Diabetic cardiac autonomic neuropathy: Insights from animal models

Stables, Catherine L.; Glasser, Rebecca; Feldman, Eva L.

doi:10.1016/j.autneu.2013.03.001

Cited by 18 publications

(18 citation statements)

References 48 publications

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“…Indices of DM cardiac autonomic neuropathy in animal models can be studied by a variety of methods, including analysis of myocardial NE content, cardiac sympathetic and parasympathetic innervation density, and heart rate variability [37]. Twenty-four hour urinary NE excretion is a commonly used biomarker to measure autonomic dysfunction [38].…”

Section: Discussionmentioning

confidence: 99%

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

Marangoni

Brady

Chowdhury

et al. 2014

Cardiovasc Diabetol

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BackgroundCardiomyopathy and distal symmetrical polyneuropathy (DSPN), including sensory and autonomic dysfunction, often co-occur in diabetic mellitus (DM) patients. However, the temporal relationship and progression between these two complications has not been investigated. Using a streptozotocin DM animal model that develops insensate neuropathy, our aim was to examine in parallel the development of DSPN and DM-associated changes in cardiac structure and function as well as potential mechanisms, such as autonomic dysfunction, evaluated by changes in urinary and myocardial norepinephrine content and myocardial neuronal markers.MethodsSensory neuropathy was measured by behavioral tests using Von Frey filaments and Hargreaves methods. Echocardiography was used to evaluate myocardial structure and function. Autonomic function was evaluated by measuring urinary and myocardial norepinephrine (NE) levels by enzyme-linked immunosorbent assay and high-performance liquid chromatography/mass spectrometry. Quantitative immunohistochemistry was used to measure the myocardial neuronal markers, calcitonin gene-related peptide (CGRP) and general neuronal protein gene product 9.5 (PGP 9.5).ResultsThe DM group developed tactile and thermal insensate neuropathy 4–5 weeks after DM onset. Cardiovascular changes were found between 4 and 12 weeks after DM onset and included bradycardia, diastolic and systolic dysfunction and cardiac dilation. There was a 2.5-fold reduction in myocardial NE levels and a 5-fold increase in urinary NE levels in the DM group. Finally, there was a 2.3-fold increase in myocardial CGRP levels in the DM group and no change in PGP9.5 levels.ConclusionsCardiovascular structural and functional changes developed early in the course of DM and in combination with insensate neuropathy. In parallel, signs of cardiac autonomic dysfunction were also found and included decreased myocardial NE levels and altered CGRP levels. These results may indicate the need for early cardiovascular evaluation in DM patients with insensate neuropathy.

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Section: Discussionmentioning

confidence: 99%

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

Marangoni

Brady

Chowdhury

et al. 2014

Cardiovasc Diabetol

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“…The most commonly-used mouse models are db/db mutant mice (type-2 diabetes; secondary to hyperphagia and obesity caused by a mutation in the leptin receptor gene) and streptozotocin (STZ)-treated mice (type-1 diabetes; destruction of pancreatic islets by STZ). Published studies using these models, however, contain variable and sometimes conflicting results (Stables et al, 2013). Specifically, HR has been reported to be increased (Goncalves et al, 2009), decreased (Park et al, 2008; Semeniuk et al, 2002; Senador et al, 2009), or unaltered (Su et al, 2008) in db/db mice, and increased (Kellogg et al, 2009) or decreased (Lin et al, 2010; Mabe et al, 2011) in STZ-treated mice.…”

Section: Introductionmentioning

confidence: 99%

Differential impact of type-1 and type-2 diabetes on control of heart rate in mice

Stables

Auerbach

Whitesall

et al. 2016

Autonomic Neuroscience

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Aims Cardiac autonomic dysfunction is a serious complication of diabetes. One consequence is disruption of the normal beat-to-beat regulation of heart rate (HR), i.e. HR variability (HRV). However, our understanding of the disease process has been limited by inconsistent HR/HRV data from previous animal studies. We hypothesized that differences in the method of measurement, time of day, and level of stress account for the differing results across studies. Thus, our aim was to systematically assess HR and HRV in two common diabetic mouse models. Methods ECG radiotelemetry devices were implanted into db/db (type-2 diabetic), STZ-treated db/+ (type-1 diabetic), and control db/+ mice (n=4 per group). HR and HRV were analyzed over 24 hours and during treadmill testing. Results 24 hour analysis revealed that db/db mice had an altered pattern of circadian HR changes, and STZ-treated mice had reduced HR throughout. HRV measures linked to sympathetic control were reduced in db/db mice in the early morning and early afternoon, and partially reduced in STZ-treated mice. HR response to treadmill testing was blunted in both models. Conclusions It is important to consider both time of day and level of stress when assessing HR and HRV in diabetic mice. db/db mice may have altered circadian rhythm of sympathetic control of HR, whereas STZ-treated mice have a relative reduction. This study provides baseline data and a framework for HR analysis that may guide future investigations.

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“…Our data also indicate signs of excited sympathetic nerves, such as elevated blood pressure, increased heart rate, and high levels of serum epinephrine. HRV is the most accurate and sensitive index to judge whether diabetic patients have autonomic neuropathy [32]. Our results showed that diabetic rats had autonomic neuropathy.…”

Section: Discussionmentioning

confidence: 61%

“…This imbalance is usually measured by HRV [30-32]. HRV can comprehensively, quantitatively, and intuitively reflect at an early stage the functional status of cardiovascular, sympathetic, and vagus nerves in diabetic patients [33].…”

Section: Discussionmentioning

confidence: 99%

Effects of Baicalin on Diabetic Cardiac Autonomic Neuropathy Mediated by the P2Y12 Receptor in Rat Stellate Ganglia

Xuan

Wang²,

Guo

et al. 2018

Cell Physiol Biochem

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Background/Aims: Chronic diabetic hyperglycemia can damage various of organ systems and cause serious complications. Although diabetic cardiac autonomic neuropathy (DCAN) is the primary cause of death in diabetic patients, its pathogenesis remains to be fully elucidated. Baicalin is a flavonoid extracted from Scutellaria baicalensis root and has antibacterial, diuretic, anti-inflammatory, anti- metamorphotic, and antispasmodic effects. Our study explored the effects of baicalin on enhancing sympathoexcitatory response induced by DCAN via the P2Y12 receptor. Methods: A type 2 diabetes mellitus rat model was induced by a combination of diet and streptozotocin. Serum epinephrine was measured by enzyme-linked immunosorbent assay. Blood pressure and heart rate were measured using the indirect tail-cuff method. Heart rate variability was analyzed using the frequency-domain of electrocardiogram recordings. The expression levels of P2Y12, interleukin-1beta (IL-1β), tumor necrosis factor alpha (TNF-α), and connexin 43 (Cx43) were determined by quantitative real-time reverse transcription-polymerase chain reaction and western blotting. The interaction between baicalin and P2Y12 determined using by molecular docking. Results: Baicalin alleviated elevated blood pressure and heart rate, improved heart rate variability, and decreased the elevated expression levels of P2Y12, IL-1β, TNF-α, and Cx43 in the stellate ganglia of diabetic rats. Baicalin also reduced the elevated concentration of serum epinephrine and the phosphorylation of p38 mitogen-activated protein kinase in diabetic rats. Conclusion: Baicalin decreases sympathetic activity by inhibiting the P2Y12 receptor in stellate ganglia satellite glial cells to maintain the balance between sympathetic and parasympathetic nerves and relieves DCAN in the rat.

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Diabetic cardiac autonomic neuropathy: Insights from animal models

Cited by 18 publications

References 48 publications

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

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

Differential impact of type-1 and type-2 diabetes on control of heart rate in mice

Effects of Baicalin on Diabetic Cardiac Autonomic Neuropathy Mediated by the P2Y12 Receptor in Rat Stellate Ganglia

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