Diabetes increases the risk of developing congestive heart failure, even in the absence of coronary heart disease or hypertension. A growing body of experimental and clinical evidence is accumulating to show diabetes-related cardiac dysfunction (1). The molecular and pathophysiological mechanisms that are responsible for cardiac dysfunction in diabetes include impaired calcium homeostasis, upregulated renin-angiotensin system, increased oxidative stress, altered myocardial substrate and energy metabolism, and mitochondrial dysfunction (1). Dysfunction of the autonomic nervous system is one of the common and serious complications of diabetes, which also can be the major mechanism implicated in the pathogenesis leading to the manifestation of impaired cardiac function in diabetes. Autonomic dysfunction in diabetes impairs exercise tolerance, reduces response in heart rate and blood pressure, and blunts increases in cardiac output in response to exercise (2).
In a rat model of streptozotocin (STZ)-induced type 1 diabetes, the impaired release of norepinephrine from cardiac sympathetic nerves in response to electrical field stimulation has been demonstrated (3), indicating reduced cardiac sympathetic nerve activity. An earlier report showed increases in turnover, uptake, and synthesis of norepinephrine in STZ-induced diabetic hearts (4), but this observation does not reach general agreement according to later reports (3,5,6). Whatever changes in norepinephrine stored in cardiac sympathetic nerve terminals, the fall in overflow of norepinephrine produced by cardiac electrical stimulation (3) would reflect an impairment of the presynaptic functional process for releasing norepinephrine from sympathetic nerve endings in hearts from STZ-induced diabetic rats (Fig. 1). Interestingly, the lack of ability of atropine or yohimbine to enhance the norepinephrine release from cardiac sympathetic nerves in STZ rats suggests that the regulation of norepinephrine release through presynaptic inhibitory receptors may be impaired in the heart of this type 1 diabetic model (3).
Sympathetic stimulation in the heart activates β1-adrenoceptors and thereby increases the rate and force of cardiac contractions. Diminished cardiac functional responses to β1-adrenoceptor stimulation have been found in different cardiac preparations from STZ-induced diabetic rats (7). In accordance with the decreased functional responses, reductions in the number of cardiac β1-adrenoceptors, but not of cardiac β2-adrenoceptors, have been shown in many studies (7–11). The reduced density of β1-adrenoceptors in STZ-induced diabetic hearts is more likely to occur at the level of transcription (9). Among the signal transducing G proteins, Gs and Gi play a pivotal role in mediating the responses of the heart to stimulation of the sympathetic nervous system. Gs mediates activation of adenylate cyclase via β1-adrenoceptors, and Gi mediates inhibition of β1-adrenoceptor–stimulated adenylate cyclase activity (12). STZ-induced diabetes leads to a differential regulation of G protein expression in the heart. Thus, despite normal Gsα expression, a significant decrease in Giα expression has been found in STZ-induced diabetic rats (13,14). This may partly account for the apparently preserved adenylate cyclase responses in STZ-induced diabetic rat hearts (8). Besides, it may be noted that the impaired cardiac β1-adrenergic stimulatory pathway in type 1 diabetes involves defects upstream of the G protein-adenylate cyclase system (Fig. 1).
In this issue of Diabetes, Thaung et al. (15), using direct in vivo recording of the left efferent cardiac sympathetic nerve, underscore that cardiac sympathetic nerve activity can be highly elevated rather than decreased in Zucker type 2 diabetic fatty (ZDF) rats compared with their nondiabetic littermates. They assume that elevated cardiac sympathetic input may be a compensatory response to the diabetes-associated hypofunction in the heart to ensure the maintenance of normal hemodynamic status. In their experiments, male ZDF rats were used at 20 weeks of age. Male ZDF rats display marked hyperglycemia, developing at 7–10 weeks of age, which is kept for at least 6 months (16). Then, differences in altered cardiac sympathetic nerve activity might arise depending on the stage of the disease, if the animals were examined at ages ∼6 and ∼12 weeks corresponding to a prediabetic state and onset of type 2 diabetes, respectively.
The new study by Thaung et al. (15) demonstrates that the expression level of β1-adrenoceptors was downregulated in ZDF rat hearts, whereas that of β2-adrenoceptors was upregulated. Cardiac gene expression level of β1-adrenoceptors has been reported to be unaltered in type 2 diabetic obese db/db mice (17). Whether the downregulation of cardiac β1-adrenoceptor expression in ZDF rats occurred through transcriptional or posttranscriptional mechanisms remains an open question. Thaung et al. (15) also found a decrease in Gsα protein and an increase in Giα protein in ZDF rat hearts. This is in striking contrast to the results obtained in STZ rat models of type 1 diabetes (13,14). However, such changes in cardiac β1-adrenoceptor–G protein adenylate cyclase system would give a logical explanation for the reduced functional responsiveness to β1-adrenoceptor agonist dobutamine in ZDF rats (Fig. 1). It has been proposed that, unlike β1-adrenoceptors, cardiac β2-adrenoceptors couples dually to Gs and Gi proteins, and the β2-adrenoceptor–Gi signaling pathway may play a crucial role in dampening the ability of β1-adrenoceptors, the primary cardiac subtype, to stimulate cardiac functions (18). In this regard, it remains the subject of ongoing studies to address whether the upregulation of β2-adrenoceptor–coupled Gi signaling can adversely affect the overall outcome of cardiac β-adrenoceptor stimulation with nonselective or β2-adrenoceptor selective agonists in ZDF rats.
The study by Thaung et al. (15) shows no difference in in vivo resting heart rate between ZDF rats and their nondiabetic littermates despite the observation that the intrinsic heart rate was markedly lowered in ex vivo perfused hearts from ZDF rats, suggesting that the resting heart rate in ZDF rats under in vivo conditions could be redressed by elevated cardiac sympathetic nerve activity. Clinically, resting tachycardia can be observed in patients with diabetes with vagal impairment, occurring earlier in the course of cardiovascular autonomic neuropathy than sympathetic nerve function (2). Patients with diabetes have low values of the spectral analysis of heart rate variability (HRV) (19). HRV is defined as variability of R-R intervals of the electrocardiogram, and measures of HRV are currently used to assess cardiovascular autonomic dysfunction. As the low-frequency component of the power spectrum, HRV primarily reflects sympathetic activity (2), and it may be rewarding to note hereto that reduced low-frequency power is associated with elevated heart problems in patients with diabetes (20).
In summary, cardiac functional responsiveness to β1-adrenoceptor stimulation appears to be impaired in animal models for both type 1 and type 2 diabetes. Although the downregulation of cardiac β1-adrenoceptor expression can be commonly recognized, there is a striking difference in cardiac sympathetic nerve activity and expression of β-adrenoceptor–coupled G proteins between rat models of type 1 and type 2 diabetes (Fig. 1). The new understanding of changes related to type 1 and type 2 diabetes in cardiac sympathetic-β-adrenoceptor–G protein cascades may offer a clue to open a novel therapeutic avenue for the treatment of diabetic cardiomyopathy and could form the basis to warrant future studies that are actually applicable and relevant to human diabetes.
See accompanying article, p. 2944.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.