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Insulin restores myocardial presynaptic sympathetic neuronal integrity in insulin-resistant diabetic rats

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Journal of Nuclear Cardiology Aims and scope

Abstract

Background

Diabetes is associated with increased sympathetic activity, elevated norepinephrine, impaired heart rate variability, and the added risk of cardiovascular mortality. The temporal development of sympathetic neuronal dysfunction, response to therapy, and relation to ventricular function is not well characterized.

Methods and Results

Sympathetic neuronal integrity was serially investigated in high fat diet-fed streptozotocin diabetic rats using [11C]meta-hydroxyephedrine (HED) positron emission tomography at baseline, 8 weeks of diabetes, and after a further 8 weeks of insulin or insulin-sensitizing metformin therapy. Myocardial HED retention was reduced in diabetic rats (n = 16) compared to non-diabetics (n = 6) at 8 weeks by 52-57% (P = .01) with elevated plasma and myocardial norepinephrine levels. Echocardiography pulse-wave Doppler measurements demonstrated prolonged mitral valve deceleration and increased early-to-atrial filling velocity, consistent with diastolic dysfunction. Insulin but not metformin evoked recovery of HED retention and plasma norepinephrine (P < .05), whereas echocardiography measurements of diastolic function were not improved by either treatment. Relative expressions of norepinephrine reuptake transporter and β-adrenoceptors were lower in metformin-treated as compared to insulin-treated diabetic and non-diabetic rats. Diabetic rats exhibited depressed heart rate variability and impaired diastolic function which persisted despite insulin treatment.

Conclusions

HED imaging provides sound estimation of sympathetic function. Effective glycemic control can recover sympathetic function in diabetic rats without the corresponding recovery of echocardiography indicators of diastolic dysfunction. HED positron emission tomography imaging may be useful in stratifying cardiovascular risk among diabetic patients and in evaluating the effect of glycemic therapy on the heart.

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Acknowledgments

The authors would like to thank the PET BioTesting, Imaging Physics, and Radiochemistry laboratories for their excellent technical expertise and assistance with these studies.

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Authors and Affiliations

  1. Molecular Function & Imaging Program, National Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, K1Y 4W7, Canada

    James T. Thackeray PhD, Robert A. deKemp PhD, Rob S. Beanlands MD & Jean N. DaSilva PhD

  2. Department of Cellular & Molecular Medicine, Faculty of Graduate and Postdoctoral Studies, University of Ottawa, Ottawa, ON, Canada

    James T. Thackeray PhD, Rob S. Beanlands MD & Jean N. DaSilva PhD

  3. Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany

    James T. Thackeray PhD

Authors
  1. James T. Thackeray PhD
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  2. Robert A. deKemp PhD
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  3. Rob S. Beanlands MD
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  4. Jean N. DaSilva PhD
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Corresponding author

Correspondence to James T. Thackeray PhD.

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Financial Assistance

Experiments were funded by the Heart and Stroke Foundation of Ontario (NA7213, PRG6242). JTT was supported by a Heart and Stroke Foundation of Canada Doctoral Research Award. RSB is a Career Investigator of the Heart and Stroke Foundation of Canada, a Tier 1 University of Ottawa Chair in Cardiovascular Disease Research, and the Goldfarb Chair in Cardiac Imaging Research.

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Thackeray, J.T., deKemp, R.A., Beanlands, R.S. et al. Insulin restores myocardial presynaptic sympathetic neuronal integrity in insulin-resistant diabetic rats. J. Nucl. Cardiol. 20, 845–856 (2013). https://doi.org/10.1007/s12350-013-9759-2

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  • DOI: https://doi.org/10.1007/s12350-013-9759-2

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