343-LB: The Type 2 Diabetes-Associated Lipid Binding Protein STARD10 Controls Insulin Secretory Granule Biogenesis
| Autor: | Fabien Alpy, Elizabeth Haythorne, D J Hodson, Alexandra Piunti, Alice P. Kong, Gaelle Carrat, Isabelle Leclerc, Eleni Georgiadou, Timothy J. Pullen, Annie C. Fung, Peter Arvan, Victoria Salem, Andrew Cakebread, Alejandra Tomas, Walter Distaso, Theodoros Stylianides, Richard B. Sessions, Leena Haataja, Guy A. Rutter |
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| Rok vydání: | 2019 |
| Předmět: |
Dense core granule
geography medicine.medical_specialty geography.geographical_feature_category Endocrinology Diabetes and Metabolism Insulin medicine.medical_treatment Type 2 diabetes Biology Islet medicine.disease Endocrinology Diabetes mellitus Internal medicine Internal Medicine medicine Secretion STARD10 Proinsulin |
| Zdroj: | Diabetes. 68 |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | Aim: Risk alleles for type 2 diabetes (T2D) in the STARD10 locus, impair insulin secretion and are associated with decreased proinsulin:insulin ratios. We have shown that the T2D risk associated with variation at this locus is likely to be mediated through lowered STARD10 expression in the β cell. Here, we investigate the mechanisms by which STARD10 may regulate insulin secretion. Materials and Methods: A 3-dimensional model of STARD10 was constructed from the structure of STARD2, using the modelling tools Chimera and Modeller. Islets were isolated from StarD10fl/fl-Ins1Cre male mice (βStarD10KO). Electron Microscopy (EM) images were obtained from isolated islets after chemical fixation. Total zinc content was measured by inductively coupled plasma mass spectrometry. Pulse-chase analysis of proinsulin processing was performed using 35S-labelled amino acids. RNA-Seq was done on polyadenylated transcripts selected during the preparation of paired-end, directional RNAseq libraries, sequenced on an Illumina HiSeq 4000 machine. Results: Molecular modelling indicated that STARD10 binds either phosphatidylcholine or phosphatidylethanolamine. EM analysis of islets from βStarD10KO mice revealed a markedly altered dense core granule appearance, with a dramatic increase (Fold change = 4.3; p Conclusion: We identify STARD10 as a critical regulator of insulin granule biogenesis and β cell zinc homeostasis. Our data also suggest that increased β cell Zn2+ secretion in risk allele carriers may decrease the clearance of mature insulin to lower plasma proinsulin:insulin ratio. Disclosure G. Carrat: None. E. Haythorne: None. L. Haataja: None. P. Arvan: None. A. Tomas: None. A. Piunti: None. T.J. Pullen: None. E. Georgiadou: None. T. Stylianides: None. V. Salem: None. W. Distaso: None. A. Cakebread: None. D. Hodson: None. A.C. Fung: None. R.B. Sessions: None. F. Alpy: None. A.P. Kong: Advisory Panel; Self; Lilly Diabetes. Research Support; Self; AstraZeneca, Lilly Diabetes. Speaker's Bureau; Self; Abbott. Other Relationship; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Sanofi. I. Leclerc: None. G.A. Rutter: Consultant; Self; Sun Pharma. Funding Medical Research Council UK; UK Wellcome Trust; Royal Society; Societe Francophone du Diabete |
| Databáze: | OpenAIRE |
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