Template to improve glycemic control without reducing adiposity or dietary fat

R. Krishnapuram, E. J. Dhurandhar, O. Dubuisson, H. Kirk-Ballard, S. Bajpeyi, N. Butte, M. S. Sothern, E. Larsen-Meyer, S. Chalew, B. Bennett, A. K. Gupta, F. L. Greenway, W. Johnson, M. Brashear, G. Reinhart, T. Rankinen, C. Bouchard, W. T. Cefalu, J. Ye, R. JavierA. Zuberi, N. V. Dhurandhar

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

Drugs that improve chronic hyperglycemia independently of insulin signaling or reduction of adiposity or dietary fat intake may be highly desirable. Ad36, a human adenovirus, promotes glucose uptake in vitro independently of adiposity or proximal insulin signaling. We tested the ability of Ad36 to improve glycemic control in vivo and determined if the natural Ad36 infection in humans is associated with better glycemic control. C57BL/6J mice fed a chow diet or made diabetic with a high-fat (HF) diet were mock infected or infected with Ad36 or adenovirus Ad2 as a control for infection. Postinfection (pi), systemic glycemic control, hepatic lipid content, and cell signaling in tissues pertinent to glucose metabolism were determined. Next, sera of 1,507 adults and children were screened for Ad36 antibodies as an indicator of past natural infection. In chow-fed mice, Ad36 significantly improved glycemic control for 12 wk pi. In HF-fed mice, Ad36 improved glycemic control and hepatic steatosis up to 20 wk pi. In adipose tissue (AT), skeletal muscle (SM), and liver, Ad36 upregulated distal insulin signaling without recruiting the proximal insulin signaling. Cell signaling suggested that Ad36 increases AT and SM glucose uptake and reduces hepatic glucose release. In humans, Ad36 infection predicted better glycemic control and lower hepatic lipid content independently of age, sex, or adiposity. We conclude that Ad36 offers a novel tool to understand the pathways to improve hyperglycemia and hepatic steatosis independently of proximal insulin signaling, and despite a HF diet. This metabolic engineering by Ad36 appears relevant to humans for developing more practical and effective antidiabetic approaches.

Original languageEnglish
Pages (from-to)E779-E789
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume300
Issue number5
DOIs
StatePublished - May 2011

Keywords

  • Adenovirus-36
  • Adipose tissue
  • Diabetes
  • Glucose disposal
  • Glucose uptake
  • Hepatic steatosis
  • Infectobesity
  • Insulin resistance
  • Metabolic remodeling
  • Nonalcoholic fatty liver disease

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