Glucagon-like peptide 1 receptor (GLP-1R) agonists fail to reduce weight and improve glucose control in a sizable minority of people with type 2 diabetes. We hypothesized that stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by GLP-1R agonists, thus inducing cortisol secretion, could explain this unresponsiveness to GLP-1R agonists. To assess the effects of GLP-1R agonist treatment on the HPA axis, we selected ten individuals with type 2 diabetes with (5 women/5 men) and nine without (4 women/5 men) an adequate response to GLP-1R agonists and used [68Ga]Ga-NODAGA-exendin-4 positron emission tomography (PET)/computed tomography (CT) to quantify GLP-1R expression in the pituitary. Oral glucose tolerance and 24 h urinary cortisol excretion was measured in all participants. Pituitary tracer uptake was observed in all participants with no significant difference between responders and non-responders. Pituitary tracer uptake correlated with the area under the curve for ACTH, urinary cortisol to creatinine ratio and age. Interestingly, men had higher pituitary tracer uptake than women. In conclusion, this study does not indicate a role for pituitary GLP-1R expression and HPA axis stimulation to explain the difference in treatment response to GLP-1R agonists among individuals with type 2 diabetes. The findings of substantial pituitary GLP-1R expression and the significant sex differences require further research.

中文翻译：

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HPA 轴的激活并不能解释 2 型糖尿病患者对 GLP-1R 激动剂治疗无反应


胰高血糖素样肽 1 受体 （GLP-1R） 激动剂无法减轻相当少数 2 型糖尿病患者的体重和改善血糖控制。我们假设 GLP-1R 激动剂刺激下丘脑-垂体-肾上腺 （HPA） 轴，从而诱导皮质醇分泌，可以解释这种对 GLP-1R 激动剂无反应的情况。为了评估 GLP-1R 激动剂治疗对 HPA 轴的影响，我们选择了 10 例 （5 名女性/5 名男性） 和 9 名没有 （4 名女性/5 名男性） 对 GLP-1R 激动剂有充分反应的 2 型糖尿病患者，并使用 [68Ga]Ga-NODAGA-exendin-4 正电子发射断层扫描 （PET）/计算机断层扫描 （CT） 量化垂体中的 GLP-1R 表达。测量所有参与者的口服葡萄糖耐量和 24 h 尿皮质醇排泄量。在所有参与者中观察到垂体示踪剂摄取，反应者和非反应者之间没有显着差异。垂体示踪剂摄取与 ACTH 曲线下面积、尿皮质醇与肌酐比值和年龄相关。有趣的是，男性的垂体示踪剂摄取率高于女性。总之，本研究并未表明垂体 GLP-1R 表达和 HPA 轴刺激的作用来解释 2 型糖尿病患者对 GLP-1R 激动剂治疗反应的差异。垂体 GLP-1R 大量表达和显着性别差异的发现需要进一步研究。