The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes.
OBJECTIVE
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
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.
Walder
K
K
Metabolic Research Unit, School of Health Sciences, Deakin University, Pigdons Road, Waurn Ponds, 3217, Australia.
Kerr-Bayles
L
L
Civitarese
A
A
Jowett
J
J
Curran
J
J
Elliott
K
K
Trevaskis
J
J
Bishara
N
N
Zimmet
P
P
Mandarino
L
L
Ravussin
E
E
Blangero
J
J
Kissebah
A
A
Collier
G R
GR
D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004195:Disease Models, Animal; D005190:Family; D005260:Female; D005849:Gerbillinae; D006801:Humans; D008297:Male; D045726:Metalloproteases / Q000235:genetics*; D008928:Mitochondria / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D035781:Siblings
D024101:Mitochondrial Proteins; D045726:Metalloproteases; C485223:PARL protein, human
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