Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-alpha activator.
Hearts from diabetic db/db mice, a model of Type 2 diabetes, exhibit left ventricular failure and altered metabolism of exogenous substrates. Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) ligands reduce plasma lipid and glucose concentrations and improve insulin sensitivity in db/db mice. Consequently, the effect of 4- to 5-wk treatment of db/db mice with a novel PPAR-alpha ligand (BM 17.0744; 25-38 mg x kg(-1) x day(-1)), commencing at 8 wk of age, on ex vivo cardiac function and metabolism was determined. Elevated plasma concentrations of glucose, fatty acids, and triacylglycerol (34.0 +/- 3.6, 2.0 +/- 0.4, and 0.9 +/- 0.1 mM, respectively) were reduced to normal after treatment with BM 17.0744 (10.8 +/- 0.6, 1.1 +/- 0.1, and 0.6 +/- 0.1 mM). Plasma insulin was also reduced significantly in treated compared with untreated db/db mice. Chronic treatment of db/db mice with the PPAR-alpha agonist resulted in a 50% reduction in rates of fatty acid oxidation, with a concomitant increase in glycolysis (1.7-fold) and glucose oxidation (2.3- fold). Correction of the diabetes-induced abnormalities in systemic and cardiac metabolism after BM 17.0744 treatment did not, however, improve left ventricular contractile function.
Department of Medical Physiology, University of Tromsø, N-9037 Tromsø, Norway. ellenaa@fagmed.uit.no
Ellen
E
Aasum
Darrell D
DD
Belke
David L
DL
Severson
Rudolph A
RA
Riemersma
Marie
M
Cooper
Morten
M
Andreassen
Terje S
TS
Larsen
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D006019:Glycolysis; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D007850:Lauric Acids / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood; D016277:Ventricular Function, Left / Q000502:physiology*
C116893:2,2-dichloro-12-(p-chlorophenyl)-dodecanoic acid; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D007850:Lauric Acids; D010168:Palmitates; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides