Benoit Hastoy
PhD
Diabetes UK RD Lawrence Research Fellow
I am currently a Diabetes UK R.D Lawrence Fellow at the Oxford Centre for Diabetes Endocrinology and Metabolism (OCDEM) funded for 5 years. I investigate the impact of Type 2 Diabetes (T2D) risk variants on pancreatic beta-cell secretory capacity.
Type 2 Diabetes (T2D) is a complex disease involving the interaction between genetic and lifestyle factors. In T2D, β-cells do not secrete correct amount of insulin to reduce high blood-sugar levels after a meal. This defect can originate from the inability of β-cells to sense high blood sugar levels but also from their inability to deliver insulin. My fellowship focuses on the latter.
The process of conversion of proinsulin into insulin happens in secretory vesicles and this is well described. Along with the conversion of insulin, the secretory vesicle switches from an immature to a mature state. Normal insulin secretion involves mainly mature vesicles. Increased release of proinsulin is a T2D feature that can be the result of a default in insulin maturation, but can also be the result of a change in regulation of vesicular traffic. The latter suggests that a higher proportion of immature vesicles is involved. However, how the defective trafficking of immature vesicles in T2D occurs remains an enigma. The aim of my work is to identify the regulatory mechanisms of vesicle organisation supported by genes that are associated with T2D-risk. For this I use extensively the human beta cell line EndoC-βH1, and human primary islets when available.
Background: I started as a PhD student in Professor Jochen Lang's group in Bordeaux in 2008. My project was on the molecular mechanisms promoting exocytosis of insulin; more precisely, on the specific role of the transmembrane domain of the SNARE VAMP2 protein. I was also able to broaden my knowledge by interacting closely with researchers from different scientific backgrounds (biophysicians, bioinformaticians). In 2012, I moved to Oxford and joined Professor Patrik Rorsman's team for my first postdoctoral position. There, I learnt electrophysiology and broadened my skills on live cell imaging (i.e. calcium imaging). While involved in several collaborations, I characterised using electrophysiology the human beta-cell lines EndoC-betah1/-betah2. During this time, I also investigated the impact of T2D associated genes such as SOX4 on exocytosis. In January 2015, I joined Professors Anna Gloyn's and Mark McCarthy's teams as a postdoctoral researcher working on an MRC Experimental Challenge Grant (DIVA) awarded to Professors McCarthy, Gloyn, Karpe and Rorsman. As a member of the DIVA consortium, I investigated the cellular physiology that underlies genetic predisposition for diabetes such as those associated with PAM and SLC30A8 genes. In September 2019, I started my R.D Lawrence fellowship funded by Diabetes UK for 5 years.
Key publications
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Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.
Journal article
Dwivedi OP. et al, (2019), Nat Genet
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Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic β-cells.
Journal article
Thomsen SK. et al, (2018), Nat Genet, 50, 1122 - 1131
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Electrophysiological properties of human beta-cell lines EndoC-βH1 and -βH2 conform with human beta-cells.
Journal article
Hastoy B. et al, (2018), Sci Rep, 8
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A Central Small Amino Acid in the VAMP2 Transmembrane Domain Regulates the Fusion Pore in Exocytosis.
Journal article
Hastoy B. et al, (2017), Sci Rep, 7
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Increased Expression of the Diabetes Gene SOX4 Reduces Insulin Secretion by Impaired Fusion Pore Expansion.
Journal article
Collins SC. et al, (2016), Diabetes, 65, 1952 - 1961
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Fusion pore in exocytosis: More than an exit gate? A β-cell perspective.
Journal article
Hastoy B. et al, (2017), Cell Calcium, 68, 45 - 61
Recent publications
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Loss of tetraspanin-7 expression reduces pancreatic beta-cell exocytosis Ca2+ sensitivity but has limited effect on systemic metabolism.
Journal article
McLaughlin K. et al, (2022), Diabet Med
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Erratum: Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion (Cell Reports (2021) 34(5), (S2211124721000164), (10.1016/j.celrep.2021.108703))
Journal article
Hu M. et al, (2021), Cell Reports, 34
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Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion.
Journal article
Hu M. et al, (2021), Cell Rep, 34
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Author Correction: Super-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics.
Journal article
Ast J. et al, (2020), Nat Commun, 11
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A CRISPR/Cas9 genome editing pipeline in the EndoC-βH1 cell line to study genes implicated in beta cell function
Journal article
Grotz AK. et al, (2020), Wellcome Open Research, 4, 150 - 150
ORCID
0000-0003-1244-7857