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Mol Cell Endocrinol. 2018 Jul 15;470:105-114. doi: 10.1016/j.mce.2017.10.003. Epub 2017 Oct 3.

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

Author information

1
Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Diseases and Stroke, Bethesda, MD, United States.
2
Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke, Bethesda, MD, United States; Department of Orthopedic Surgery, Stanford Medicine, Stanford, CA, United States.
3
Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke, Bethesda, MD, United States.
4
Department of Neurological Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH, United States.
5
Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Diseases and Stroke, Bethesda, MD, United States; Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke, Bethesda, MD, United States. Electronic address: prashant.chittiboina@nih.gov.

Abstract

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

KEYWORDS:

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

PMID:
28986303
PMCID:
PMC5882598
[Available on 2019-07-15]
DOI:
10.1016/j.mce.2017.10.003
[Indexed for MEDLINE]
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