Influence of dietary state and insulin on myocardial, skeletal muscle and brain [18F]-fluorodeoxyglucose kinetics in mice (original) (raw)
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Journal of Nuclear Medicine, 2008
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.
Glucose metabolism in reperfused myocardium measured by [2-18F] 2-fluorodeoxyglucose and PET
Cardiovascular Research, 2000
Objective: [2-F] 2-fluorodeoxyglucose (FDG) is widely used to trace glucose metabolism for cardiac imaging with positron emission tomography. Because the transport and phosphorylation rates differ for glucose and FDG, a lumped constant (LC) is used to correct for these differences. The effects of ischemia and reperfusion on the LC in vivo are unknown. To determine the validity of FDG as a tracer of glucose metabolism in post-ischemic myocardium in vivo, the relationship between glucose uptake (GU) and FDG metabolic rate (FDG-MR) was assessed early post-reperfusion following a transient ischemic event. Methods: FDG metabolic rate, measured with FDG and PET, was compared to invasive measurements of substrate metabolism in reperfused and global myocardium of dogs subjected to 25 min ischemia and 2 h reperfusion. Results: The FDG metabolic rate was decreased 2064% in reperfused relative to remote myocardium. Glucose oxidation and lactate uptake were also decreased in reperfused relative to global myocardium, by 2666% and 6068% respectively. Glucose uptake did not differ significantly between reperfused and global myocardium. A linear correlation between FDG metabolic rate and glucose uptake was found in both reperfused and remote myocardium. Estimates of the LC from the slopes of the regression lines were similar in reperfused and remote myocardium, 1.25 and 1.44 respectively, and did not differ significantly from the LC determined in control dogs, 1.1. Conclusions: We conclude that the FDG metabolic rate continues to correlate well with glucose metabolism in reperfused myocardium. While FDG metabolic rate was modestly decreased in the absence of a significant change in glucose uptake, large alterations in the LC are not found 2 h post-reperfusion in vivo.
Assessment of Myocardial Metabolism in Diabetic Rats Using Small-Animal PET: A Feasibility Study
2000
This feasibility study was undertaken to determine whether kinetic modeling in conjunction with small-animal PET could noninvasively quantify alterations in myocardial perfusion and substrate metabolism in rats. Methods: All small-animal PET was performed on either of 2 tomographs. Myocardial blood flow and substrate metabolism were measured in 10 male Zucker diabeticfattyrats(ZDF,fa/fa)and10leanlittermates(Lean,Fa/1) using 15O-water, 1-11C-glucose, 1-11C-acetate, and 1-11C- palmitate. Animals were
The Journal of Nutritional Biochemistry, 2000
Male Wistar rats chronically (15 weeks) fed a sucrose-rich diet (SRD; 63% w/w) developed hypertriglyceridemia and impaired glucose homeostasis. Hearts from these animals were isolated and perfused using the Langendorff recirculating method. Glucose at levels similar to those found in the animal in vivo was used as the only exogenous substrate. The hearts were perfused for 30 minutes in the presence or absence of insulin (30 mU/mL) in the perfusion medium. In the absence of the hormone, glucose uptake was impaired and the glucose utilization was reduced, with a significant increase of lactate release. Glucose oxidation, which was estimated from the activation state of the enzyme pyruvate dehydrogenase complex (PDHc), was depressed mainly due to both an increase of PDH kinase and a decrease of PDHa (active form of PDHc) activities. Although the addition of insulin in the perfusion medium improved the above parameters, it was unable to normalize them. The present results suggest that at least two different mechanisms might contribute to insulin resistance and to the impaired glucose metabolism in the perfused hearts of the dyslipemic SRD-fed animals: (1) reduced basal and insulin-stimulated glucose uptake and its utilization or (2) increased availability and oxidation of lipids (low PDHa and high PDH kinase activities), which in turn decrease glucose uptake and utilization. Thus, this nutritional experimental model may be useful to study how impaired glucose homeostasis, increases plasma free fatty acid levels and hypertriglyceridemia could contribute to heart tissue malfunction. (J. Nutr. Biochem. 11: 30 -37, 2000)
Journal of Nuclear Medicine
Quantitative assessment of myocardial glucose uptake by the glucose tracer analog 2-deoxy-2-[18F]fluoro-D-glucose (FDG) depends on a correction factor (lumped constant [LC]), which may vary. We propose that this variability is caused by different affinities of FDG and glucose for membrane transport and phosphorylation and can be predicted from the time course of FDG retention. We therefore measured the LC under steadystate metabolic conditions and compared the results with values predicted from the tracer retention alone. Methods: We mea sured rates of myocardial glucose uptake by tracer ([2-3H]glucose) and tracer analog methods (FDG) in isolated working Sprague-Dawley rat hearts perfused with Krebs buffer and glucose, or glucose plus insulin or ß-hydroxybutyrate.In sepa rate experiments, we established the theoretical upper and lower limits for the LC (R, and Rp),which are determined by the relative rates of FDG and glucose membrane transport (Ft,, 1.73 ±0.22) and the relative rales of FDG and glucose phosphorylation (Rp, 0.15 ±0.04). Results: The LC was decreased in the presence of insulin or ß-hydroxybutyrateor both (from 1.14 ±0.3 to 0.58 ± 0.16 [insulin], to 0.75 ±0.17 [ß-hydroxybutyrate]or to 0.53 ± 0.17 [both], P < 0.05). The time-activity curves of FDG retention reflected these changes. Combining the upper and lower limits for the LC with the ratio between unidirectional and steady-state FDG uptake rates allowed the prediction of individual LCs, which agreed well with the actually measured values (r = 0.96, P < 0.001 ). Conclusion: The LC is not a constant but is a predictable quotient. As a result of the fixed relation between tracer and tracéefor both membrane transport and phosphorylation, the quotient can be determined from the FDG time-activity curve and true rates of myocardial glucose uptake can be measured.
Molecular Imaging
Using longitudinal micro positron emission tomography (microPET)/computed tomography (CT) studies, we quantified changes in myocardial metabolism and perfusion in spontaneously hypertensive rats (SHRs), a model of left ventricular hypertrophy (LVH). Fatty acid and glucose metabolism were quantified in the hearts of SHRs and Wistar-Kyoto (WKY) normotensive rats using longchain fatty acid analog 18 F-fluoro-6-thia heptadecanoic acid (18 F-FTHA) and glucose analog 18 F-fluorodeoxyglucose (18 F-FDG) under normal or fasting conditions. We also used 18 F-fluorodihydrorotenol (18 F-FDHROL) to investigate perfusion in their hearts without fasting. Rats were imaged at 4 or 5 times over their life cycle. Compartment modeling was used to estimate the rate constants for the radiotracers. Blood samples were obtained and analyzed for glucose and free fatty acid concentrations. SHRs demonstrated no significant difference in 18 F-FDHROL wash-in rate constant (P ¼ .1) and distribution volume (P ¼ .1), significantly higher 18 F-FDG myocardial influx rate constant (P ¼ 4Â10 À8), and significantly lower 18 F-FTHA myocardial influx rate constant (P ¼ .007) than WKYs during the 2009-2010 study without fasting. SHRs demonstrated a significantly higher 18 F-FDHROL wash-in rate constant (P ¼ 5Â10 À6) and distribution volume (P ¼ 3Â10 À8), significantly higher 18 F-FDG myocardial influx rate constant (P ¼ 3Â10 À8), and a higher trend of 18 F-FTHA myocardial influx rate constant (not significant, P ¼ .1) than WKYs during the 2011-2012 study with fasting. Changes in glucose plasma concentrations were generally negatively correlated with corresponding radiotracer influx rate constant changes. The study indicates a switch from preferred fatty acid metabolism to increased glucose metabolism with hypertrophy. Increased perfusion during the 2011-2012 study may be indicative of increased aerobic metabolism in the SHR model of LVH.
2004
The goal of this study was to determine whether changes in cardiac metabolism in Type-2 diabetes were associated with contractile dysfunction or impaired response to ischemia. Hearts from Zucker diabetic fatty rats (ZDF) and lean Controls were isolated, perfused and glucose, lactate, pyruvate and palmitate oxidation rates and glycolytic rates determined during baseline perfusion, low flow ischemia (LFI; 0.3mls/min for 30min) and following LFI and reperfusion.
In vivo dose response curves of insulin action in heart: Anomalous effects at high insulin doses
Journal of Molecular and Cellular Cardiology, 1985
981-985. The euglycaemic hyperinsulaemic clamp technique in conscious unrestrained rats was used to compile insulin dose response curves of glucose metabolism in the heart in vivo. An estimate of heart glucose uptake (Rg') was obtained using [3H]-2-deoxyglucose and glucose disposal was examined by measuring cardiac glycogen content. Elevation of insulin from 29 to 54 mU/1 resulted in a significant increase in Rg' in heart from 41 + 6 to 77 _+ 4 ~mol/100 g/min (P < 0.01) with no effect on glycogen content. This is consistent with increased glucose oxidation. At 150 mU/l of insulin both Rg' and glycogen synthesis were increased. Glycogen content increased from 18.5 + 1.7 ,umol/g under basal conditions to 27.9 _ 1.6 #mol/g with insulin. However, at subsequent insulin doses producing plasma levels exceeding 600 mU/1 there was an anomalous reversal of Rg' back to basal levels while glycogen content was significantly elevated (2.4-fold, P < 0.01). This effect may be related to feedback inhibition of tissue glycogen on glucose transport or to accumulation of tissue metabolites such as glucose-6-phosphate. The dose response curve for insulin stimulated Rg' in heart does not resemble either the whole body glucose utilization curve or that in individual skeletal muscles.