Published online before print July 21, 2009, doi: 10.1161/CIRCIMAGING.108.843227
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Original Articles |
In Vivo Metabolic Phenotyping of Myocardial Substrate Metabolism in Rodents
Differential Efficacy of Metformin and Rosiglitazone Monotherapy
From the Mallinckrodt Institute of Radiology, Division of Radiological Sciences; the Department of Medicine (K.S., T.S., P.H., R.J.G., M.W.), Division of Geriatrics and Nutritional Science (B.N.F.); and the Division of Biostatistics (K.B.S.), Washington University School of Medicine, St Louis, Mo.
Correspondence to Kooresh Shoghi, PhD, Washington University School of Medicine, Mallinckrodt Institute of Radiology, 510 South Kingshighway Blvd, Campus Box 8225, St Louis, MO 63110. E-mail shoghik{at}wustl.edu
Received December 11, 2008; accepted June 24, 2009.
Background— Cardiovascular disease is the leading cause of death among diabetic patients, with alteration in myocardial substrate metabolism being a likely contributor. We aimed to assess noninvasively the efficacy of metformin and rosiglitazone monotherapy in normalizing myocardial substrate metabolism in an animal model of type 2 diabetes mellitus.
Methods and Results— The study used 18 male ZDF rats (fa/fa) with 6 rats in each group: an untreated group; a group treated with metformin (16.6 mg/kg/d), and a group treated with rosiglitazone (4 mg/kg). Each rat was scanned at age 14 weeks (baseline) and subsequently at 19 weeks with small-animal positron emission tomography to estimate myocardial glucose utilization (MGU) and myocardial utilization (MFAU), oxidation (MFAO), and esterification (MFAE). Treatment lasted for 5 weeks after baseline imaging. At week 19, rats were euthanized and hearts were extracted for expression analysis of select genes encoding for GLUT transporters and fatty acid transport and oxidation genes. In addition, echocardiography measurements were obtained at weeks 13 and 18 to characterize cardiac function. Metformin had no significant effect on either MGU or MFAU and MFAO. In contrast, rosiglitazone tended to enhance MGU and significantly reduced MFAU and MFAO. Rosiglitazone-induced increase in glucose uptake correlated significantly with increased expression of GLUT4, whereas diminished MFAO correlated significantly with decreased expression of FATP-1 and MCAD. Finally, changes in fractional shortening as a measure of cardiac function were unchanged throughout the study.
Conclusions— Treatment with rosiglitazone enhanced glucose utilization and diminished MFAO, thus reversing the metabolic phenotype of the diabetic heart.
Key Words: metabolic imaging • type 2 diabetes • gene expression • response to therapy