Imperial College London
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ProfessorNickOliver

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Wynn Chair in Human Metabolism (Clinical)
 
 
 
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Contact

 

+44 (0)20 7594 1796nick.oliver

 
 
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Location

 

7S7aCommonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Avari:2023:jendso/bvac196,
author = {Avari, P and Eng, PC and Hu, M and Chen, R and Popovic, N and Polychronakos, C and Spalding, D and Rutter, GA and Oliver, N and Wernig, F},
doi = {jendso/bvac196},
journal = {Journal of the Endocrine Society},
pages = {1--5},
title = {A novel somatic mutation implicates ATP6V0D1 in proinsulin processing},
url = {http://dx.doi.org/10.1210/jendso/bvac196},
volume = {7},
year = {2023}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - ContextProhormone convertase 1/3 (PC1/3), encoded by protein convertase subtilisin kexin type 1 (PCSK1), converts inactive prohormones into biologically active peptides. Somatic mutations of insulinomas are associated with genetic defects interfering with control of insulin secretion from pancreatic beta cells. However, somatic mutations in proinsulinomas have not been described.ObjectiveWe report a case of a proinsulinoma, with suppressed insulin and C-peptide levels.MethodsA 70-year-old woman presented with a 20-year history of “blackouts.” During a 72-hour fast, blood glucose level dropped to 1.9mmol/L with suppressed plasma insulin and C-peptide levels, but proinsulin levels were raised at 37pmol/L (<10pmol/L).ResultsImaging revealed 3 distinct DOTATATE-avid pancreatic lesions. Laparoscopic spleen-preserving distal pancreatomy was performed. In view of discordant insulin, C-peptide, and proinsulin levels, whole exome sequencing analysis was performed on the tumor. In the somatic exome of the tumor, we found mutations in PCSK expression regulators, as well as a novel truncating somatic mutation in ATP6V0D1, a subunit of the ion pump that acidifies the β-cell compartments where the PCSKs act.ConclusionAppropriately suppressed insulin levels in the context of hypoglycemia do not always indicate the absence of a neuroendocrine islet cell tumor and proinsulin levels may be indicated to solidify the diagnosis. In the context of elevated proinsulin levels, low insulin and C-peptide levels might be explained by somatic mutations that likely implicate proinsulin processing within the tumor. Furthermore, we propose several mechanistic candidates, including ATP6V0D1. Experimental validation using cellular approaches may in future confirm pathomechanisms involved in this rare condition.
AU  - Avari,P
AU  - Eng,PC
AU  - Hu,M
AU  - Chen,R
AU  - Popovic,N
AU  - Polychronakos,C
AU  - Spalding,D
AU  - Rutter,GA
AU  - Oliver,N
AU  - Wernig,F
DO  - jendso/bvac196
EP  - 5
PY  - 2023///
SN  - 2472-1972
SP  - 1
TI  - A novel somatic mutation implicates ATP6V0D1 in proinsulin processing
T2  - Journal of the Endocrine Society
UR  - http://dx.doi.org/10.1210/jendso/bvac196
UR  - https://academic.oup.com/jes/article/7/3/bvac196/6964655
UR  - http://hdl.handle.net/10044/1/101588
VL  - 7
ER  -
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