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Insulin receptor-independent upregulation of cellular glucose uptake

International Journal of Obesity volume 37, pages 146–153 (2013)Cite this article

Subjects

Abstract

Background:

Cellular glucose uptake can be enhanced by upregulating Ras signaling in either insulin-dependent or -independent manner. In presence of insulin and intact insulin signaling, Ras has a negligible role in glucose uptake. Conversely, when insulin signaling is impaired in obesity or diabetes, the insulin-independent Ras pathway may be valuable for enhancing glucose disposal. We previously reported that Ad36, a human adenovirus, enhances cellular glucose uptake by upregulating the Ras/Glut4 pathway. Here, we investigated if Ad36-upregulated Ras via the insulin-independent pathway, to enhance glucose uptake. Furthermore, uncontrolled upregulation of Ras is linked with oncogenic cell transformation, if the tumor-suppressor gene p53 is also downregulated. Hence, we determined if upregulation of Ras by Ad36 would induce oncogenic cell transformation. Finally, we determined the relevance of Ad36 to insulin resistance in humans.

Methods:

Insulin receptor (IR) was knocked down with small interfering RNA in 3T3-L1 adipocytes, to determine if Ad36 increases the Ras/Glut4 pathway and glucose uptake without IR-signaling. Next, the effects of Ad36 on cell transformation and p53 abundance were determined. Finally, overweight or obese women were screened for seropositivity to Ad36, as an indicator of natural Ad36 infection. Associations of Ad36 infection with adiposity and C-reactive proteins (CRPs)—two key markers of insulin resistance, and with glucose disposal, were determined.

Results:

Unaffected by IR knock-down, Ad36 significantly increased the Ras pathway, Glut4 translocation and glucose uptake in 3T3-L1 adipocytes. Despite Ras upregulation, Ad36 did not transform 3T3-L1 cells. This may be because Ad36 significantly increased p53 protein in 3T3-L1 cells or mice adipose tissue. Ad36 seropositivity was associated with greater adiposity and CRP levels, yet a significantly higher systemic glucose disposal rate.

Conclusions:

Overall, the study offers Ras/Glut4 pathway as an alternate to enhance glucose disposal when insulin signaling is impaired, and, importantly, provides Ad36 as a tool to understand the modulation of that pathway.

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Acknowledgements

The research was funded in part by the American Diabetes Association 1-09-IN-13 and the Mathile Institute for the Advancement of Human Nutrition, awarded to NVD. This work used Genomics core facilities at the Pennington Biomedical Research Center, that are supported in part by COBRE (NIH P20-RR021945) and NORC (NIH 1P30-DK072476) center grants from the National Institutes of Health. The human studies were supported by CIHR (Canadian Institute for Health Research) grants: 63279 MONET study (Montreal Ottawa New Emerging Team) as well and from Genome Canada-Quebec (CAO, Complications Associated with Obesity project) to RRL. RRL holds scholarships from the Fonds de Recherche en Santé du Québec (FRSQ) and the J-A DeSève chair in clinical research.

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Author notes

  1. R Krishnapuram and H Kirk-Ballard: These authors contributed equally to this work.

Authors and Affiliations

  1. Infections and Obesity Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA

    R Krishnapuram, H Kirk-Ballard, E J Dhurandhar, O Dubuisson, V Hegde, S Aggarwal & N V Dhurandhar

  2. Institut de Recherches Cliniques de Montréal (IRCM) 110, Avenue Des Pins Ouest, Montreal, Quebec, Canada

    V Messier & R Rabasa-Lhoret

  3. Nutrition Department, Université de Montréal, Montreal, Quebec, Canada

    V Messier & R Rabasa-Lhoret

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Correspondence to N V Dhurandhar.

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Competing interests

The authors declare no conflict of interest associated with this paper other than the following: (a) Patent filed: NV Dhurandhar and TC Holland. Ad-36 E4orf1, E1A and obesity and diabetes. November 2006. File No. 05P09. (b) Provisional patent filed: adenovirus Ad36 E4orf1 protein for prevention and treatment of non-alcoholic fatty liver disease (July 2010). (c) United States patent granted: adenovirus 36 E4orf1 gene and protein and their uses (US 8,008,436B2, dated 30 August 2011).

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Krishnapuram, R., Kirk-Ballard, H., Dhurandhar, E. et al. Insulin receptor-independent upregulation of cellular glucose uptake. Int J Obes 37, 146–153 (2013). https://doi.org/10.1038/ijo.2012.6

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