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

Xue, Mingzhan, Weickert, Martin, Qureshi, Sheharyar, Kandala, Ngianga-Bakwin, Anwar, Attia, Waldron, Molly, Shafie, Alaa, Messenger, David, Fowler, Mark, Jenkins, Gail, Rabbani, Naila and Thornalley, Paul (2016) Improved glycemic control and vascular function in overweight and obese subjects by glyoxalase 1 inducer formulation. Diabetes, 65 (8). pp. 2282-2294. ISSN 0012-1797

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Abstract

Risk of insulin resistance, impaired glycemic control and cardiovascular disease is excessive in overweight and obese populations. We hypothesised that increasing expression of glyoxalase 1 (Glo1) – an enzyme that catalyses 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 confirmed in cell culture and an optimised Glo1 inducer formulation evaluated in a randomised, placebo-controlled crossover clinical trial in 29 overweight and obese subjects. We found trans-resveratrol (tRES) and hesperetin (HESP), at concentrations achieved clinically, synergised to increase Glo1 expression. In highly overweight subjects (BMI >27.5 kg/m2), tRES-HESP co-formulation increased expression and activity of Glo1 (+ 27%. P<0.05), 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 – 6%, P<0.03, respectively), increased Oral Glucose Insulin Sensitivity index (+42 mlmin-1m-2, P<0.02) and improved arterial dilatation ΔFMD/ΔGTND (95%CI 0.13–2.11). In all subjects, it decreased vascular inflammation marker sICAM-1 (-10%, P<0.01). In previous clinical evaluations, tRES and HESP individually were ineffective. tRES-HESP co-formulation could be a suitable treatment for improved metabolic and vascular health in overweight and obese populations.

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