CLINICAL STUDY Improved glycemic control induced by both metformin and repaglinide is associated with a reduction in blood levels of 3-deoxyglucosone in nonobese patients with type 2 diabetes Lian Engelen 1,2, *, Søren S Lund 3, *, Isabel Ferreira 1,2,4 , Lise Tarnow 3 , Hans-Henrik Parving 5,6 , Jørgen Gram 7,8 , Kaj Winther 9 , Oluf Pedersen 6,10,11 , Tom Teerlink 12 , Rob Barto 12 , Coen D A Stehouwer 1,2 , Allan A Vaag 3,13 and Casper G Schalkwijk 1,2 1 Cardiovascular Research Institute Maastricht (CARIM) 2 Laboratory for Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht University Medical Centre, Debeyelaan 25, PO Box 5800, 6202AZ Maastricht, The Netherlands, 3 Steno Diabetes Center, 2820 Gentofte, Denmark, 4 Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA), Maastricht University Medical Centre, 6202 Maastricht, The Netherlands, 5 Department of Medical Endocrinology, University Hospital of Copenhagen, 2100 Copenhagen, Denmark, 6 Faculty of Health Science, University of Aarhus, Aarhus, Denmark, 7 Department of Thrombosis Research, University of Southern Denmark, Esbjerg, Denmark, 8 Department of Clinical Biochemistry, Hospital of South West Denmark, 6700 Esbjerg, Denmark, 9 Department of Clinical Biochemistry, Frederiksberg Hospital, 2000 Frederiksberg, Denmark, 10 Hagedorn Research Institute, 2820 Gentofte, Denmark, 11 Faculty of Health Sciences, Institute of Biomedical Science, University of Copenhagen, 1165 Copenhagen, Denmark, 12 Department of Clinical Chemistry, VU University Medical Center, 1007 MB Amsterdam, The Netherlands and 13 Department of Endocrinology, University of Lund, 205 02 Malmo ¨, Sweden (Correspondence should be addressed to C G Schalkwijk at Laboratory for Metabolism and Vascular Medicine, Maastricht University Medical Centre; Email: c.schalkwijk@intmed.unimaas.nl) *(L Engelen and S S Lund contributed equally to this work) Abstract Objective: Metformin has been reported to reduce a-dicarbonyls, which are known to contribute to diabetic complications. It is unclear whether this is due to direct quenching of a-dicarbonyls or to an improvement in glycemic control. We therefore compared the effects of metformin versus repaglinide, an antihyperglycemic agent with an insulin-secreting mechanism, on the levels of the a-dicarbonyl 3-deoxyglucosone (3DG). Methods: Weconducted a single-center, double-masked, double-dummy, crossover study involving 96 nonobese patients with type 2 diabetes. After a 1-month run-in on diet-only treatment, patients were randomized to either repaglinide (6 mg daily) followed by metformin (2 g daily) or vice versa each during 4 months with a 1-month washout between interventions. Results: 3DG levels decreased after both metformin (K19.3% (95% confidence interval (CI): K23.5, K14.8)) and repaglinide (K20.8% (95% CI: K24.9, K16.3)) treatments, but no difference was found between treatments (1.8% (95% CI: K3.8, 7.8)). Regardless of the treatment, changes in glycemic variables were associated with changes in 3DG. Specifically, 3DG decreased by 22.7% (95% CI: 19.0, 26.5) per S.D. decrease in fasting plasma glucose (PG), by 20.0% (95% CI: 16.2, 23.9) per S.D. decrease in seven-point mean plasma glucose, by 22.5% (95% CI: 18.6, 26.6) per S.D. decrease in area under the curve for PG, by 17.2% (95% CI: 13.8, 20.6) per S.D. decrease in HbAlc, and by 10.9% (95% CI: 6.4, 15.5) per S.D. decrease in Amadori albumin. In addition, decreases in 3DG were associated with decreases in advanced glycation endproducts and endothelial markers. Conclusion: Improved glycemic control induced by both metformin and repaglinide is associated with a reduction in 3DG levels in nonobese individuals with type 2 diabetes. This may constitute a shared metabolic pathway through which both treatments have a beneficial impact on the cardiovascular risk. European Journal of Endocrinology 164 371–379 Introduction The mechanisms underlying the development of vascular complications in diabetes are not completely understood. A potential mechanism by which hypergly- cemia and its immediate biochemical sequelae induce vascular complications involves the increased formation of advanced glycation endproducts (AGEs) (1) . The deleterious effects of AGEs are attributed to direct modification of extracellular matrix proteins, resulting in collagen cross-links, which lead to increased vascular stiffness (1). In addition, binding of AGEs to a variety of cell-surface receptors, such as the receptor for AGEs, triggers signal transduction pathways and the production of reactive oxygen species, resulting in proinflammatory cellular responses (2). Given these European Journal of Endocrinology (2011) 164 371–379 ISSN 0804-4643 q 2011 European Society of Endocrinology DOI: 10.1530/EJE-10-0851 Online version via www.eje-online.org