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.
Hypaphorine, an a-N,N,N-trimethyltryptophan betaine, is isolated as major constituent from Impatiens niamniamensis seeds (Balsaminaceae) for the first time. The structure of the compound was established by spectroscopic data. This is the first report of its in vivo evaluation for antihyperglycemic activity. The ethanolic extract of the seeds showed mild antihyperglycemic activity at the dose of 200 mg/kg body weight, whereas, hypaphorine showed significant activity in streptozotocin-induced diabetic rats at the dose of 50 mg/kg body weight when compared to standard drug metformin (100 mg/kg).
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