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

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journal contribution
posted on 2005-03-01, 00:00 authored by Ken WalderKen Walder, L Kerr-Bayles, Anthony Civitarese, Jeremy Jowett, J Curran, K Elliott, J Trevaskis, N Bishara, P Zimmet, L Mandarino, E Ravussin, J Blangero, A Kissebah, Gregory Collier
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.

History

Journal

Diabetologia

Volume

48

Issue

3

Pagination

459 - 468

Publisher

Springer-Verlag

Location

Berlin , Germany

ISSN

0012-186X

eISSN

1432-0428

Language

eng

Publication classification

C1 Refereed article in a scholarly journal

Copyright notice

Springer-Verlag, 2005