@article{08484710d8174467a62e1a11cea81488,
title = "The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes",
abstract = "Aims/hypothesis: This study aimed to identify genes that are expressed in skeletal muscle, encode proteins with functional significance in mitochondria, and are associated with type 2 diabetes. Methods: We screened for differentially expressed genes in skeletal muscle of Psammomys obesus (Israeli sand rats), and prioritised these on the basis of genomic localisation and bioinformatics analysis for proteins with likely mitochondrial functions. Results: We identified a mitochondrial intramembrane protease, known as presenilins- associated rhomboid-like protein (PSARL) that is associated with insulin resistance and type 2 diabetes. Expression of PSARL was reduced in skeletal muscle of diabetic Psammomys obesus, and restored after exercise training to successfully treat the diabetes. PSARL gene expression in human skeletal muscle was correlated with insulin sensitivity as assessed by glucose disposal during a hyperinsulinaemic-euglycaemic clamp. In 1,031 human subjects, an amino acid substitution (Leu262Val) in PSARL was associated with increased plasma insulin concentration, a key risk factor for diabetes. Furthermore, this variant interacted strongly with age to affect insulin levels, accounting for 5% of the variation in plasma insulin in elderly subjects. Conclusions/interpretation: Variation in PSARL sequence and/or expression may be an important new risk factor for type 2 diabetes and other components of the metabolic syndrome.",
keywords = "Association, Gene expression, Gene-environment interaction, Psammomys obesus",
author = "K. Walder and L. Kerr-Bayles and A. Civitarese and J. Jowett and J. Curran and K. Elliott and J. Trevaskis and N. Bishara and P. Zimmet and L. Mandarino and E. Ravussin and J. Blangero and A. Kissebah and Collier, {G. R.}",
note = "Funding Information: Acknowledgements Funding for this study was provided by Chem-Genex Pharmaceuticals, Australia. The human genetics work was supported by Grants HL34989, DK54026, MH59490, and RR00058 from the National Institutes of Health. The genotyping was undertaken under the auspices of the Mammalian Genotyping Service of the National Institutes of Health, funds being allocated to the Marshfield Medical Research Foundation. TOPS provided funds for establishment of the family database, phenotyping, and linkage analysis. Part of the phenotyping costs was also provided through a collaborative research agreement with Millennium Pharmaceuticals. Funding Information: Duality of interest: K. Walder, L. Kerr-Bayles and N. Bishara are employed by Deakin University which is currently in receipt of a grant from ChemGenex Pharmaceuticals (formerly AGT Bioscience) to investigate the genetic basis of type 2 diabetes, obesity and related metabolic disorders. P. Zimmet, J. Jowett, J. Curran and K. Elliott are employed by the International Diabetes Institute, which is currently in receipt of a research grant from ChemGenex Pharmaceuticals to investigate the genetic basis of type 2 diabetes, obesity and related metabolic disorders. G. Collier is the Chief Executive Officer of ChemGenex Pharmaceuticals. P. Zimmet chairs the Scientific Advisory Board of ChemGenex Pharmaceuticals and hold shares in the company. K. Walder holds a part-time position as a consultant for ChemGenex Pharmaceuticals, and J. Blangero is a member of the Scientific Advisory Board for ChemGenex Pharmaceuticals. J. Jowett, J. Curran and K. Elliott are holders of unexercised options for shares in ChemGenex Pharmaceuticals.",
year = "2005",
month = mar,
doi = "10.1007/s00125-005-1675-9",
language = "English (US)",
volume = "48",
pages = "459--468",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Science and Business Media Deutschland GmbH",
number = "3",
}