The characterization of Abelson helper integration site-1 in skeletal muscle and its links to the metabolic syndrome.
The human Abelson helper integration site-1 (AHI1) gene is associated with both neurologic and hematologic disorders; however, it is also located in a chromosomal region linked to metabolic syndrome phenotypes and was identified as a type 2 diabetes mellitus susceptibility gene from a genomewide association study. To further define a possible role in type 2 diabetes mellitus development, AHI1 messenger RNA expression levels were investigated in a range of tissues and found to be highly expressed in skeletal muscle as well as displaying elevated levels in brain regions and gonad tissues. Further analysis in a rodent polygenic animal model of obesity and type 2 diabetes mellitus identified increased Ahi-1 messenger RNA levels in red gastrocnemius muscle from fasted impaired glucose-tolerant and diabetic rodents compared with healthy animals (P < .002). Moreover, elevated gene expression levels were confirmed in skeletal muscle from fasted obese and type 2 diabetes mellitus human subjects (P < .02). RNAi-mediated suppression of Ahi-1 resulted in increased glucose transport in rat L6 myotubes in both the basal and insulin-stimulated states (P < .01). Finally, single nucleotide polymorphism association studies identified 2 novel AHI1 genetic variants linked with fasting blood glucose levels in Mexican American subjects (P < .037). These findings indicate a novel role for AHI1 in skeletal muscle and identify additional genetic links with metabolic syndrome phenotypes suggesting an involvement of AHI1 in the maintenance of glucose homeostasis and type 2 diabetes mellitus progression.
Prior
Matthew J
MJ
School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia.
Foletta
Victoria C
VC
Jowett
Jeremy B
JB
Segal
David H
DH
Carless
Melanie A
MA
Curran
Joanne E
JE
Dyer
Tom D
TD
Moses
Eric K
EK
McAinch
Andrew J
AJ
Konstantopoulos
Nicky
N
Bozaoglu
Kiymet
K
Collier
Greg R
GR
Cameron-Smith
David
D
Blangero
John
J
Walder
Ken R
KR
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D002478:Cells, Cultured; D015331:Cohort Studies; D003847:Deoxyglucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism*; D017058:Mexican Americans; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
C487178:AHI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D003847:Deoxyglucose; D005947:Glucose