Activation of the HPA Axis Does Not Explain Nonresponsiveness to GLP-1R Agonist Treatment in Individuals With Type 2 Diabetes

Glucagon-like peptide 1 receptor (GLP-1R) agonists fail to reduce weight or improve glucose control in a sizable minority of individuals 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 10 individuals with type 2 diabetes with (n = 5 women and 5 men) and nine without (n = 4 and 5) an adequate response to GLP-1R agonists and used [68Ga]Ga-NODAGA-exendin-4 positron emission tomography/computed tomography to quantify GLP-1R expression in the pituitary. Oral glucose tolerance and 24-h urinary cortisol excretion were measured in all participants. Pituitary tracer uptake was observed in all participants, with no significant difference between responders and nonresponders. 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 or HPA axis stimulation in 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.Article Highlights It is unclear why some individuals with type 2 diabetes are unresponsive to treatment with glucagon-like peptide 1 receptor (GLP-1R) agonists, but hypothalamic-pituitary-adrenal (HPA) axis activation could play a role. We used [68Ga]Ga-NODAGA-exendin-4 positron emission tomography/computed tomography to compare pituitary GLP-1R expression between responders and nonresponders to treatment with GLP-1R agonists. Pituitary GLP-1R expression and HPA axis activation did not differ between responders and nonresponders to GLP-1R agonist treatment. In addition, pituitary radiolabeled exendin uptake was markedly higher in men than in women. Further study is required to explain treatment differences and understand sex differences in pituitary radiolabeled exendin uptake.