The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes

Walder, Ken, Kerr-Bayles, L., Civitarese, A., Jowett, J., Curran, J., Elliott, K., Trevaskis, J., Bishara, N., Zimmet, P., Mandarino, L., Ravussin, E., Blangero, J., Kissebah, A. and Collier, Gregory 2005, The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes, Diabetologia, vol. 48, no. 3, pp. 459-468, doi: 10.1007/s00125-005-1675-9.

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Title The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes
Author(s) Walder, KenORCID iD for Walder, Ken
Kerr-Bayles, L.
Civitarese, A.
Jowett, J.
Curran, J.
Elliott, K.
Trevaskis, J.
Bishara, N.
Zimmet, P.
Mandarino, L.
Ravussin, E.
Blangero, J.
Kissebah, A.
Collier, Gregory
Journal name Diabetologia
Volume number 48
Issue number 3
Start page 459
End page 468
Publisher Springer-Verlag
Place of publication Berlin , Germany
Publication date 2005-03
ISSN 0012-186X
Keyword(s) association
gene–environment interaction
gene expression
psammomys obesus
Summary 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.
Language eng
DOI 10.1007/s00125-005-1675-9
Field of Research 060405 Gene Expression (incl Microarray and other genome-wide approaches)
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©Springer-Verlag, 2005
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Document type: Journal Article
Collection: School of Exercise and Nutrition Sciences
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