Synergistic effects of metformin, resveratrol, and hydroxymethylbutyrate on insulin sensitivity

ergistic effects of metformin, resveratrol, and hydroxymethylbutyrate on insulin sensitivity Original Research (1830) Total Article Views Authors: Bruckbauer A, Zemel MB Published Date February 2013 Volume 2013:6 Pages 93 - 102 DOI: http://dx.doi.org/10.2147/DMSO.S40840 Received: 28 November 2012 Accepted: 14 January 2013 Published: 13 February 2013 Antje Bruckbauer,1 Michael B Zemel1,2 1NuSirt Sciences Inc, 2Department of Nutrition, University of Tennessee, Knoxville, TN, USA Background: The purpose of this study was to determine whether a mixture of the polyphenol, resveratrol, and the leucine metabolite, hydroxymethylbutyrate (HMB), acts synergistically with low doses of metformin to impact insulin sensitivity and AMP-activated protein kinase-dependent outcomes in cell culture and in diabetic mice. Methods: C2C12 skeletal myotubes and 3T3-L1 adipocytes were treated with resveratrol 0.2 μM, HMB 5 μM, and metformin 0.1 mM alone or in combination. db/db mice were treated for 2 weeks with high (1.5 g/kg diet), low (0.75 g/kg diet), or very low (0.25 g/kg diet) doses of metformin alone or in combination with a diet containing resveratrol 12.5 mg and CaHMB 2 g/kg. Results: The combination of metformin-resveratrol-HMB significantly increased fat oxidation, AMP-activated protein kinase, and Sirt1 activity in muscle cells compared with metformin or resveratrol-HMB alone. A similar trend was found in 3T3L1 adipocytes. In mice, the two lower doses of metformin exerted no independent effect but, when combined with resveratrol-HMB, both low-dose and very low-dose metformin improved insulin sensitivity (HOMAIR), plasma insulin levels, and insulin tolerance test response to a level comparable with that found for high-dose metformin. In addition, the metformin-resveratrol-HMB combination decreased visceral fat and liver weight in mice. Conclusion: Resveratrol-HMB combined with metformin may act synergistically on AMP-activated protein kinase-dependent pathways, leading to increased insulin sensitivity, which may reduce the therapeutic doses of metformin necessary in the treatment of diabetes.