Comparison of the antilipolytic effects of an A1 adenosine receptor partial agonist in normal and diabetic rats.
OBJECTIVE
Elevated plasma free fatty acid (FFA) concentrations play a role in the pathogenesis of type 2 diabetes (2DM). Antilipolytic agents that reduce FFA concentrations may be potentially useful in the treatment of 2DM. Our previous observation that CVT-3619 lowered plasma FFA and triglyceride concentrations in rats and enhanced insulin sensitivity in rodents with dietary-induced forms of insulin resistance suggested that it might be of use in the treatment of patients with 2DM. The present study was undertaken to compare the antilipolytic effects of CVT-3619 in normal (Sprague Dawley, SD) and Zucker diabetic fatty (ZDF) rats.


RESULTS
ZDF rats had significantly higher fat pad weight, glucose, insulin and FFA concentrations than those of SD rats. EC(50) values for forskolin-stimulated FFA release from isolated adipocytes from SD and ZDF rats were 750 and 53 nM, respectively (p < 0.05). Maximal forskolin stimulation of FFA release was significantly (p < 0.01) less in ZDF rats (133 +/- 60 microM) compared with SD rats (332 +/- 38 microM). EC(50) values for isoproterenol to increase lipolysis in adipocytes from SD and ZDF rats were 2 and 7 nM respectively. Maximal isoproterenol-stimulated lipolysis was significantly (p < 0.01) lower in adipocytes from ZDF rats (179 +/- 23 microM) compared with SD rats (343 +/- 27 microM). Insulin inhibited lipolysis in adipocytes from SD rats with an IC(50) value of 30 pM, whereas adipocytes from ZDF rats were resistant to the antilipolytic actions of insulin. In contrast, IC(50) values for CVT-3619 to inhibit the release of FFA from SD and ZDF adipocytes were essentially the same (63 and 123 nM respectively). CVT-3619 inhibited lipolysis more than insulin in both SD (86 vs. 46%, p < 0.001) and ZDF (80 vs. 13%, p < 0.001) adipocytes. In in vivo experiments, CVT-3619 (5 mg/kg, PO) lowered FFA to a similar extent in both groups. Plasma concentrations of CVT-3619 were not different in SD and ZDF rats. There was no significant difference in the messenger RNA expression of the A(1) receptors relative to beta-actin expression in adipocytes from SD (0.98 +/- 0.2) and ZDF rats (0.99 +/- 0.3).


CONCLUSIONS
The antilipolytic effects of CVT-3619 appear to be independent of insulin resistance and animal model.
Dhalla
A K
AK
Department of Pharmacological Sciences, CV Therapeutics, Inc., Palo Alto, CA 94304, USA. arvinder.dhalla@cvt.com
Santikul
M
M
Chisholm
J W
JW
Belardinelli
L
L
Reaven
G M
GM
D000241:Adenosine / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D058907:Adenosine A1 Receptor Agonists; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D007333:Insulin Resistance; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D043682:Receptor, Adenosine A1 / Q000378:metabolism
C510789:2-(6-((2-hydroxycyclopentyl)amino)purin-9-yl)-5-((2-fluorophenylthio)methyl)oxolane-3,4-diol; D058907:Adenosine A1 Receptor Agonists; D005230:Fatty Acids, Nonesterified; D043682:Receptor, Adenosine A1; D000241:Adenosine