title: 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/m(2)), 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.
authors.affiliation: Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K.
authors.forename: Mingzhan
authors.initials: M
authors.lastname: Xue
authors.affiliation: Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K. Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals of Coventry and Warwickshire National Health Service Trust, Coventry, U.K.
authors.forename: Martin O
authors.initials: MO
authors.lastname: Weickert
authors.affiliation: Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K. Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals of Coventry and Warwickshire National Health Service Trust, Coventry, U.K.
authors.forename: Sheharyar
authors.initials: S
authors.lastname: Qureshi
authors.affiliation: Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, U.K.
authors.forename: Ngianga-Bakwin
authors.initials: NB
authors.lastname: Kandala
authors.affiliation: Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K.
authors.forename: Attia
authors.initials: A
authors.lastname: Anwar
authors.affiliation: Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K.
authors.forename: Molly
authors.initials: M
authors.lastname: Waldron
authors.affiliation: Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K.
authors.forename: Alaa
authors.initials: A
authors.lastname: Shafie
authors.affiliation: Unilever Research & Development Colworth, Bedford, U.K.
authors.forename: David
authors.initials: D
authors.lastname: Messenger
authors.affiliation: Unilever Research & Development Colworth, Bedford, U.K.
authors.forename: Mark
authors.initials: M
authors.lastname: Fowler
authors.affiliation: Unilever Research & Development Colworth, Bedford, U.K.
authors.forename: Gail
authors.initials: G
authors.lastname: Jenkins
authors.affiliation: Warwick Systems Biology Centre, University of Warwick, Coventry, U.K.
authors.forename: Naila
authors.initials: N
authors.lastname: Rabbani
authors.affiliation: Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K. Warwick Systems Biology Centre, University of Warwick, Coventry, U.K. p.j.thornalley@warwick.ac.uk.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Thornalley
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose / Q000187:drug effects*; D002460:Cell Line; D018592:Cross-Over Studies; D005260:Female; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D056945:Hep G2 Cells; D006569:Hesperidin / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D050177:Overweight / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D011765:Pyruvaldehyde / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D013267:Stilbenes; D011765:Pyruvaldehyde; D006569:Hesperidin; D007791:Lactoylglutathione Lyase; D005978:Glutathione; D000077185:Resveratrol; C013015:hesperetin; D019803:Glutathione Disulfide