Metformin inhibition of glycation processes.

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.

Reaction of metformin with dicarbonyl compounds. Possible implication in the inhibition of advanced glycation end product formation.

Dicarbonyl compounds such as methylglyoxal and glyoxal are extremely reactive glycating agents involved in the formation of advanced glycation end products (AGEs), which in turn are associated with diabetic vascular complications. Guanidino compounds such as aminoguanidine appear to inhibit AGE formation by reacting with alpha-dicarbonyl compounds. The aim of this work was to study whether the antihyperglycemic agent metformin (a guanidine-like compound) might react with reactive alpha-dicarbonyls.

In vitro and in vivo alterations of enzymatic glycosylation in diabetes.

Carbohydrate composition changes of glycoconjugates constituting the glycocalix of microvascular cells could be involved in the alterations of cell-cell interactions observed in diabetic retinopathy. In this field, we have recently reported that advanced glycation end products (AGEs) modify galactose, fucose and sialic acid contents of specific cellular glycoproteins. To better understand the mechanisms involved in glycoprotein modifications in diabetes, we now investigate whether glucose and AGEs could affect the activities of enzymes involved in galactose, fucose and sialic acid metabolism : glycosyltransferases (synthesis) and glycosidases (catabolism).

Growth modulation of retinal microvascular cells by early and advanced glycation products.

To investigate the possible implication of non-enzymatic glycosylation in the etiopathogenesis of the diabetic retinopathy, we studied the effect of early and advanced glycation products on the growth of retinal microvascular cells. Glucose modified products were obtained by incubating bovine serum albumin or fetal bovine serum with 0.5 M glucose for 10 (early glycation products: EG-BSA and EG-FBS, respectively) or 60 days (advanced glycation end products: AGE-BSA and AGE-FBS, respectively).

Developmental changes in intestinal glycosylation: nutrition-dependent multi-factor regulation of the fucosylation pathway at weaning time.

Developmental changes in the fucoglycoproteins of the intestinal brush-border membranes were determined by lectin affinoblotting after electrophoresis. Whereas only two alpha(1-6)-fucoglycoproteins were detected in brush-border membranes from suckling rats, a large number of N-fucoglycoproteins with alpha(1-2)- and/or alpha(1-6)-linked fucose residues were detected in rat membranes after weaning. Dietary manipulations at weaning time were used to investigate the effect of nutritional factors in the development of fucosylation in the small intestine of prolonged-nursed rats fed with milk (a high-fat, low-carbohydrate diet) compared to rats weaned normally with a standard high-carbohydrate diet.