The new antidiabetic drug MCC-555 acutely sensitizes insulin signaling in isolated cardiomyocytes.
Freshly isolated adult rat ventricular cardiomyocytes have been used to characterize the action profile of the new thiazolidinedione antidiabetic drug MCC-555. Preincubation of cells with the compound (100 microM for 30 min or 10 microM for 2 h) did not modify basal 3-O-methylglucose transport, but produced a marked sensitizing effect (2- to 3-fold increase in insulin action at 3 x 10(-11) M insulin) and a further enhancement of maximum insulin action (1.8-fold). MCC-555 did not modulate autophosphorylation of the insulin receptor and tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). However, insulin action (10(-10) and 10(-7) M) on IRS-1-associated phosphatidylinositol (PI) 3-kinase activity was enhanced 2-fold in the presence of MCC-555. Association of the p85 adapter subunit of PI 3-kinase to IRS-1 was not modified by the drug. Immunoblotting experiments demonstrated expression of the peroxisomal proliferator-activated receptor-gamma in cardiomyocytes reaching about 30% of the abundance observed in adipocytes. The insulin-sensitizing effect of MCC-555 was lost after inhibition of protein synthesis by preincubation of the cells with cycloheximide (1 mM; 30 min). Cardiomyocytes from obese Zucker rats exhibited a completely blunted response of glucose transport at 3 x 10(-11) M insulin. MCC-555 ameliorates this insulin resistance, producing a 2-fold stimulation of glucose transport, with maximum insulin action being 1.6-fold higher than that in control cells. This drug effect was paralleled by a significant dephosphorylation of IRS-1 on Ser/Thr. In conclusion, MCC-555 rapidly sensitizes insulin-stimulated cardiac glucose uptake by enhancing insulin signaling resulting from increased intrinsic activity of PI 3-kinase. Acute activation of protein expression leading to a modulation of the Ser/Thr phosphorylation state of signaling proteins such as IRS-1 may be underlying this process. It is suggested that MCC-555 may provide a causal therapy of insulin resistance by targeted action on the defective site in the insulin signaling cascade.
Liu
L S
LS
Molecular Cardiology, Diabetes Research Institute, Düsseldorf, Germany.
Tanaka
H
H
Ishii
S
S
Eckel
J
J
D000818:Animals; D015153:Blotting, Western; D005947:Glucose / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000502:physiology*; D008297:Male; D009206:Myocardium / Q000166:cytology*; D009765:Obesity / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011233:Precipitin Tests; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones
D007004:Hypoglycemic Agents; D007328:Insulin; D011500:Protein Synthesis Inhibitors; D013844:Thiazoles; D045162:Thiazolidinediones; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose; C115174:netoglitazone