title: Altered myocardial substrate metabolism is associated with myocardial dysfunction in early diabetic cardiomyopathy in rats: studies using positron emission tomography.
abstract: BACKGROUND
  In vitro data suggest that changes in myocardial substrate metabolism may contribute to impaired myocardial function in diabetic cardiomyopathy (DCM). The purpose of the present study was to study in a rat model of early DCM, in vivo changes in myocardial substrate metabolism and their association with myocardial function.
  
  
  METHODS
  Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats underwent echocardiography followed by [11C]palmitate positron emission tomography (PET) under fasting, and [18F]-2-fluoro-2-deoxy-D-glucose PET under hyperinsulinaemic euglycaemic clamp conditions. Isolated cardiomyocytes were used to determine isometric force development.
  
  
  RESULTS
  PET data showed a 66% decrease in insulin-mediated myocardial glucose utilisation and a 41% increase in fatty acid (FA) oxidation in ZDF vs. ZL rats (both p < 0.05). Echocardiography showed diastolic and systolic dysfunction in ZDF vs. ZL rats, which was paralleled by a significantly decreased maximal force (68%) and maximal rate of force redevelopment (69%) of single cardiomyocytes. Myocardial functional changes were significantly associated with whole-body insulin sensitivity and decreased myocardial glucose utilisation. ZDF hearts showed a 68% decrease in glucose transporter-4 mRNA expression (p < 0.05), a 22% decrease in glucose transporter-4 protein expression (p = 0.10), unchanged levels of pyruvate dehydrogenase kinase-4 protein expression, a 57% decreased phosphorylation of AMP activated protein kinase alpha1/2 (p < 0.05) and a 2.4-fold increased abundance of the FA transporter CD36 to the sarcolemma (p < 0.01) vs. ZL hearts, which are compatible with changes in substrate metabolism. In ZDF vs. ZL hearts a 2.4-fold reduced insulin-mediated phosphorylation of Akt was found (p < 0.05).
  
  
  CONCLUSIONS
  Using PET and echocardiography, we found increases in myocardial FA oxidation with a concomitant decrease of insulin-mediated myocardial glucose utilisation in early DCM. In addition, the latter was associated with impaired myocardial function. These in vivo data expand previous in vitro findings showing that early alterations in myocardial substrate metabolism contribute to myocardial dysfunction.
authors.affiliation: Department of Endocrinology, Diabetes Centre, VU University Medical Centre, Amsterdam, The Netherlands. c.vandenbrom@vumc.nl
authors.forename: Charissa E
authors.initials: CE
authors.lastname: van den Brom
authors.forename: Marc C
authors.initials: MC
authors.lastname: Huisman
authors.forename: Ronald
authors.initials: R
authors.lastname: Vlasblom
authors.forename: Nicky M
authors.initials: NM
authors.lastname: Boontje
authors.forename: Suzanne
authors.initials: S
authors.lastname: Duijst
authors.forename: Mark
authors.initials: M
authors.lastname: Lubberink
authors.forename: Carla F M
authors.initials: CF
authors.lastname: Molthoff
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Lammertsma
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
authors.forename: Christa
authors.initials: C
authors.lastname: Boer
authors.forename: D Margriet
authors.initials: DM
authors.lastname: Ouwens
authors.forename: Michaela
authors.initials: M
authors.lastname: Diamant
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D011924:Rats, Zucker; D013379:Substrate Specificity / Q000502:physiology