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

MOLECULAR AND CELLULAR ENDOCRINOLOGY

卷:470

Article

Lu, Jie¹  Montgomery, Blake K.^2,3  Chatain, Gregoire P.¹  Bugarini, Alejandro²  Zhang, Qi²  Wang, Xiang²  Edwards, Nancy A.²  Ray-Chaudhury, Abhik²  Merrill, Marsha J.²  Lonser, Russell R.⁴  Chittiboina, Prashant^1,2 

[1] NINDS, Neurosurg Unit Pituitary & Inheritable Dis, Bethesda, MD 20892 USA

[2] NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA

[3] Stanford Med, Dept Orthoped Surg, Stanford, CA USA

[4] Ohio State Univ, Wexner Med Ctr, Dept Neurol Surg, Columbus, OH 43210 USA

关键词: Cushing's disease;    Corticotropinoma;    PET;    FDG;    Glucose uptake;    Secretagogue;    CRH;    Metabolic reprogramming;   

DOI  :  10.1016/j.mce.2017.10.003

来源: Elsevier

【 摘 要 】

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. F-18-fluorodeoxyglucose (F-18-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 F-18-FDG PET. Previous attempts with simultaneous CRH stimulation have failed to demonstrate increased F-18-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 F-18-FDG PET could improve microadenoma detection. Published by Elsevier Ireland Ltd.

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