Treatment of type 2 diabetic db/db mice with a novel PPARgamma agonist improves cardiac metabolism but not contractile function.
Hearts from insulin-resistant type 2 diabetic db/db mice exhibit features of a diabetic cardiomyopathy with altered metabolism of exogenous substrates and reduced contractile performance. Therefore, the effect of chronic oral administration of 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (COOH), a novel ligand for peroxisome proliferator-activated receptor-gamma that produces insulin sensitization, to db/db mice (30 mg/kg for 6 wk) on cardiac function was assessed. COOH treatment reduced blood glucose from 27 mM in untreated db/db mice to a normal level of 10 mM. Insulin-stimulated glucose uptake was enhanced in cardiomyocytes from COOH-treated db/db hearts. Working perfused hearts from COOH-treated db/db mice demonstrated metabolic changes with enhanced glucose oxidation and decreased palmitate oxidation. However, COOH treatment did not improve contractile performance assessed with ex vivo perfused hearts and in vivo by echocardiography. The reduced outward K+ currents in diabetic cardiomyocytes were still attenuated after COOH. Metabolic changes in COOH-treated db/db hearts are most likely indirect, secondary to changes in supply of exogenous substrates in vivo and insulin sensitization.
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Andrew N
AN
Carley
Lisa M
LM
Semeniuk
Yakhin
Y
Shimoni
Ellen
E
Aasum
Terje S
TS
Larsen
Joel P
JP
Berger
David L
DL
Severson
D000085:Acetates / Q000008:administration & dosage*; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D004452:Echocardiography; D006321:Heart / Q000187:drug effects*; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000172:deficiency; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D054411:Receptors, Leptin; D014157:Transcription Factors / Q000819:agonists*; D016896:Treatment Outcome
C483845:2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid; D000085:Acetates; D001786:Blood Glucose; D007211:Indoles; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D054411:Receptors, Leptin; D014157:Transcription Factors