Corticotropin releasing hormone can selectively stimulate glucose uptake in corticotropinoma via glucose transporter 1

Background: Pre-operative detection of corticotropin (ACTH) secreting microadenomas causing Cushing's disease (CD) improves surgical outcomes. Current best magnetic resonance imaging fails to detect up to 40% of these microadenomas. ¹⁸ F-fluorodeoxyglucose ( ¹⁸ F-FDG) positron emission tomography (PET) is specific, but not sensitive in detecting corticotropinomas. Theoretically, secretagogue stimulation with corticotropin releasing hormone (CRH) could improve detection of adenomas with ¹⁸ F-FDG PET. Previous attempts with simultaneous CRH stimulation have failed to demonstrate increased ¹⁸ F-FDG uptake in corticotropinomas. We hypothesized that CRH stimulation leads to a delayed elevation in glucose uptake in corticotropinomas. Methods: Clinical data was analyzed for efficacy of CRH in improving ¹⁸ FDG-PET detection of corticotropinomas in CD. Glucose transporter 1 (GLUT1) immunoreactivity was performed on surgical specimens. Ex-vivo, viable cells from these tumors were tested for secretagogue effects (colorimetric glucose uptake), and for fate of intracellular glucose (glycolysis stress analysis). Validation of ex-vivo findings was performed with AtT-20 cells. Results: CRH increased glucose uptake in human-derived corticotroph tumor cells and AtT-20, but not in normal murine or human corticotrophs (p < 0.0001). Continuous and intermittent (1 h) CRH exposure increased glucose uptake in AtT-20 with maximal effect at 4 h (p = 0.001). Similarly, CRH and 8-Br-cAMP led to robust GLUT1 upregulation and increased membrane translocation at 2 h, while fasentin suppressed baseline (p < 0.0001) and CRH-mediated glucose uptake. Expectedly, intra-operatively collected corticotropinomas demonstrated GLUT1 overexpression. Lastly, human derived corticotroph tumor cells demonstrated increased glycolysis and low glucose oxidation. Conclusion: Increased and delayed CRH-mediated glucose uptake differentially occurs in adenomatous corticotrophs. Delayed secretagogue-stimulated ¹⁸ F-FDG PET could improve microadenoma detection.