triazepinone and Diabetes-Mellitus

A number of studies have shown that metformin is beneficial in reducing diabetes associated vascular risk beyond the benefits expected from its antihyperglycaemic effect. One of the main pathogenic mechanisms leading to chronic complications of diabetes is non-enzymatic glycation where damage is mediated through increased production of highly chemically reactive glucose and alpha-dicarbonyl compounds which lead to production of advanced glycation products (AGEs). We present laboratory and clinical data supporting the hypothesis that one important explanation of metformin's effect on diabetic complications could be its ability to reduce toxic dicarbonyls and AGEs. This effect could be related either to the binding of the alpha-dicarbonyls, methylglyoxal (MG) or 3-deoxyglucosone, or to an increase in enzymatic detoxification. Our studies presented in this manuscript document extracellular binding of MG by metformin to form a specific product (triazepinone) in vivo. This condensation product appears to be only one of several inactive end products resulting from this chemical reaction and we discuss the possibility that these or other condensation products (hydroimidazolones) could be indicative of inactivation of MG by metformin. Additional studies of other possible condensation products, as well as other potential cellular effects of metformin on MG production, will help to clarify this potentially important effect of metformin and provide a further rationale for using metformin to prevent long-term complications.

Topics: Azepines; Deoxyglucose; Diabetes Complications; Diabetes Mellitus; Glycation End Products, Advanced; Glycosylation; Humans; Hypoglycemic Agents; Metformin; Pyruvaldehyde; Randomized Controlled Trials as Topic