Whole-Body Evaluation of MIBG Tissue Extraction in a Mouse Model of Long-Lasting Type II Diabetes and Its Relationship with Norepinephrine Transport Protein Concentration

Abstract

Accelerated cardiac washout of 123 I-metaiodobenzylguanidine (MIBG), which is clinically used as an index of cardiac neuropathy in diabetes, is ascribed to decreased norepinephrine reuptake into synaptic vesicles. However, accelerated washout frequently contrasts with preserved early tracer uptake, whose significance remains undetermined. The aim of this study was to investigate in a mouse model of long-lasting type II diabetes whether the mismatch between MIBG early uptake and washout is the consequence of a more generalized disorder of the autonomic nervous system. Methods: Nine mice were given low doses of streptozotocin by intraperitoneal injection for 5 consecutive days. At 7 mo after streptozotocin, MIBG kinetics were evaluated by heart and liver time-activity curves and by tracer accumulation in the bladder. Data were compared with those obtained in 10 sham mice and correlated with the cardiac and hepatic tissue expression of norepinephrine transporter (NET) as assessed with a 3 H-desipramine saturation binding assay. Results: In diabetic mice, myocardial and liver MIBG retention was reduced at 2 h and was associated with both increased tracer washout and reduced NET density. The rate of myocardial washout correlated with the degree of urinary MIBG excretion. Conclusion: The paradoxic observation of preserved early uptake associated with accelerated washout of MIBG in diabetes seems to be explained by a generalized disorder in NET function leading to reduced whole-body tracer removal from the blood and increased tracer availability for early myocardial uptake.

The co-occurrence of myocardial dysfunction and peripheral insensate neuropathy in a streptozotocin-induced rat model of diabetes

“…In the present study, a significant reduction in myocardial NE content was found at 8 weeks, suggesting cardiac sympathetic denervation, impaired release or synthesis. In addition, similar to our study and using a low-dose STZ non-insulin-dependent DM mouse model, Kusmic et al found increased urinary NE excretion and reduced myocardial NE content at 7 weeks post DM induction [45]. Using imaging of 123 I-metaiodobenzylguanidine myocardial retention by single-photon emission computed tomography to evaluate the function of sympathetic neuronal endings, Kusmic et al found accelerated tracer washout, indicating reduced NE uptake, and they suggested this might be due to decreased NE transporter expression [45].…”

Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia

“…These data suggest that diabetic autonomic neuropathy associated with reduced cardiac NE content is not present at 8 weeks of diabetes, rather displaying dysregulated sympathetic signaling characterized by elevated NE release. Recently, small animal single photon emission computed tomography (SPECT) imaging using the [ 11 C]HED analogue [ 123 I] meta -iodobenzylguanidine (MIBG) in db/db type 2 diabetic mice demonstrated maintained tracer uptake with enhanced washout rate [8]. These findings are consistent with elevated sympathetic activity without a pronounced decrease in NET density; that is, enhanced local release of catecholamines and vesicle-packaged MIBG.…”

“…The mechanisms involved in the progression of ventricular dysfunction in diabetes are diverse and unclear, with several pathways having been implicated including disrupted metabolic processes [2,3], glycation and interstitial fibrosis of myocardium [4], oxidative stress and apoptosis [5], and impairment of autonomic, particularly sympathetic, signal transduction [5-8]. …”

“…Retention of [ 11 C]HED is blocked by NET inhibitors and reduced by treatments elevating synaptic NE [22,23]. Altered uptake of [ 11 C]HED and other presynaptic tracers has been described extensively in diabetic rats and mice [8,13], as well as clinically [7]. The temporal progression of cardiac sympathetic dysregulation and its relation to left ventricular dysfunction remains unclear.…”

Enhanced Catecholamine Flux and Impaired Carbonyl Metabolism Disrupt Cardiac Mitochondrial Oxidative Phosphorylation in Diabetes Patients

“…A smaller portion of catecholamines are transported into nonneuronal cells, including the myocardium, through isoforms of the organic cation transporter-3 and extraneuronal monoamine transporters, while the remaining catecholamines enter the general circulation (i.e., spillover). In experimental models of type 2 diabetes, several groups have shown an attenuation in NET function, increased NE spillover, and decreased NE release (9,40,43). We were unable to measure catecholamine transport and re-uptake parameters within our patient cohort.…”