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

Diabetes. 2025 Feb 1;74(2):212-222. doi: 10.2337/db24-0463.

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.

MeSH terms

  • Aged
  • Diabetes Mellitus, Type 2* / diagnostic imaging
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetes Mellitus, Type 2* / metabolism
  • Exenatide
  • Female
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Glucagon-Like Peptide-1 Receptor Agonists*
  • Humans
  • Hypoglycemic Agents* / therapeutic use
  • Hypothalamo-Hypophyseal System* / diagnostic imaging
  • Hypothalamo-Hypophyseal System* / drug effects
  • Hypothalamo-Hypophyseal System* / metabolism
  • Male
  • Middle Aged
  • Pituitary Gland / diagnostic imaging
  • Pituitary Gland / drug effects
  • Pituitary Gland / metabolism
  • Pituitary-Adrenal System* / diagnostic imaging
  • Pituitary-Adrenal System* / drug effects
  • Pituitary-Adrenal System* / metabolism
  • Positron Emission Tomography Computed Tomography

Substances

  • Glucagon-Like Peptide-1 Receptor Agonists
  • Hypoglycemic Agents
  • Exenatide
  • Glucagon-Like Peptide-1 Receptor