucose but not fatty acid clearance in HF-fed animals. Results show that the acute administration of CVT-3619 lowers circulating fatty acid levels, leading to improved whole-body and cardiac glucose clearance in a model of diet-induced insulin resistance. As such, CVT-3619 may be a treatment option for the restoration of substrate balance in the insulin-resistant heart.
Footnotes
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This study was supported by CV Therapeutics (Palo Alto, CA); the Canadian Institutes of Health Research [Grant MOP79397]; and Genome Canada.
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J.S. holds salary support awards from the Alberta Heritage Foundation for Medical Research, Heart and Stroke Foundation of Canada and the Canadian Diabetes Association.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.143594.
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ABBREVIATIONS: FFA, free fatty acid; CVT-3619, 2-{6-[((1R,2R)-2-hydroxycyclopentyl) amino]purin-9-yl(4S,5S,2R,3R)-5-[(2-fluorophenylthio)-methyl]oxolane-3,4-diol; CH, chow; [3H]BROMO, [9,10-3H]-(R)-2-bromopalmitate; [2-14C]DG, 2-deoxy[14C]glucose; NEFA, nonesterified fatty acid; Kf, long-chain fatty acid clearance; Rf, index of long-chain fatty acid utilization; Kg, glucose clearance; Rg, index of glucose utilization; LCFA, long-chain fatty acid; MCRf, whole-body fatty acid clearance; MCRg, whole-body glucose metabolic clearance; Uf, fatty acid disposal; Ug, glucose uptake; ANOVA, analysis of variance; HF, high fat.
- Received July 15, 2008.
- Accepted October 23, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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