In vivo metabolic phenotyping of myocardial substrate metabolism in rodents: Differential efficacy of metformin and rosiglitazone monotherapy

Kooresh I. Shoghi, Brian N. Finck, Kenneth B. Schechtman, Terry Sharp Pilar Herrero, Robert J. Gropler, Michael J. Welch

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

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 grouptreated 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 enhanceMGU 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 themetabolic phenotype of the diabetic heart. (Circ Cardiovasc Imaging. 2009;2:373-381.)

Original languageEnglish
Pages (from-to)373-381
Number of pages9
JournalCirculation: Cardiovascular Imaging
Volume2
Issue number5
DOIs
StatePublished - Sep 1 2009

Keywords

  • Gene expression
  • Metabolic imaging
  • Response to therapy
  • Type 2 diabetes

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