Improved Glycemic Control and Vascular Function in Overweight and Obese Subjects by Glyoxalase 1 Inducer Formulation

• Published in: Diabetes (New York, N.Y.) Vol. 65; no. 8; pp. 2282 - 2294
• Main Authors: Xue, Mingzhan, Weickert, Martin O., Qureshi, Sheharyar, Kandala, Ngianga-Bakwin, Anwar, Attia, Waldron, Molly, Shafie, Alaa, Messenger, David, Fowler, Mark, Jenkins, Gail, Rabbani, Naila, Thornalley, Paul J.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.08.2016
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose - drug effects; Cardiovascular disease; Cell culture; Cell Line; Cross-Over Studies; Female; Glutathione - metabolism; Glutathione Disulfide - metabolism; Hep G2 Cells; Hesperidin - pharmacology; Hesperidin - therapeutic use; Humans; Insulin resistance; Lactoylglutathione Lyase - metabolism; Male; Metabolism; Metabolites; Middle Aged; Models, Biological; Obesity; Obesity - blood; Obesity - drug therapy; Obesity - metabolism; Overweight - blood; Overweight - drug therapy; Overweight - metabolism; Pyruvaldehyde - metabolism; Stilbenes - pharmacology; Stilbenes - therapeutic use; Young Adult
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db16-0153

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 flow-mediated dilatation/Δdilation response to glyceryl nitrate (95% CI 0.13–2.11). In all subjects, it decreased vascular inflammation marker soluble intercellular adhesion molecule-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.