Role of phosphodiesterase III in the antilipolytic effect of insulin in vivo.
The effect of three types of phosphodiesterase (PDE) inhibitors on in vivo antilipolysis was investigated in healthy subjects using a 2-h euglycemic, hyperinsulinemic (40 mU.m-2.min) clamp together with microdialysis of abdominal subcutaneous adipose tissue. During hyperinsulinemia (approximately 330 pmol/l), the circulating glycerol concentration was reduced to approximately 50% of the basal level of 53.2 +/- 3.6 mumol/l, indicating an antilipolytic effect. The decrease in adipose tissue dialysate glycerol, which mirrors the change in interstitial glycerol concentration, was about 40% during hyperinsulinemia when Ringer's solution alone was perfused. Local perfusion with a selective PDE IV inhibitor, rolipram (10(-4) mol/l), did not influence the insulin-induced decrease in dialysate glycerol (F = 0.8 vs. perfusion with Ringer's solution by two-factor analysis of variance [ANOVA]), although rolipram increased the dialysate glycerol level by 144 +/- 7% of the baseline value. However, local perfusion with a selective PDE III inhibitor, amrinone (10(-3) mol/l), or a nonselective PDE inhibitor, theophylline (10(-2) mol/l), abolished the ability of insulin to lower dialysate glycerol (F = 16.5, P < 0.01 and F = 8.5, P < 0.01, respectively, as compared with perfusion with Ringer's solution). The findings could not be explained by changes in the local blood flow (as measured by a microdialysis--ethanol escape technique), which was not affected by hyperinsulinemia in the presence or the absence of PDE inhibitors in the dialysis solvent. We conclude that PDEs play an important role in mediating the antilipolytic effect of insulin in vivo and that PDE III is the dominant isoenzyme modulating this effect.
Hagström-Toft
E
E
Department of Medicine, Huddinge Hospital, Karolinska Institute, Sweden.
Bolinder
J
J
Eriksson
S
S
Arner
P
P
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D005215:Fasting; D005260:Female; D015309:Glucose Clamp Technique; D005990:Glycerol / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism; D007328:Insulin / Q000097:blood* / Q000494:pharmacology*; D007700:Kinetics; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D017551:Microdialysis; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D013997:Time Factors
D001786:Blood Glucose; D007328:Insulin; D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D005990:Glycerol