Time Course of Alterations in Myocardial Glucose Utilization in the Zucker Diabetic Fatty Rat with Correlation to Gene Expression of Glucose Transporters: A Small-Animal PET Investigation

Abstract

Diabetic cardiomyopathy is associated with abnormalities in glucose metabolism. We evaluated myocardial glucose metabolism in a rodent model of type 2 diabetes, namely the Zucker diabetic fatty (ZDF) rat, and validated PET measurements of glucose uptake against gene and protein expression of glucose transporters (GLUTs). Methods: Six lean and ZDF rats underwent small-animal PET at the age of 14 wk and at the age of 19 wk. The imaging protocol consisted of a 60-min dynamic acquisition with 18 F-FDG (18.5-29.6 MBq). Dynamic images were reconstructed using filtered backprojection with a 2.5 zoom on the heart and 40 frames per imaging session. PET measurements of myocardial glucose uptake (MGUp) rate and utilization were determined with an input function derived by the hybrid image-blood-sampling algorithm on recovery-corrected anterolateral myocardial regions of interest. After the PET session at week 19 (W19), hearts were extracted for gene and protein expression analysis of GLUT-1 and GLUT-4. The dependence of MGUp on gene expression of GLUT-1 and GLUT-4 was characterized by multiple-regression analysis. Results: MGUp in ZDF rats at both week 14 (W14) and W19 (P , 0.006) was significantly lower than MGUp in lean littermate control rats. Moreover, lean rats at W19 displayed significantly higher MGUp than they did at W14 (P 5 0.007). Consistent with a diminished MGUp result, gene expression of GLUT-4 was significantly (P 5 0.004) lower in ZDF rats. Finally, MGUp significantly (P 5 0.0003) correlated with gene expression of GLUT-4. Conclusion: Using small-animal PET, we confirmed alterations in myocardial glucose utilization and validated PET measurement of MGUp against gene and protein expression of GLUTs in the diabetic heart of an animal model of type 2 diabetes.

Impact of Image-Derived Input Function and Fit Time Intervals on Patlak Quantification of Myocardial Glucose Uptake in Mice

“…This deployment has resulted in a myriad of studies using 18 F-FDG that apply widely divergent methods for quantification of myocardial glucose utilization (1,2).…”

Repeatable Noninvasive Measurement of Mouse Myocardial Glucose Uptake with 18F-FDG: Evaluation of Tracer Kinetics in a Type 1 Diabetes Model

“…The 18 F-FDG uptake rate constant, K i 5 (K 1 · k 3 )/(k 2 1 k 3 ), can be estimated using Patlak graphical kinetic analysis, assuming there is negligible tracer washout (k 4 5 0) (5). 18 F-FDG has been modeled extensively with Patlak analysis in humans (6,7) and rats (8)(9)(10)(11)(12). Studies in mice have evaluated the effects of diet (13), anesthetic (14), mode of injection, and blood glucose levels (15) on 18 F-FDG uptake.…”

Imaging diabetes mellitus with coronary computed tomography angiography, cardiovascular magnetic resonance, and positron emission tomography

“…MGUp was significantly lower in lean littermates at both 14 and 19 weeks, and the insulin-sensitive glucose transporter, GLUT4, was significantly lower when measured at 19 weeks. 23 The presumptive basal glucose transporter, GLUT1, was lower but the change was not significant, perhaps because of the small sample size. In a study of GLUT4 null (G4N) mice, myocardial glucose utilization (MGU) at baseline was comparable to wild-type but following administration of insulin, MGU demonstrated no initial increase and a markedly delayed time response.…”