Human adenovirus type 36 enhances glucose uptake in diabetic and non-diabetic human skeletal muscle cells independent of insulin signaling

Abstract

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 skeletal muscle cells.

Research Design and Methods: The effect of Ad-36 on glucose uptake and cell signaling was determined in human primary skeletal muscle (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 non-diabetic HSKM cells. Ad-36 increased gene expression and protein abundance of GLUT1 and GLUT4, GLUT4 translocation to plasma membrane, and phosphotidyl inositol-3-kinase (PI3K) activity, in an insulin independent manner. In fact, Ad-36 decreased IRS-1 tyrosine phosphorylation, and IRS-1 and IRS-2 associated PI3K activities. On the other hand, Ad-36 increased Ras gene expression and protein abundance, and Ras RNAi abrogated Ad-36 induced PI3K activation, GLUT4 protein abundance and glucose uptake. These effects were not observed with Ad-2 infection.

Conclusion: Ad-36 infection increases glucose uptake in HSKM cells via Ras activated PI3K 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.