Dataset Information

Delineating the role of FANCA in glucose-stimulated insulin secretion in ? cells through its protein interactome.

ABSTRACT: Hyperinsulinemia affects 72% of Fanconi anemia (FA) patients and an additional 25% experience lowered glucose tolerance or frank diabetes. The underlying molecular mechanisms contributing to the dysfunction of FA pancreas ? cells is unknown. Therefore, we sought to evaluate the functional role of FANCA, the most commonly mutated gene in FA, in glucose-stimulated insulin secretion (GSIS). This study reveals that FANCA or FANCB knockdown impairs GSIS in human pancreas ? cell line EndoC-?H3. To identify potential pathways by which FANCA might regulate GSIS, we employed a proteomics approach to identify FANCA protein interactions in EndoC-?H3 differentially regulated in response to elevated glucose levels. Glucose-dependent changes in the FANCA interaction network were observed, including increased association with other FA family proteins, suggesting an activation of the DNA damage response in response to elevated glucose levels. Reactive oxygen species increase in response to glucose stimulation and are necessary for GSIS in EndoC-?H3 cells. Glucose-induced activation of the DNA damage response was also observed as an increase in the DNA damage foci marker ?-H2AX and dependent upon the presence of reactive oxygen species. These results illuminate the role of FANCA in GSIS and its protein interactions regulated by glucose stimulation that may explain the prevalence of ? cell-specific endocrinopathies in FA patients.

SUBMITTER: Lagundzin D

PROVIDER: S-EPMC6713327 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Delineating the role of FANCA in glucose-stimulated insulin secretion in β cells through its protein interactome.

Lagundžin Dragana D Hu Wen-Feng WF Law Henry C H HCH Krieger Kimiko L KL Qiao Fangfang F Clement Emalie J EJ Drincic Andjela T AT Nedić Olgica O Naldrett Michael J MJ Alvarez Sophie S Woods Nicholas T NT

PloS one 20190828 8

Hyperinsulinemia affects 72% of Fanconi anemia (FA) patients and an additional 25% experience lowered glucose tolerance or frank diabetes. The underlying molecular mechanisms contributing to the dysfunction of FA pancreas β cells is unknown. Therefore, we sought to evaluate the functional role of FANCA, the most commonly mutated gene in FA, in glucose-stimulated insulin secretion (GSIS). This study reveals that FANCA or FANCB knockdown impairs GSIS in human pancreas β cell line EndoC-βH3. To ide ...[more]

PMID: 31461451

Similar Datasets

Project description:For glucose-stimulated insulin secretion (GSIS) by pancreatic β-cells in animals, it is believed that ATP generated from glucose metabolism is primarily responsible. However, this ignores two well-established aspects in literature: (a) intracellular ATP generation from other sources resulting in an overall pool of ATP, regardless of the original source, and (b) that intracellular glucose transport is 10- to 100-fold higher than intracellular glucose phosphorylation in β-cells. The latter especially provides an earlier unaddressed, but highly appealing, observation pertaining to (at least transient) the presence of intracellular glucose molecules. Could these intracellular glucose molecules be responsible for the specificity of GSIS to glucose (instead of the widely believed ATP production from its metabolism)? In this work, we provide a comprehensive compilation of literature on glucose and GSIS using various cellular systems - all studies focus only on the extracellular role of glucose in GSIS. Further, we carried out a comprehensive analysis of differential gene expression in Mouse Insulinoma 6 (MIN6) cells, exposed to low and high extracellular glucose concentrations (EGC), from the existing whole transcriptome data. The expression of other genes involved in glycolysis, Krebs cycle, and electron transport chain was found to be unaffected by EGC, except Gapdh, Atp6v0a4, and Cox20. Remarkably, 3 upregulated genes (Atp6v0a4, Cacnb4, Kif11) in high EGC were identified to have an association with cellular secretion. Using glucose as a possible ligand for the 3 proteins, computational investigations were carried out (that will require future 'wet validation', both in vitro and in vivo, e.g., using primary islets and animal models). The glucose-affinity/binding scores (in kcal/mol) obtained were also compared with glucose binding scores for positive controls (GCK and GLUT2), along with negative controls (RPA1, KU70-80, POLA1, ACAA1A, POLR1A). The binding affinity scores of glucose molecules for the 3 proteins were found to be closer to positive controls. Therefore, we report the glucose binding ability of 3 secretion-related proteins and a possible direct role of intracellular glucose molecules in GSIS.

Dataset Information

Delineating the role of FANCA in glucose-stimulated insulin secretion in ? cells through its protein interactome.

Publications

Delineating the role of FANCA in glucose-stimulated insulin secretion in β cells through its protein interactome.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets