Published Online
on July 21, 2009

A more recent version of this article appeared on September 1, 2009

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Original Article

In Vivo Metabolic Phenotyping of Myocardial Substrate Metabolism in Rodents: Differential Efficacy of Metformin and Rosiglitazone Monotherapy

Kooresh I. Shoghi¹; Brian N. Finck; Kenneth B. Schechtman; Terry Sharp; Pillar Herrero; Robert J. Gropler and Michael J. Welch

Washington University School of Medicine, St. Louis, MO

^* Corresponding author; email: shoghik{at}wustl.edu

Background—Cardiovascular disease is the leading cause of death among diabetic patients with alterations 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 utilized 18 male ZDF rats (fa/fa) with 6 rats in each group: an untreated group; a group treated with Metformin (16.6mg/kg/day) and a group treated with Rosiglitazone (4mg/kg). Each rat was scanned at age 14 weeks (baseline) and subsequently at 19 weeks with small animal PET to estimate myocardial glucose utilization (MGU) and myocardial utilization (MFAU), oxidation (MFAO) and esterification (MFAE). Treatment lasted for 5 weeks following baseline imaging. At week 19, rats were sacrificed and hearts extracted for expression analysis of select genes encoding for GLUT transporters and fatty acid transport and oxidation genes. In addition, echocardiography (ECHO) measurements were obtained at week 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 while 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: cardiovascular diseases • diabetes mellitus • echocardiography • gene expression • metabolic imaging • response to therapy • type 2 diabetes