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Diabetes Publish Ahead of Print published online ahead of print March 15, 2007
DOI: 10.2337/db06-0655
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Original Research

Effects of Insulin Replacements, Inhibitors of Angiotensin and Protein Kinase Cß's Actions to Normalize Cardiac Gene Expression and Fuel Metabolism in Diabetic Rats

Emi Arikawa1, Ronald C. W. Ma1, Keiji Isshiki1, Ivan Luptak2, Zhiheng He1, Yutaka Yasuda1, Yasuhiro Maeno1, Mary Elizabeth Patti1, Gordon C. Weir1, Robert A. Harris3, Victor A. Zammit4, Rong Tian2, and George L. King1

1Joslin Diabetes Center, Harvard Medical School (HMS), Boston, MA
2Brigham and Women's Hospital, HMS, Boston, MA
3Indiana University School of Medicine, Indianapolis, IN
4Warwick Medical School, Coventry, U.K

Correspondence: george.king{at}joslin.harvard.edu

Key Words: experimental diabetes • metabolism • cardiomyopathy • genes • protein kinase C

High-density oligonucleotide arrays were used to compare gene expression of rat hearts from control, untreated diabetic, and diabetic groups treated with islet cell transplantation (ICT), protein kinase C ß (PKCß) inhibitor ruboxistaurin (RBX), or angiotensin converting enzyme inhibitor (ACEI) captopril. Among the 376 genes which were differentially expressed between untreated diabetic and control hearts included key metabolic enzymes that account for the decreased glucose and increased free fatty acid (FFA) utilization in the diabetic heart. ICT or insulin replacements reversed these gene changes with normalization of hyperglycemia, dyslipidemia, and cardiac PKC activation in diabetic rats. Surprisingly, both RBX and ACEI improved the metabolic gene profile (confirmed by real-time RT-PCR and protein analysis) and ameliorated PKC activity in diabetic hearts without altering circulating metabolites. Functional assessments using Langendorff preparations and 13C-NMR spectroscopy showed a 36% decrease in glucose utilization and an impairment in diastolic function in diabetic rats hearts, which were normalized by all three treatments. In cardiomyocytes, PKC inhibition attenuated FA-induced increases in the metabolic genes PDK4 and UCP3 and also prevented FA-mediated inhibition of basal and insulin-stimulated glucose oxidation. Thus, PKCß inhibitor or ACEI may ameliorate cardiac metabolism and function in diabetes partly by normalization of fuel metabolic gene expression directly in the myocardium.


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Copyright © 2007 by the American Diabetes Association.