Metformin reduces systemic methylglyoxal levels in type 2 diabetes.

Abstract

Methylglyoxal (MG) is a reactive alpha-dicarbonyl that is thought to contribute to diabetic complications either as a direct toxin or as a precursor for advanced glycation end products. It is produced primarily from triose phosphates and is detoxified to D-lactate (DL) by the glyoxalase pathway. Because guanidino compounds can block dicarbonyl groups, we have investigated the effects of the diamino biguanide compound metformin and of hyperglycemia on MG and its detoxification products in type 2 diabetes. MG and DL were measured by high-performance liquid chromatography in plasma from 57 subjects with type 2 diabetes. Of these subjects, 27 were treated with diet, sulfonylureas, or insulin (nonmetformin), and 30 were treated with metformin; 28 normal control subjects were also studied. Glycemic control was determined by HbA1c. MG was significantly elevated in diabetic subjects versus the normal control subjects (189.3 +/- 38.7 vs. 123.0 +/- 37 nmol/l, P = 0.0001). MG levels were significantly reduced by high-dosage (1,500-2,500 mg/day) metformin (158.4 +/- 44.2 nmol/l) compared with nonmetformin (189.3 +/- 38.7 nmol/l, P = 0.03) or low-dosage (< or = 1,000 mg/day) metformin (210.98 +/- 51.0 nmol/l, P = 0.001), even though the groups had similar glycemic control. Conversely, DL levels were significantly elevated in both the low- and high-dosage metformin groups relative to the nonmetformin group (13.8 +/- 7.7 and 13.4 +/- 4.6 vs. 10.4 +/- 3.9 micromol/l, P = 0.03 and 0.06, respectively). MG correlated with rising HbA1c levels (R = 0.4, P = 0.03, slope = 13.2) in the nonmetformin subjects but showed no increase with worsening glycemic control in the high-dosage metformin group (R = 0.0004, P = 0.99, slope = 0.02). In conclusion, MG is elevated in diabetes and relates to glycemic control. Metformin reduces MG in a dose-dependent fashion and minimizes the effect of worsening glycemic control on MG levels. To the extent that elevated MG levels lead to their development, metformin treatment may protect against diabetic complications by mechanisms independent of its antihyperglycemic effect.

Renal clearance of glycolaldehyde- and methylglyoxal-modified proteins in mice is mediated by mesangial cells through a class A scavenger receptor (SR-A)

“…Radioactivity was determined with a well counter. The specific activities of 111 In-BSA, 111 In-GA-BSA, and 111 In-MG-BSA were 12×10 6 , 11×10 6 and 11×10 6 cpm/mg protein, respectively.…”

“…Recent studies reported that several aldehydes such as glycolaldehyde (GA), glyoxal, methylglyoxal (MG), and 3-deoxyglucosone are generated during the Maillard reaction from glucose, a Schiff base, or Amadori products [3,4]. A much stronger chemical reactivity than that of glucose indicates the important role of these aldehydes in the in vivo generation of AGE structures [5][6][7].…”

Hydrazine compounds inhibit glycation of low-density lipoproteins and prevent the in vitro formation of model foam cells from glycolaldehyde-modified low-density lipoproteins

“…A previous study has reported a 40-50% reduction in coronary events with metformin treatment, though glycaemic control was not as effective as intensive treatment with sulphonylureas or insulin [35]. The increased methylglyoxal concentrations detected in people with diabetes is significantly reduced by metformin [36], perhaps due to carbonyl trapping reactions [31,37]. Hydralazine has been employed clinically as an antihypertensive agent, but is known to react with carbonyls [38,39]; this is consistent with a potential protective effect against glycation [25].…”

The Impact of Treatment With Metformin on Diabetic Foot Ulcer Among Diabetic Patients Visiting Jordanian Royal Medical Services

“…These studies put focus on the mechanisms by which metformin lowers the risks of microvascular and macrovascular disease such as lowering weight gain and hyperinsulinemia, enhancing the function of endothelial function, and fibrinolysis, and reduction of low grade inflammation, oxidative stress, and glycation [12][13][14] . Other studies showed that other benefits of metformin treatment through enhance glycemic control and to lower insulin needs and weight gain [16][17][18] .…”

“…Several studies have indicated to the mechanisms by which metformin lowers the risks of microvascular and macrovascular disease including reduced weight gain and hyperinsulinemia, enhancing the function of endothelial function, and fibrinolysis, and reduction of lowgrade inflammation, oxidative stress, and glycation [12][13][14] .…”