Human adenovirus type 36 enhances glucose uptake in diabetic and nondiabetic human skeletal muscle cells independent of insulin signaling.
OBJECTIVE
Human adenovirus type 36 (Ad-36) increases adiposity but improves insulin sensitivity in experimentally infected animals. We determined the ability of Ad-36 to increase glucose uptake by human primary skeletal muscle (HSKM) cells.


METHODS
The effect of Ad-36 on glucose uptake and cell signaling was determined in HSKM cells obtained from type 2 diabetic and healthy lean subjects. Ad-2, another human adenovirus, was used as a negative control. Gene expression and proteins of GLUT1 and GLUT4 were measured by real-time PCR and Western blotting. Role of insulin and Ras signaling pathways was determined in Ad-36-infected HSKM cells.


RESULTS
Ad-36 and Ad-2 infections were confirmed by the presence of respective viral mRNA and protein expressions. In a dose-dependent manner, Ad-36 significantly increased glucose uptake in diabetic and nondiabetic HSKM cells. Ad-36 increased gene expression and protein abundance of GLUT1 and GLUT4, GLUT4 translocation to plasma membrane, and phosphatidylinositol 3-kinase (PI 3-kinase) activity in an insulin-independent manner. In fact, Ad-36 decreased insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation and IRS-1-and IRS-2-associated PI 3-kinase activities. On the other hand, Ad-36 increased Ras gene expression and protein abundance, and Ras siRNA abrogated Ad-36-induced PI 3-kinase activation, GLUT4 protein abundance, and glucose uptake. These effects were not observed with Ad-2 infection.


CONCLUSIONS
Ad-36 infection increases glucose uptake in HSKM cells via Ras-activated PI 3-kinase pathway in an insulin-independent manner. These findings may provide impetus to exploit the role of Ad-36 proteins as novel therapeutic targets for improving glucose handling.
Wang
Zhong Q
ZQ
Division of Nutrition and Chronic Diseases, Louisiana State University System, Baton Rouge, Louisiana, USA. zhong.wang@pbrc.edu
Cefalu
William T
WT
Zhang
Xian H
XH
Yu
Yongmei
Y
Qin
Jianhua
J
Son
Leslie
L
Rogers
Pamela M
PM
Mashtalir
Nazar
N
Bordelon
Justin R
JR
Ye
Jianping
J
Dhurandhar
Nikhil V
NV
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000258:Adenovirus Infections, Human / Q000378:metabolism* / Q000503:physiopathology; D000260:Adenoviruses, Human / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism / Q000821:virology; D003847:Deoxyglucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism / Q000821:virology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000821:virology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D051246:Glucose Transport Proteins, Facilitative; D051272:Glucose Transporter Type 1; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C495677:SLC2A1 protein, human; C411811:SLC2A9 protein, human; D003847:Deoxyglucose; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose