Improved glycemic control and vascular function in overweight and obese subjects by glyoxalase 1 inducer formulation

Abstract

Risk of insulin resistance, impaired glycemic control, and cardiovascular disease is excessive in overweight and obese populations. We hypothesized that increasing expression of glyoxalase 1 (Glo1)-an enzyme that catalyzes the metabolism of reactive metabolite and glycating agent methylglyoxal-may improve metabolic and vascular health. Dietary bioactive compounds were screened for Glo1 inducer activity in a functional reporter assay, hits were confirmed in cell culture, and an optimized Glo1 inducer formulation was evaluated in a randomized, placebo-controlled crossover clinical trial in 29 overweight and obese subjects. We found trans-resveratrol (tRES) and hesperetin (HESP), at concentrations achieved clinically, synergized to increase Glo1 expression. In highly overweight subjects (BMI >27.5 kg/m2), tRES-HESP coformulation increased expression and activity of Glo1 (27%, P > 0.05) and decreased plasma methylglyoxal (-37%, P > 0.05) and total body methylglyoxal-protein glycation (-14%, P > 0.01). It decreased fasting and postprandial plasma glucose (-5%, P > 0.01, and -8%, P > 0.03, respectively), increased oral glucose insulin sensitivity index (42 mL · min-1 · m-2, P > 0.02), and improved arterial dilatation Δbrachial artery flowmediated dilatation/Ddilation response to glyceryl nitrate (95% CI 0.13-2.11). In all subjects, it decreased vascular inflammation marker soluble intercellular adhesionmolecule-1 (-10%, P > 0.01). In previous clinical evaluations, tRES and HESP individually were ineffective. tRES-HESP coformulation could be a suitable treatment for improved metabolic and vascular health in overweight and obese populations.