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.

OBJECTIVE Metformin has been reported to reduce α-dicarbonyls, which are known to contribute to diabetic complications. It is unclear whether this is due to direct quenching of α-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 α-dicarbonyl 3-deoxyglucosone (3DG). METHODS We conducted 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 (-19.3% (95% confidence interval (CI): -23.5, -14.8)) and repaglinide (-20.8% (95% CI: -24.9, -16.3)) treatments, but no difference was found between treatments (1.8% (95% CI: -3.8, 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.

[1]  C. Stehouwer,et al.  Hyperglycaemia-induced impairment of endothelium-dependent vasorelaxation in rat mesenteric arteries is mediated by intracellular methylglyoxal levels in a pathway dependent on oxidative stress , 2010, Diabetologia.

[2]  Paul J Thornalley,et al.  Increased Glycation and Oxidative Damage to Apolipoprotein B100 of LDL Cholesterol in Patients With Type 2 Diabetes and Effect of Metformin , 2010, Diabetes.

[3]  O. Pedersen,et al.  Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes. , 2008, European journal of endocrinology.

[4]  T. Imaizumi,et al.  Inhibitors of advanced glycation end products (AGEs): potential utility for the treatment of cardiovascular disease. , 2008, Cardiovascular therapeutics.

[5]  G. Basta.  Receptor for advanced glycation endproducts and atherosclerosis: From basic mechanisms to clinical implications. , 2008, Atherosclerosis.

[6]  O. Pedersen,et al.  Impact of metformin versus the prandial insulin secretagogue, repaglinide, on fasting and postprandial glucose and lipid responses in non-obese patients with type 2 diabetes. , 2008, European journal of endocrinology.

[7]  O. Pedersen,et al.  Targeting hyperglycaemia with either metformin or repaglinide in non‐obese patients with type 2 diabetes: results from a randomized crossover trial , 2007, Diabetes, obesity & metabolism.

[8]  L. Bouter,et al.  Endothelial Dysfunction and Low-Grade Inflammation Explain Much of the Excess Cardiovascular Mortality in Individuals With Type 2 Diabetes: The Hoorn Study , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[9]  Jean-Paul Cristol,et al.  Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. , 2006, JAMA.

[10]  R. Nelson,et al.  Susceptibility to diabetic nephropathy is related to dicarbonyl and oxidative stress. , 2005, Diabetes.

[11]  G. Paolisso,et al.  Repaglinide administration improves brachial reactivity in type 2 diabetic patients. , 2005, Diabetes care.

[12]  A. Donker,et al.  Effects of short‐term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo‐controlled trial , 2005, Journal of internal medicine.

[13]  N. Chaturvedi,et al.  Markers of inflammation are cross-sectionally associated with microvascular complications and cardiovascular disease in type 1 diabetes—the EURODIAB Prospective Complications Study , 2005, Diabetologia.

[14]  M. Hanefeld,et al.  Postprandial glucose regulation and diabetic complications. , 2004, Archives of internal medicine.

[15]  Paul J Thornalley,et al.  Nepsilon-(Carboxymethyl)lysine and 3-DG-imidazolone are major AGE structures in protein modification by 3-deoxyglucosone. , 2004, Journal of biochemistry.

[16]  R. Marfella,et al.  Regression of Carotid Atherosclerosis by Control of Postprandial Hyperglycemia in Type 2 Diabetes Mellitus , 2004, Circulation.

[17]  C. Schalkwijk,et al.  Measurement of Nε-(Carboxymethyl)lysine and Nε-(Carboxyethyl)lysine in Human Plasma Protein by Stable-Isotope-Dilution Tandem Mass Spectrometry , 2004 .

[18]  J. Shaw,et al.  Waist circumference, waist–hip ratio and body mass index and their correlation with cardiovascular disease risk factors in Australian adults , 2003, Journal of internal medicine.

[19]  Paul J Thornalley.  Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation endproducts. , 2003, Archives of biochemistry and biophysics.

[20]  N. Chaturvedi,et al.  Vascular risk factors and markers of endothelial function as determinants of inflammatory markers in type 1 diabetes: the EURODIAB Prospective Complications Study. , 2003, Diabetes care.

[21]  M. Kasuga,et al.  Relation between serum 3-deoxyglucosone and development of diabetic microangiopathy. , 2003, Diabetes care.

[22]  M. Brownlee.  Biochemistry and molecular cell biology of diabetic complications , 2001, Nature.

[23]  B. Szwergold,et al.  alpha-Dicarbonyls increase in the postprandial period and reflect the degree of hyperglycemia. , 2001, Diabetes care.

[24]  M. Lagarde,et al.  Reaction of metformin with dicarbonyl compounds. Possible implication in the inhibition of advanced glycation end product formation. , 1999, Biochemical pharmacology.

[25]  H. Parving,et al.  Amadori albumin in type 1 diabetic patients: correlation with markers of endothelial function, association with diabetic nephropathy, and localization in retinal capillaries. , 1999, Diabetes.

[26]  Paul J Thornalley,et al.  Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose. , 1999, The Biochemical journal.

[27]  T. Niwa.  3-Deoxyglucosone: metabolism, analysis, biological activity, and clinical implication. , 1999, Journal of Chromatography B: Biomedical Sciences and Applications.

[28]  C. Schalkwijk,et al.  Induction of 1,2-Dicarbonyl Compounds, Intermediates in the Formation of Advanced Glycation End-Products, during Heat-Sterilization of Glucose-Based Peritoneal Dialysis Fluids , 1999, Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis.

[29]  B. Szwergold,et al.  Metformin reduces systemic methylglyoxal levels in type 2 diabetes. , 1999, Diabetes.

[30]  R. Holman,et al.  Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) , 1998, The Lancet.

[31]  J. Spaan,et al.  Coronary circulation : from basic mechanisms to clinical implications , 1987 .