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

Jie Lu,Grégoire P Chatain,Marsha J Merrill,Prashant Chittiboina,Alejandro Bugarini,Abhik Ray-Chaudhury,Blake K Montgomery,Russell R Lonser,Nancy A Edwards,Qi Zhang,Xiang Wang

doi:10.1016/j.mce.2017.10.003

Abstract

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. 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-20cells. 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 (1h) CRH exposure increased glucose uptake in AtT-20 with maximal effect at 4h (p=0.001). Similarly, CRH and 8-Br-cAMP led to robust GLUT1 upregulation and increased membrane translocation at 2h, 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. Increased and delayed CRH-mediated glucose uptake differentially occurs in adenomatous corticotrophs. Delayed secretagogue-stimulated 18F-FDG PET could improve microadenoma detection.

Highlights

IntroductionCorticotropin releasing hormone (CRH) has secretagogue effects on adrenocorticotropic hormone or corticotropin (ACTH) secreting pituitary adenomas[9], but not on suppressed adjacent normal gland
These results suggest that adenomatous cells but not normal corticotrophs have increased glucose uptake that may be modulated with secretagogues stimulation
A number of glucose transporters are involved in glucose uptake by cells of the central nervous system.[32]. We identified glucose transporter 1 (GLUT1) overexpression in 10 human corticotropinomas and identified GLUT1 as the predominant glucose transporter modulated by corticotropin releasing hormone (CRH) stimulation

Summary

Introduction

Corticotropin releasing hormone (CRH) has secretagogue effects on adrenocorticotropic hormone or corticotropin (ACTH) secreting pituitary adenomas[9], but not on suppressed adjacent normal gland. This effect could theoretically improve the imaging detection of adenomas with 18F-FDG PET imaging following secretagogue stimulation. We demonstrate for the first time that CRH stimulation results in a differential glucose uptake in adenomatous, but not in normal corticotrophs This was associated with a robust increase in glucose transporter 1 (GLUT1) expression. Taken together, these novel findings support the potential use of delayed 18F-FDG PET imaging following CRH stimulation to improve microadenoma detection in CD. We hypothesized that CRH stimulation leads to a delayed elevation in glucose uptake in corticotropinomas

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