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

Abstract

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.

Graphical abstract

Figure 1

A: SUV_max of the tracer uptake in pituitary between responders and nonresponders (unpaired t test P = 0.85). B and C: [⁶⁸Ga]Ga-NODAGA-exendin-4 PET/CT image of head of participant with high (B) and low (C) radiolabeled exendin tracer uptake in pituitary, indicated by white arrow.

Figure 2

PET fused to MRI for four participants (sagittal view). Blue and green arrows depict anterior and posterior parts of pituitary shown by hyperintense area, respectively. Uptake of radiolabeled exendin, shown in bright color, is located toward the anterior part of pituitary in two of four participants (A and B).

Figure 3

HPA axis stimulation test revealed similar levels in AUCs for ACTH and cortisol between responders and nonresponders on stimulation with subcutaneously injected exenatide (unpaired t test P = 0.45 and P = 0.72, respectively) (A–D) or intravenously injected exendin (Mann-Whitney U test P = 0.71 and unpaired t test P = 0.93, respectively) (E–H).

Figure 4

A–C: Correlations of SUV_max in pituitary with subcutaneously stimulated AUC_{ACTH s.c.} (Pearson correlation r = 0.61; P = 0.015) (A), AUC_{cortisol s.c.} (r = −0.14; P = 0.62) derived from HPA axis stimulation test (B), and urinary cortisol-to-creatine ratio (r = 0.55; P = 0.026) (C). D and E: SUV_max did not correlate with intravenously stimulated AUC_{ACTH i.v.} (r = 0.44; P = 0.14) (D) or AUC_{cortisol i.v.} (r = −0.11; P = 0.72) (E). Green and red dots represent responders and nonresponders, respectively.

Figure 5

Correlations of SUV_max in pituitary with age (Pearson correlation r = 0.58; P = 0.019) (A), BMI (r = 0.38; P = 0.15) (B), and duration of type 2 diabetes (r = −0.069; P = 0.80) (C). Green and red dots represent responders and nonresponders, respectively.

Figure 6

Sex differences in radiolabeled exendin uptake and HPA axis hormones. A: Men showed higher SUV_max of tracer uptake in pituitary compared with women (unpaired t test P = 0.024). B–E: HPA axis stimulation test revealed higher AUC for subcutaneously stimulated ACTH in men compared with women (unpaired t test P = 0.013) (B) but similar AUC for subcutaneously stimulated cortisol (unpaired t test P = 0.17) (C), intravenously stimulated ACTH (unpaired t test P = 0.24) (D), and intravenously stimulated cortisol (unpaired t test P = 0.070) (E). F: Urinary cortisol-to-creatine ratio was higher in women compared with men (unpaired t test P = 0.00070).