Key result
Islet transplantation, ruboxistaurin, and captopril reverse ~36% reduced glucose utilization and diastolic impairment in diabetic hearts.
Why the study?
Diabetes alters cardiac gene expression and fuel metabolism, and the effects of insulin replacements, PKCbeta inhibitors, and ACE inhibitors on these changes were unclear.
Does treatment with islet cell transplantation, ruboxistaurin, or captopril improve cardiac gene expression, fuel metabolism, and diastolic function in diabetic rats?
Does treatment with islet cell transplantation, ruboxistaurin, or captopril improve cardiac gene expression, fuel metabolism, and diastolic function in diabetic rats?
PKCbeta inhibitors and ACE inhibitors can normalize cardiac metabolic gene expression and improve diastolic function in diabetic models independent of changes in circulating metabolites.
Suggests metabolic targets in diabetic cardiomyopathy models; hypothesis-generating and leaves open human translation.
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)beta 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 (13)C 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, PKCbeta or ACE inhibitors may ameliorate cardiac metabolism and function in diabetes partly by normalization of fuel metabolic gene expression directly in the myocardium.
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Arikawa et al. (2007) studied Diabetes (animal model). Islet cell transplantation, ruboxistaurin, or captopril vs. Untreated diabetic and control rats was evaluated on Cardiac gene expression and glucose utilization. Islet cell transplantation, ruboxistaurin, and captopril normalized cardiac metabolic gene expression and reversed a 36% decrease in glucose utilization and diastolic impairment in diabetic rat hearts.
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