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

Abstract

BackgroundThe 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.MethodsC2C12 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.ResultsThe 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.ConclusionResveratrol-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.

Targeting Apoptosis, Advanced Glycation End Products and Transforming Growth Factor-β1 by Biguanides and Resveratrol to Ameliorate Experimentally-induced Diabetic Nephropathy

“…This may be attributed to their combined antihyperglycemic, anti-oxidant and antiinflammatory properties together with their ability to affect TGF-β1 and advanced glycation end products together with induction of apoptosis. This was in agreement with Bruckbauer and Zemel [33] who reported that resveratrol combined with metformin may act synergistically on AMP-activated protein kinase-dependent pathways, leading to increased insulin sensitivity, which in turn may reduce the therapeutic doses of metformin needed for treatment of diabetes and may ameliorate its complications including DN. Moreover, Movahed et al [34] found that the antihyperglycemic effect of resveratrol had an additive effect when combined with metformin in treatment of type-2 diabetes mellitus.…”

Protective Effects of Total Extracts of <b><i>Averrhoa carambola</i></b> L. (Oxalidaceae) Roots on Streptozotocin-Induced Diabetic Mice

“…Clinically, metformin acting as one of the antidiabetic drugs, has been shown to effectively prevent against diabetes and related complications. The pharmacological action of metformin is primarily involved in enhancing insulin sensitivity and increasing peripheral glucose uptake, thereby reducing hyperglycemia and metabolic disturbance [29]. Therefore, this study indicated that for diabetes patients, metformin treatment and EACR supplement may contribute to diabetes management, and may yield additional benefits through combined administration.…”

Resveratrol Suppresses Oxidised Low-Density Lipoprotein-Induced Macrophage Apoptosis through Inhibition of Intracellular Reactive Oxygen Species Generation, LOX-1, and the p38 MAPK Pathway

“…RSV has been the subject of intense scientific and public interest in recent years, mainly due to its widely reported ability to delay ageing and prevent age-related diseases [23,24,25]. The beneficial effects of RSV were originally thought to derive from its antioxidant properties [26].…”