Does the hypothalamus-pituitary-adrenal axis play a role in the difference in treatment response to GLP-1 receptor agonists in type 2 diabetes?

Ziel/Aim Glucagon-like peptide-1 receptor agonists (GLP-1RA), which stimulate insulin secretion, are potent antidiabetic drugs for treatment of type 2 diabetes (T2D). For unknown reasons, not all patients respond to treatment with GLP-1RA. Besides the effects on pancreatic beta cells, GLP-1RAs can stimulate the hypothalamic-pituitary-adrenal (HPA) axis, inducing cortisol secretion. Since cortisol is pro diabetogenic and induces insulin resistance, we hypothesize that this effect could be at the root of the differences in GLP-1RA treatment response. To investigate this, we used PET/CT imaging with a radiolabeled stable GLP-1 analogue ([68Ga]Ga-NODAGA-exendin-4) to quantify GLP-1R expression in the pituitary of patients with T2D with (responders) and without (non-responders) an adequate response to GLP-1RA treatment and assessed the stimulatory effect of GLP-1RA on the HPA axis.