Cardiovascular autonomic dysfunction in non-obese diabetic mice
Introduction
The prevalence of diabetes in modern society has been increasing at epidemic rates, largely related to the prevalence of obesity and sedentary lifestyles. Diabetes increases cardiovascular morbidity and mortality related to autonomic dysfunction, nephropathy and neuropathy (Zimmet et al., 1997).
Among these complications, autonomic neuropathy is a common alteration presented in diabetes mellitus which results in autonomic nerve fiber dystrophy in axons and dendrite abnormalities (Schmidt, 2002). In addition, cardiovascular autonomic neuropathy seems to be related to increased mortality in diabetic patients (Vinik and Ziegler, 2007). Moreover, both the parasympathetic and sympathetic neurons can be affected by diabetic neuropathy resulting in alterations of heart rate control and vascular dynamics (Schumer et al., 1998). Our group has showed several autonomic, hemodynamic and functional cardiac alterations promoted by experimental diabetes, resulting in higher mortality (Wichi et al., 2007, Mostarda et al., 2009, Jorge et al., 2012). Additionally, it is widely acknowledged that neuropathy promotes a decrease in heart rate variability (HRV) both in time and frequency domains, as demonstrated by alterations in low frequency and high frequency components. On the other hand, it is well established that HRV is an important prognostic marker of mortality (Malik et al., 1996).
Among several experimental models used to study the pathophysiology of diabetes, non-obese diabetic mice (NOD) have been widely used to evaluate several mechanisms affected by type 1diabetes. These mice exhibit spontaneous autoimmune diabetes by causing the destruction of insulin producing cells, similar to that observed in humans (Kodama et al., 2003). Furthermore, polydipsia, polyuria, glycosuria, hyperglycemia and insulin deficiency are equally observed in these animals, accompanied by a rapid weight loss (Makino et al., 1980).
Although the association of diabetes and autonomic dysfunction has been widely recognized, data on cardiovascular autonomic function in NOD mice remain scarce. Therefore, the aim of this study was to investigate the cardiovascular autonomic profile of NOD mice.
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Experimental groups
Groups studied: (1) female hyperglycemic NOD mice (n = 6): blood glucose > 300 mg/dl (> 17 mmol/l); and (2) Swiss female mice (n = 6): used as control, blood glucose < 110 mg/dl (< 6 mmol/l).
All surgical procedures and protocols used were approved by the Nove de Julho University Ethical Committee (protocol number AN0029-2012) and strictly followed National Institutes of Health Guide for the Care and Use of Laboratory Animals.
Blood glucose level measurements
Ten-week-old female mice had their blood glucose levels determined weekly using
Cardiovascular measurements
AP (systolic, diastolic and mean) and HR were not significantly different between NOD and control groups (Table 1). The results of BRS are shown in Fig. 1. There was significant difference between baroreflex bradycardic responses evoked by phenylephrine in NOD group when compared to the control group (P = 0.036). Additionally, baroreflex tachycardic responses were significantly lower in NOD group when compared to the control group (P = 0.027).
Time and frequency domains of cardiovascular autonomic
Discussion
The main finding of the present study was that autonomic dysfunction was found in NOD mice, as demonstrated by different methods and analysis. In contrast to a previous study of the autonomic profile in NOD mice (Gross et al., 2008), we showed BRS impairment and changes in sympathetic and parasympathetic modulation. Furthermore, the autonomic alterations observed in the present study were correlated with glycemic levels. Both the increase in sympathetic activity, as well as the reduction in
Conclusions
Grounded on the methods adopted in this study and on our focus on the age and the phase of diabetes progression, we may suggest that the NOD mice present autonomic function impairment, probably related to their glycemic levels.
Competing interests
The author(s) declare that they have no competing interests.
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These authors contributed equally to this work.