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

Authors Bruckbauer A, Zemel M

Received 28 November 2012

Accepted for publication 14 January 2013

Published 13 February 2013 Volume 2013:6 Pages 93—102

DOI https://doi.org/10.2147/DMSO.S40840

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

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.

Keywords: diabetes, AMP-activated protein kinase, Sirt1, fat oxidation

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