PDF(Pubmed)
Abstract：
Major depressive disorder (MDD) increases the risk of type 2 diabetes (T2D) by 60% in untreated patients, and hypercortisolism is common in MDD as well as in some patients with T2D. Patients with MDD, despite hypercortisolism, show inappropriately normal levels of corticotropin-releasing hormone (CRH) and plasma adrenocorticotropin (ACTH) in the cerebrospinal fluid, which might implicate impaired negative feedback. Also, a positive feedback loop of the CRH-norepinephrine (NE)-CRH system may be involved in the hypercortisolism of MDD and T2D. Dysfunctional CRH receptor 1 (CRHR1) and CRH receptor 2 (CRHR2), both of which are involved in glucose regulation, may explain hypercortisolism in MDD and T2D, at least in a subgroup of patients. CRHR1 increases glucose-stimulated insulin secretion. Dysfunctional CRHR1 variants can cause hypercortisolism, leading to serotonin dysfunction and depression, which can contribute to hyperglycemia, insulin resistance, and increased visceral fat, all of which are characteristics of T2D. CRHR2 is implicated in glucose homeostasis through the regulation of insulin secretion and gastrointestinal functions, and it stimulates insulin sensitivity at the muscular level. A few studies show a correlation of the CRHR2 gene with depressive disorders. Based on our own research, we have found a linkage and association (i.e., linkage disequilibrium [LD]) of the genes CRHR1 and CRHR2 with MDD and T2D in families with T2D. The correlation of CRHR1 and CRHR2 with MDD appears stronger than that with T2D, and per our hypothesis, MDD may precede the onset of T2D. According to the findings of our analysis, CRHR1 and CRHR2 variants could modify the response to prolonged chronic stress and contribute to high levels of cortisol, increasing the risk of developing MDD, T2D, and the comorbidity MDD-T2D. We report here the potential links of the CRH system, NE, and their roles in MDD and T2D.
摘要：
在未经治疗的患者中，重度抑郁症（MDD）使2型糖尿病（T2D）的风险增加60％，皮质醇增多症在MDD和一些T2D患者中很常见。MDD患者,尽管皮质醇增多症,显示脑脊液中促肾上腺皮质激素释放激素（CRH）和血浆促肾上腺皮质激素（ACTH）的不适当正常水平，这可能意味着负面反馈受损。此外，CRH-去甲肾上腺素（NE）-CRH系统的正反馈回路可能参与MDD和T2D的皮质醇增多症。功能失调的CRH受体1（CRHR1）和CRH受体2（CRHR2），两者都参与葡萄糖调节，可以解释MDD和T2D中的皮质醇增多症，至少在一组患者中。CRHR1增加葡萄糖刺激的胰岛素分泌。功能失调的CRHR1变体可导致皮质醇增多症，导致5-羟色胺功能障碍和抑郁，这可能导致高血糖，胰岛素抵抗，内脏脂肪增加，所有这些都是T2D的特征。CRHR2通过调节胰岛素分泌和胃肠功能参与葡萄糖稳态，它刺激肌肉水平的胰岛素敏感性。一些研究表明CRHR2基因与抑郁症的相关性。根据我们自己的研究，我们发现了一种联系和关联(即，在T2D家族中，基因CRHR1和CRHR2与MDD和T2D的连锁不平衡[LD]）。CRHR1和CRHR2与MDD的相关性似乎强于与T2D的相关性，根据我们的假设，MDD可能先于T2D的发作。根据我们的分析结果,CRHR1和CRHR2变体可以改变对长期慢性应激的反应，并有助于高水平的皮质醇，增加发展MDD的风险，T2D,和MDD-T2D共病。我们在这里报告CRH系统的潜在联系，NE,以及它们在MDD和T2D中的作用。
