Effects of insulin replacements, inhibitors of angiotensin, and PKCβ's actions to normalize cardiac gene expression and fuel metabolism in diabetic rats

Emi Arikawa, Ronald C W Ma, Keiji Isshiki, Ivan Luptak, Zhiheng He, Yutaka Yasuda, Yasuhiro Maeno, Mary Elizabeth Patti, Gordon C. Weir, Robert Harris, Victor A. Zammit, Rong Tian, George L. King

Research output: Contribution to journalArticle

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Abstract

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 (PKC)β inhibitor ruboxistaurin, or ACE inhibitor captopril. Among the 376 genes that were differentially expressed between untreated diabetic and control hearts included key metabolic enzymes that account for the decreased glucose and increased free fatty acid 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 ruboxistaurin and ACE inhibitors 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 nuclear magnetic resonance spectroscopy showed a 36% decrease in glucose utilization and an impairment in diastolic function in diabetic rat hearts, which were normalized by all three treatments. In cardiomyocytes, PKC inhibition attenuated fatty acid-induced increases in the metabolic genes PDK4 and UCP3 and also prevented fatty acid-mediated inhibition of basal and insulin-stimulated glucose oxidation. Thus, PKCβ or ACE inhibitors may ameliorate cardiac metabolism and function in diabetes partly by normalization of fuel metabolic gene expression directly in the myocardium.

Original languageEnglish
Pages (from-to)1410-1420
Number of pages11
JournalDiabetes
Volume56
Issue number5
DOIs
StatePublished - May 2007

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Angiotensins
Protein Kinase C
ruboxistaurin
Insulin
Gene Expression
Angiotensin-Converting Enzyme Inhibitors
Islets of Langerhans Transplantation
Protein C Inhibitor
Cell Transplantation
Protein Kinase Inhibitors
Islets of Langerhans
Glucose
Genes
Fatty Acids
Metabolome
Captopril
Dyslipidemias
Oligonucleotide Array Sequence Analysis
Nonesterified Fatty Acids
Cardiac Myocytes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Effects of insulin replacements, inhibitors of angiotensin, and PKCβ's actions to normalize cardiac gene expression and fuel metabolism in diabetic rats. / Arikawa, Emi; Ma, Ronald C W; Isshiki, Keiji; Luptak, Ivan; He, Zhiheng; Yasuda, Yutaka; Maeno, Yasuhiro; Patti, Mary Elizabeth; Weir, Gordon C.; Harris, Robert; Zammit, Victor A.; Tian, Rong; King, George L.

In: Diabetes, Vol. 56, No. 5, 05.2007, p. 1410-1420.

Research output: Contribution to journalArticle

Arikawa, E, Ma, RCW, Isshiki, K, Luptak, I, He, Z, Yasuda, Y, Maeno, Y, Patti, ME, Weir, GC, Harris, R, Zammit, VA, Tian, R & King, GL 2007, 'Effects of insulin replacements, inhibitors of angiotensin, and PKCβ's actions to normalize cardiac gene expression and fuel metabolism in diabetic rats', Diabetes, vol. 56, no. 5, pp. 1410-1420. https://doi.org/10.2337/db06-0655
Arikawa, Emi ; Ma, Ronald C W ; Isshiki, Keiji ; Luptak, Ivan ; He, Zhiheng ; Yasuda, Yutaka ; Maeno, Yasuhiro ; Patti, Mary Elizabeth ; Weir, Gordon C. ; Harris, Robert ; Zammit, Victor A. ; Tian, Rong ; King, George L. / Effects of insulin replacements, inhibitors of angiotensin, and PKCβ's actions to normalize cardiac gene expression and fuel metabolism in diabetic rats. In: Diabetes. 2007 ; Vol. 56, No. 5. pp. 1410-1420.
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