title: Insulin restores myocardial presynaptic sympathetic neuronal integrity in insulin-resistant diabetic rats.
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.
  
  
  RESULTS
  Sympathetic neuronal integrity was serially investigated in high fat diet-fed streptozotocin diabetic rats using [(11)C]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.
authors.affiliation: Molecular Function & Imaging Program, National Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, K1Y 4W7, Canada, jdasilva@ottawaheart.ca.
authors.forename: James T
authors.initials: JT
authors.lastname: Thackeray
authors.forename: Robert A
authors.initials: RA
authors.lastname: deKemp
authors.forename: Rob S
authors.initials: RS
authors.lastname: Beanlands
authors.forename: Jean N
authors.initials: JN
authors.lastname: DaSilva
mesh_terms: D000818:Animals; D003287:Contrast Media / Q000737:chemistry; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004452:Echocardiography; D004809:Ephedrine / Q000031:analogs & derivatives; D015309:Glucose Clamp Technique; D006321:Heart / Q000187:drug effects; D007328:Insulin / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000737:chemistry; D008943:Mitral Valve / Q000473:pathology; D009206:Myocardium / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism*; D049268:Positron-Emission Tomography; D017729:Presynaptic Terminals / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012306:Risk; D013564:Sympathetic Nervous System / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology; D013686:Telemetry; D018608:Ultrasonography, Doppler
chemical_list: D003287:Contrast Media; D007328:Insulin; C065363:3-hydroxyephedrine; D008687:Metformin; D004809:Ephedrine; D009638:Norepinephrine