LETTER TO THE EDITOR
Improved endothelial function with metformin in type 2 diabetes mellitus
N. Norman Chan, MB, MRCP, DCHa
a EURODIAB, University College London, 1-19 Torrington Place, London WC1E 6BT, United Kingdom
NNKAChan{at}aol.com
Although the idea that metformin could improve endothelial function in humans is not new (1), Mather et al. (2) are to be congratulated in providing the first in vivo evidence that, in type 2 diabetic patients, metformin therapy for 12 weeks significantly improved acetylcholine-stimulated, endothelium-dependent vasodilation compared to placebo. They postulated potential mechanisms for metformin’s beneficial effects (other than glucose-lowering), including reduction in insulin resistance, antioxidant effects, favorable effects on lipids and free fatty acids as well as direct vasodilative effects (2). I would like to suggest an additional mechanism that might have important clinical implications.
Over recent years, there is growing evidence that accumulation of advanced glycation end products (AGEs) in hyperglycemic states plays a dominant role in endothelial dysfunction, which could lead to diabetic vasculopathy (3). Glycation is a nonenzymatic, posttranslational modification of protein, resulting from chemical reactions between glucose and primary amino acids.  -Dicarbonyl molecules such as methylglyoxal (MG) and 3-deoxyglucosone are precursors of AGEs, which are increased in diabetes. It has been shown that metformin reduces MG in vitro (4). Similarly, in diabetic subjects treated with metformin, plasma MG concentrations are significantly lower compared with those treated with diet, sulfonylurea or insulin (5). This effect is independent of glycemic control. This novel mechanism provides the rationale of potential use of metformin (in addition to insulin) to reduce vascular complications in type 1 diabetes. Large-scale randomized control trials will be required to test this hypothesis. Furthermore, other inhibitors of glycation, such as aminoguanidine, in conjunction with conventional antihyperglycemic treatment for type 2 diabetes, may confer additional benefits in reduction of vascular complications.
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1. Chan NN, Feher MD. Metformin therapy in type 2 diabetes: beneficial effects beyond glucose-lowering. Current Medical Literature: Diabetes. 2000;17:57–62
2. Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol. 2001;37:1344–1350[Abstract/Free Full Text]
3. Chan NN, Vallance P, Colhoun HM. Nitric oxide and vascular responses in type 1 diabetes. Diabetologia. 2000;43:137–147[CrossRef][Medline]
4. Ruggiero-Lopez D, Lecomte M, Moinet G, et al. Reaction of metformin with dicarbonyl compounds. Possible implication in the inhibition of advanced glycation end product formation. Biochem Pharmacol. 1999;58:1765–1773[CrossRef][Medline]
5. Beisswenger PJ, Howell SK, Touchette AD, Lal S, Szwergold BS. Metformin reduces systemic methylglyoxal levels in type 2 diabetes. Diabetes. 1999;48:198–202[Abstract]
Related Article
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Improved endothelial function with metformin in type 2 diabetes mellitus: Reply
- Kieren Mather, Subodh Verma, and Todd Anderson
J. Am. Coll. Cardiol. 2001 38: 2131-2132.
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