Yamamoto Masaaki, Bando Hironori
Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Division of Diabetes and Endocrinology, Kobe University Hospital, Kobe 650-0017, Japan.
Endocr J. 2023 Sep 28;70(9):867-874. doi: 10.1507/endocrj.EJ23-0264. Epub 2023 Aug 5.
GH activates GH receptors, which activates IGF-1 in the liver through a cascade of processes. The GH/IGF-1 axis plays an important role in the regulation of metabolism. Insufficient GH secretion results in short stature in childhood, while adult GH deficiency (AGHD) is observed in adulthood. The early diagnosis of AGHD is important for early initiation of GH replacement therapy. This review described the regulatory mechanisms of GH signaling based on nutritional status and a novel disease concept pathogenesis that causes AGHD. GH-dependent IGF-1 production in the liver is regulated by a complex interplay between nutritional status, hormones, and growth factors. GH resistance is an adaptive response that enhances survival during starvation and malnutrition. Sirtuin 1 (SIRT1) negatively regulates GH-induced IGF-I production in the liver by directly inhibiting STAT5 activation, which causes GH resistance under starvation and malnutrition. The presence of autoantibodies is strongly associated with the disruption of immune tolerance in pituitary cells. Pituitary-specific transcription factors (PIT-1) are essential for the development, differentiation, and maintenance of GH, PRL, and TSH producing cells. However, the underlying mechanism that causes immune intolerance to PIT-1 remain unclear. The GH-IGF-1 system plays a pivotal role in growth, and the involvement of SIRT1 in this regulatory mechanism presents an intriguing perspective on the interplay between nutrient metabolism and lifespan. The discovery of the anti-PIT-1 pituitary antibody, a novel disease concept associated with AGHD, has provided valuable insights, which serves as a significant milestone towards unraveling the complete pathogenesis of the disease.
生长激素（GH）激活生长激素受体，通过一系列过程在肝脏中激活胰岛素样生长因子-1（IGF-1）。GH/IGF-1轴在代谢调节中起重要作用。儿童期GH分泌不足会导致身材矮小，而成人GH缺乏症（AGHD）则在成年期出现。AGHD的早期诊断对于早期开始GH替代治疗很重要。本综述描述了基于营养状况的GH信号调节机制以及导致AGHD的一种新的疾病概念发病机制。肝脏中GH依赖的IGF-1产生受营养状况、激素和生长因子之间复杂相互作用的调节。GH抵抗是一种适应性反应，可增强饥饿和营养不良期间的生存能力。沉默调节蛋白1（SIRT1）通过直接抑制信号转导和转录激活因子5（STAT5）的激活来负向调节肝脏中GH诱导的IGF-I产生，这在饥饿和营养不良时会导致GH抵抗。自身抗体的存在与垂体细胞免疫耐受的破坏密切相关。垂体特异性转录因子（PIT-1）对于GH、催乳素（PRL）和促甲状腺激素（TSH）产生细胞的发育、分化和维持至关重要。然而，导致对PIT-1免疫不耐受的潜在机制仍不清楚。GH-IGF-1系统在生长中起关键作用，SIRT1参与这一调节机制为营养代谢与寿命之间的相互作用提供了一个有趣的视角。抗PIT-1垂体抗体的发现是一种与AGHD相关的新疾病概念，提供了有价值的见解，这是揭示该疾病完整发病机制的一个重要里程碑。
