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Diabetes. 2014 Oct;63(10):3530-44. doi: 10.2337/db13-1619. Epub 2014 May 21.

Orally active osteoanabolic agent GTDF binds to adiponectin receptors, with a preference for AdipoR1, induces adiponectin-associated signaling, and improves metabolic health in a rodent model of diabetes.

Author information

  • 1Biochemistry Division, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Lucknow, Uttar Pradesh, India.
  • 2Zydus Research Center, Moraiya, Ahmedabad, Gujarat, India.
  • 3Division of Endocrinology, CSIR-CDRI, Lucknow, Uttar Pradesh, India.
  • 4Division of Phramacokinetics, CSIR-CDRI, Lucknow, Uttar Pradesh, India.
  • 5Division of Medicinal and Process Chemistry, CSIR-CDRI, Lucknow, Uttar Pradesh, India.
  • 6Division of Toxicology, CSIR-CDRI, Lucknow, Uttar Pradesh, India.
  • 7Department of Molecular Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
  • 8Biochemistry Division, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Lucknow, Uttar Pradesh, India sanyal@cdri.res.in.

Abstract

Adiponectin is an adipocytokine that signals through plasma membrane-bound adiponectin receptors 1 and 2 (AdipoR1 and -2). Plasma adiponectin depletion is associated with type 2 diabetes, obesity, and cardiovascular diseases. Adiponectin therapy, however, is yet unavailable owing to its large size, complex multimerization, and functional differences of the multimers. We report discovery and characterization of 6-C-β-D-glucopyranosyl-(2S,3S)-(+)-5,7,3',4'-tetrahydroxydihydroflavonol (GTDF) as an orally active adiponectin mimetic. GTDF interacted with both AdipoRs, with a preference for AdipoR1. It induced adiponectin-associated signaling and enhanced glucose uptake and fatty acid oxidation in vitro, which were augmented or abolished by AdipoR1 overexpression or silencing, respectively. GTDF improved metabolic health, characterized by elevated glucose clearance, β-cell survival, reduced steatohepatitis, browning of white adipose tissue, and improved lipid profile in an AdipoR1-expressing but not an AdipoR1-depleted strain of diabetic mice. The discovery of GTDF as an adiponectin mimetic provides a promising therapeutic tool for the treatment of metabolic diseases.

© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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