The role of insulin-sensitive phosphodiesterase in insulin action.
The physiological role of the insulin-sensitive phosphodiesterase in mediating the antilipolytic actions of insulin was investigated in rat fat cells with two phosphodiesterase inhibitors, namely, 3-isobutyl-1-methylxanthine (IBMX) and griseolic acid. Insulin activates the phosphodiesterase when incubated with intact fat cells and blocks isoproterenol-induced cellular cAMP production and lipolysis, in a time- and dose-dependent manner. High concentrations of IBMX (1 mM), but not lower concentrations (0.1 mM), increased fat cell cAMP levels and lipolytic responses and overcame the antilipolytic effects of insulin; however, this treatment does not inhibit insulin-stimulated phosphodiesterase activity at earlier times (less than 30 min of incubation). These results may suggest that the level of cAMP under these conditions may be sufficient to stimulate lipolysis maximally, even though increases in cellular cAMP accumulation associated with the higher concentration of IBMX (1 mM) are partially suppressed by insulin. Cellular cAMP accumulation and the phosphodiesterase activation induced by IBMX are suppressed by the nonhydrolyzable adenosine analogue N6-phenylisopropyladenosine (PIA). These results suggest the involvement of adenosine receptors in mediating these responses. A novel phosphodiesterase inhibitor, griseolic acid, suppresses basal phosphodiesterase activity (approximately 50%), increases cellular cAMP content, and stimulates lipolysis in intact fat cells. It also partially suppresses insulin-stimulated phosphodiesterase activity (approximately 50%) and reduces the ability of insulin to decrease cellular cAMP concentration (approximately 40%) and lipolysis (approximately 65%). Because, unlike IBMX and other drugs, griseolic acid demonstrates only inhibition of phosphodiesterase activity, it may be a useful tool for studying the mechanism of insulin action in intact cells. The present work supports the concept that insulin's antilipolytic action is mediated by an activation of fat cell phosphodiesterase.
Second Department of Internal Medicine, Chiba University School of Medicine, Japan.
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H
Makino
T
T
Suzuki
H
H
Kajinuma
M
M
Yamazaki
H
H
Ito
S
S
Yoshida
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005990:Glycerol / Q000032:analysis; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014316:Tritium
D007328:Insulin; D014316:Tritium; D010660:Phenylisopropyladenosine; C046499:griseolic acid; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000241:Adenosine; D005990:Glycerol; D015056:1-Methyl-3-isobutylxanthine