Cardiac autonomic neuropathy (CAN) is an early cardiovascular manifestation of type 2 diabetes (T2D) that constitutes an independent risk factor for cardiovascular mortality and morbidity. Nevertheless, its underlying pathophysiology remains poorly understood. We recently showed that localized perivascular adipose tissue (PVAT) inflammation underlies the incidence of parasympathetic CAN in prediabetes. Here, we extend our investigation to provide a mechanistic framework for the evolution of autonomic impairment as the metabolic insult worsens. Early metabolic dysfunction was induced in rats fed a mild hypercaloric diet. Two low-dose streptozotocin injections were used to evoke a state of late decompensated T2D. Cardiac autonomic function was assessed by invasive measurement of baroreflex sensitivity using the vasoactive method. Progression into T2D was associated with aggravation of CAN to include both sympathetic and parasympathetic arms. Unlike prediabetic rats, T2D rats showed markers of brainstem neuronal injury and inflammation as well as increased serum levels of IL-1b. Experiments on PC12 cells differentiated into sympathetic-like neurons demonstrated that brainstem injury observed in T2D rats resulted from exposure to possible pro-inflammatory mediators in rat serum rather than a direct effect of the altered metabolic profile. CAN and the associated cardiovascular damage in T2D only responded to combined treatment with insulin to manage hyperglycemia in addition to a non-hypoglycemic dose of metformin or pioglitazone providing an anti-inflammatory effect, coincident with the effect of these combinations on serum IL-1b. Our present results indicate that CAN worsening upon progression to T2D involves brainstem inflammatory changes likely triggered by systemic inflammation.

中文翻译：

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对II型糖尿病进展的压力反射敏感性更差：局部炎症与全身性炎症以及抗糖尿病治疗的作用。

心脏自主神经病变（CAN）是2型糖尿病（T2D）的早期心血管表现，是构成心血管疾病死亡率和发病率的独立危险因素。然而，其潜在的病理生理学仍然知之甚少。我们最近发现，局部性血管周围脂肪组织（PVAT）炎症是前驱糖尿病中副交感神经CAN发生的基础。在这里，我们扩展了研究范围，为代谢损伤恶化时自主神经功能损害的发展提供了一个机制框架。喂养轻度高热量饮食的大鼠会诱发早期代谢功能障碍。两次低剂量链脲佐菌素注射用于引起晚期失代偿的T2D状态。使用血管活性方法，通过有创测量压力反射敏感性来评估心脏自主神经功能。向T2D的进展与CAN的恶化相关，包括交感神经和副交感神经。与糖尿病前期大鼠不同，T2D大鼠表现出脑干神经元损伤和炎症的标志物以及血清IL-1b水平升高。对分化为交感神经样神经元的PC12细胞进行的实验表明，在T2D大鼠中观察到的脑干损伤是由于暴露于大鼠血清中可能的促炎介质引起的，而不是改变的代谢谱的直接影响。除了非降糖剂量的二甲双胍或吡格列酮可提供抗炎作用外，CAN和T2D中相关的心血管损害仅响应胰岛素联合治疗以控制高血糖，这与这些组合对血清IL-1b的作用相吻合。