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

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: 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 (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.

Role of advanced glycation endproducts and glyoxalase I in diabetic peripheral sensory neuropathy

“…Pyridoxamine showed benefit in clinical studies of diabetic nephropathy including reductions in urinary N(epsilon)-(carboxymethyl)lysine and N(epsilon)-(carboxyethyl)lysine [124]. Metformin, a common treatment for type 2 diabetes, was able to reduce levels of serum reactive dicarbonyls and AGEs in type 2 diabetic patients [125, 126]. Other compounds including aspirin, pioglitazone, benfotiamine, angiotensin converting enzyme inihbitors, angiostensin II-receptor blockers, and thiamine have also been shown to have anti-AGE effects [127].…”

Targeting advanced glycation endproducts and mitochondrial dysfunction in cardiovascular disease

“…Many studies provide a link between the development of CVD and pathological events [13]. These include endothelial cell dysfunction (ECD), atherosclerosis, arterial stiffening, ischaemic events and reperfusion injury [14,15]. The mounting evidence illuminates a link between the AGEs-RAGE axis and development of risk factors for CVD development.…”

“…These studies include the use of aminoguanidine (inhibitors), alagebrium chloride; Vitamin B compounds: pyridoxamine, thiamine, benfotiamine; glucose lowering agents: metformin, rosiglitazone, sulphonylureas; Angiotensin receptor blockers and AGEs restricted diets [11,14]. Animal studies have presented beneficial results in reduction of diabetic complications and possible under laying causes of CVD.…”

Effects on post-prandial glucose and AGE precursors from two initial insulin strategies in patients with Type 2 diabetes uncontrolled by oral agents

“…Furthermore, a reduction in 3-DG levels has been seen in improved glycemic control in non-obese type 2 diabetic patients (Engelen et al, 2011). On the other hand, MG is produced from a variety of sources and not only in the hyperglycemic state.…”