Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark; Medical Research Laboratory, Department of Clinical Medicine, Aarhus University Hospital, Denmark.
Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark; Department of Endocrinology, Aalborg University Hospital, Denmark; Steno Diabetes Centre North, Aalborg University Hospital, Aalborg, Denmark.
EBioMedicine. 2022 Jan;75:103763. doi: 10.1016/j.ebiom.2021.103763. Epub 2021 Dec 17.
Patients with active acromegaly exhibit insulin resistance despite a lean phenotype whereas controlled disease improves insulin sensitivity and increases fat mass. The mechanisms underlying this paradox remain elusive, but growth hormone (GH)-induced lipolysis plays a central role. The aim of the study was to investigative the molecular mechanisms of insulin resistance dissociated from obesity in patients with acromegaly.
In a prospective study, twenty-one patients with newly diagnosed acromegaly were studied at diagnosis and after disease control obtained by either surgery alone (n=10) or somatostatin analogue (SA) treatment (n=11) with assessment of body composition (DXA scan), whole body and tissue-specific insulin sensitivity and GH and insulin signalling in adipose tissue and skeletal muscle.
Disease control of acromegaly significantly reduced lean body mass (p<0.001) and increased fat mass (p<0.001). At diagnosis, GH signalling (pSTAT5) was constitutively activated in fat and enhanced expression of GH-regulated genes (CISH and IGF-I) were detected in muscle and fat. Insulin sensitivity in skeletal muscle, liver and adipose tissue increased after disease control regardless of treatment modality. This was associated with enhanced insulin signalling in both muscle and fat including downregulation of phosphatase and tensin homolog (PTEN) together with reduced signalling of GH and lipolytic activators in fat.
In conclusion, the study support that uncontrolled lipolysis is a major feature of insulin resistance in active acromegaly, and is characterized by upregulation of PTEN and suppression of insulin signalling in both muscle and fat.
This work was supported by a grant from the Independent Research Fund, Denmark (7016-00303A) and from the Alfred Benzon Foundation, Denmark.
尽管患有肢端肥大症的患者表现出瘦素表型，但仍存在胰岛素抵抗，而控制疾病可改善胰岛素敏感性并增加脂肪量。导致这种矛盾的机制仍然难以捉摸，但生长激素（GH）诱导的脂肪分解起着核心作用。本研究旨在研究与肢端肥大症患者肥胖无关的胰岛素抵抗的分子机制。
在一项前瞻性研究中，在诊断时和通过单独手术（n=10）或生长抑素类似物（SA）治疗（n=11）获得疾病控制后，对 21 例新诊断的肢端肥大症患者进行了研究，评估了身体成分（DXA 扫描）、全身和组织特异性胰岛素敏感性以及脂肪组织和骨骼肌中的 GH 和胰岛素信号。
肢端肥大症的疾病控制显著降低了瘦体重（p<0.001）并增加了脂肪量（p<0.001）。在诊断时，脂肪中的 GH 信号（pSTAT5）被持续激活，并在肌肉和脂肪中检测到 GH 调节基因（CISH 和 IGF-I）的增强表达。无论治疗方式如何，疾病控制后骨骼肌、肝脏和脂肪组织的胰岛素敏感性均增加。这与肌肉和脂肪中的胰岛素信号增强有关，包括磷酸酶和张力蛋白同源物（PTEN）下调以及脂肪中 GH 和脂肪分解激活剂的信号减少。
该研究支持未控制的脂肪分解是活跃的肢端肥大症中胰岛素抵抗的主要特征，其特征在于肌肉和脂肪中 PTEN 的上调和胰岛素信号的抑制。
这项工作得到了丹麦独立研究基金（7016-00303A）和丹麦 Alfred Benzon 基金会的支持。
