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1.  Chronic AMPK activity dysregulation produces myocardial insulin resistance in the human Arg302Gln-PRKAG2 glycogen storage disease mouse model 
EJNMMI Research  2013;3:48.
The cardiac PRKAG2 mutation in the γ2-subunit of adenosine monophosphate activated kinase (AMPK) is characterized by excessive glycogen deposition, hypertrophy, frequent arrhythmias, and progressive conduction system disease. We investigated whether myocardial glucose uptake (MGU) was augmented following insulin stimulation in a mouse model of the PRKAG2 cardiac syndrome.
Myocardial and skeletal muscle glucose uptake was assessed with 2-[18F]fluoro-2-deoxyglucose positron emission tomography imaging in n = 3 transgenic wildtype (TGwt) vs n = 7 PRKAG2 mutant (TGmut) mice at baseline and 1 week later, 30 min following acute insulin. Systolic function, cardiac glycogen stores, phospho-AMPK α, and insulin-receptor expression levels were analyzed to corroborate to the in vivo findings.
TGmut Patlak Ki was reduced 56% at baseline compared to TGwt (0.3 ± 0.2 vs 0.7 ± 0.1, t test p = 0.01). MGU was augmented 71% in TGwt mice following acute insulin from baseline (0.7 ± 0.1 to 1.2 ± 0.2, t test p < 0.05). No change was observed in TGmut mice. As expected for this cardiac specific transgene, skeletal muscle was unaffected at baseline with a 33% to 38% increase (standard uptake values) for both genotypes following insulin stimulation. TGmut mice had a 47% reduction in systolic function with a fourfold increase in cardiac glycogen stores correlated with a 29% reduction in phospho-AMPK α levels. There was no difference in cardiac insulin receptor expression between mouse genotypes.
These results demonstrate a correlation between insulin resistance and AMPK activity and provide the basis for the use of this animal model for assessing metabolic therapy in the treatment of affected PRKAG2 patients.
PMCID: PMC3707764  PMID: 23829931
Positron emission tomography; FDG; Patlak; Echocardiography; Glucose
2.  Altered sympathetic nervous system signaling in the diabetic heart: emerging targets for molecular imaging 
Diabetes is commonly associated with increased risk of cardiovascular morbidity and mortality. Perturbations in sympathetic nervous system (SNS) signaling have been linked to the progression of diabetic heart disease. Glucose, insulin, and free fatty acids contribute to elevated sympathetic nervous activity and norepinephrine release. Reduced left ventricular compliance and impaired cardiac function lead to further SNS activation. Chronic elevation of cardiac norepinephrine culminates in altered expression of pre- and post-synaptic sympathetic signaling elements, changes in calcium regulatory proteins, and abnormal contraction-excitation coupling. Clinically, these factors manifest as altered resting heart rate, depressed heart rate variability, and impaired cardiac autonomic reflex, which may contribute to elevated cardiovascular risk. Development of molecular imaging probes enable a comprehensive evaluation of cardiac SNS signaling at the neuron, postsynaptic receptor, and intracellular second messenger sites of signal transduction, providing mechanistic insights into cardiac pathology. This review will examine the evidence for abnormal SNS signaling in the diabetic heart and establish the physiological consequences of these changes, drawing from basic biological research in isolated heart and rodent models of diabetes, as well as from clinical reports. Particular attention will be paid to the use of molecular imaging approaches to non-invasively characterize and evaluate sympathetic signal transduction in diabetes, including pre-synaptic norepinephrine reuptake assessment using 11C-meta-hydroxyephedrine (11C-HED) with PET or 123I-metaiodobenzylguanidine (123I-MIBG) with SPECT, and postsynaptic β-adrenoceptor density measurements using CGP12177 derivatives. Finally, the review will attempt to define the future role of these non-invasive nuclear imaging techniques in diabetes research and clinical care.
PMCID: PMC3477737  PMID: 23133819
Sympathetic neuronal imaging; SNS signaling; norepinephrine; β-adrenoceptor; norepinephrine reuptake transporter
3.  Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia 
Diabetes mellitus is strongly associated with cardiovascular dysfunction, derived in part from impairment of sympathetic nervous system signaling. Glucose, insulin, and non-esterified fatty acids are potent stimulants of sympathetic activity and norepinephrine (NE) release. We hypothesized that sustained hyperglycemia in the high fat diet-fed streptozotocin (STZ) rat model of sustained hyperglycemia with insulin resistance would exhibit progressive sympathetic nervous dysfunction in parallel with deteriorating myocardial systolic and/or diastolic function.
Cardiac sympathetic nervous integrity was investigated in vivo via biodistribution of the positron emission tomography radiotracer and NE analogue [11C]meta-hydroxyephedrine ([11C]HED). Cardiac systolic and diastolic function was evaluated by echocardiography. Plasma and cardiac NE levels and NE reuptake transporter (NET) expression were evaluated as correlative measurements.
The animal model displays insulin resistance, sustained hyperglycemia, and progressive hypoinsulinemia. After 8 weeks of persistent hyperglycemia, there was a significant 13-25% reduction in [11C]HED retention in myocardium of STZ-treated hyperglycemic but not euglycemic rats as compared to controls. There was a parallel 17% reduction in immunoblot density for NE reuptake transporter, a 1.2 fold and 2.5 fold elevation of cardiac and plasma NE respectively, and no change in sympathetic nerve density. No change in ejection fraction or fractional area change was detected by echocardiography. Reduced heart rate, prolonged mitral valve deceleration time, and elevated transmitral early to atrial flow velocity ratio measured by pulse-wave Doppler in hyperglycemic rats suggest diastolic impairment of the left ventricle.
Taken together, these data suggest that sustained hyperglycemia is associated with elevated myocardial NE content and dysregulation of sympathetic nervous system signaling in the absence of systolic impairment.
PMCID: PMC3170183  PMID: 21831292
norepinephrine; [11C]meta-hydroxyephedrine (HED); small animal echocardiography; positron emission tomography; diabetes mellitus; cardiovascular disease

Results 1-3 (3)