Department of Anatomy and Cell Biology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, South Korea.
J Chem Neuroanat. 2010 Oct;40(2):130-9. doi: 10.1016/j.jchemneu.2010.05.003. Epub 2010 May 21.
Diabetes, especially type 2, is closely associated with hypothalamo-pituitary-adrenal (HPA) axis regulation. Short-term effects of adrenalectomy (ADX) in type 2 diabetes are well characterized; however, there have been few reports on the long-term effects of ADX in genetically engineered type 2 diabetes and the neuroendocrine system. We performed bilateral ADX in Zucker Lean Control rats (ZLC; ADX-ZLC), Zucker Diabetic Fatty rats (ZDF; ADX-ZDF), and sham control rats to evaluate how the HPA axis would be regulated in long-term corticosterone deficient type 2 diabetic animals. We evaluated arginine vasopressin (AVP), glucocorticoid receptor (GR), and corticotropin-releasing hormone (CRH) expression with immunohistochemistry (IHC), immunofluorescence, real-time PCR, and Western blot analysis in each treatment group 7 weeks post ADX to assess HPA axis regulatory patterns in connection with type 2 diabetes. Additionally, mRNA expression of AVP and CRH receptors (V1aR, V1bR, CRHR1, and CRHR2) was also measured and adrenocorticotropin hormone (ACTH) immunoreactivity was surveyed by IHC to add to data regarding the regulatory mechanism. AVP and CRH protein expression levels increased after ADX in the hypothalamus of diabetic rats based on IHC results; however, we found that the subtypes of each receptor may be regulated differently in ADX groups compared to sham groups. Immunoreactivity of ACTH in the pituitary gland was enhanced in ADX groups and GR expression levels in the hypothalamic paraventricular nuclei (PVN) remained high, as determined by IHC as well as Western blot analysis. Without the negative feedback system of corticosterone, CRH is highly enhanced and may primarily combine with CRHR1 to stimulate negative feedback through ACTH in the pituitary gland in type 2 diabetic rats with long-term ADX. Although the negative feedback signal was not transmitted appropriately following long-term ADX with type 2 diabetes, a high GR protein level was maintained as in type 2 diabetes. The long-termed lack of corticosterone in the blood stream is a very important factor for normal regulation of the HPA axis even in diabetic animals. From the data, we can conclude that the stimulated HPA axis regulation in the developing type 2 diabetic animals following long-term adrenalectomy has remained elevated rather than diminished. Therefore, the current study may provide useful information to better understand patients suffering from both type 2 diabetes and Addison's disease.
糖尿病，尤其是 2 型糖尿病，与下丘脑-垂体-肾上腺（HPA）轴调节密切相关。肾上腺切除术（ADX）对 2 型糖尿病的短期影响已得到充分描述；然而，关于 ADX 在遗传性 2 型糖尿病和神经内分泌系统中的长期影响的报道较少。我们对 Zucker Lean 对照大鼠（ZLC；ADX-ZLC）、Zucker 糖尿病肥胖大鼠（ZDF；ADX-ZDF）和假手术对照大鼠进行双侧 ADX，以评估 HPA 轴在长期皮质酮缺乏的 2 型糖尿病动物中的调节模式。我们使用免疫组织化学（IHC）、免疫荧光、实时 PCR 和 Western blot 分析评估 ADX 后 7 周每个治疗组的血管加压素（AVP）、糖皮质激素受体（GR）和促肾上腺皮质激素释放激素（CRH）的表达，以连接 2 型糖尿病评估 HPA 轴调节模式。此外，还测量了 AVP 和 CRH 受体（V1aR、V1bR、CRHR1 和 CRHR2）的 mRNA 表达，并通过 IHC 检测促肾上腺皮质激素激素（ACTH）免疫反应，以补充有关调节机制的数据。根据 IHC 结果，糖尿病大鼠下丘脑的 AVP 和 CRH 蛋白表达水平在 ADX 后增加；然而，我们发现与假手术组相比，ADX 组中每种受体的亚型可能以不同的方式受到调节。ACTH 在垂体中的免疫反应性在 ADX 组中增强，GR 表达水平在下丘脑室旁核（PVN）中保持较高，这通过 IHC 和 Western blot 分析确定。在缺乏皮质酮的负反馈系统的情况下，CRH 高度增强，并且可能主要与 CRHR1 结合，通过垂体中的 ACTH 刺激 2 型糖尿病大鼠的负反馈，在长期 ADX 中。尽管在 2 型糖尿病患者进行长期 ADX 后，负反馈信号未适当传递，但 GR 蛋白水平仍保持在 2 型糖尿病的水平。血液中长期缺乏皮质酮是 HPA 轴正常调节的一个非常重要的因素，即使在糖尿病动物中也是如此。从数据中，我们可以得出结论，在长期肾上腺切除术后，发育中的 2 型糖尿病动物中受刺激的 HPA 轴调节保持升高而不是降低。因此，本研究可能为更好地了解同时患有 2 型糖尿病和艾迪生病的患者提供有用信息。
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