Activation of the HPA axis does not explain non-responsiveness to GLP-1R agonist treatment in individuals with type 2 diabetes

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.