LETTER TO THE EDITOR
Improved endothelial function with metformin in type 2 diabetes mellitus: Reply
Kieren Mather, MD, FRCPCa,
Subodh Verma, MD, PhDa and
Todd Anderson, MD, FRCPCa
a Indiana University School of Medicine, Division of Endocrinology and Metabolism, Clinical Building 459, 541 North Clinical Drive, Indianapolis, Indiana 46202 USA
We appreciate Dr. Chan’s interest in our study, and we thank him for pointing out this additional potential mechanism for the beneficial effect of metformin in the vasculature. On the surface, it may seem unlikely that changes in advanced glycosylation end products (AGEs) would account for the findings in our study, given both the relatively short duration of therapy and the generally good glycemic control of our subjects at study entry (HbAc  7%) (1).
However, as Dr. Chan correctly points out, favorable effects of metformin on the levels of precursors of AGE such as methylglyoxal have been noted (2,3). These intermediates have been postulated to contribute to a state of "carbonyl stress" analogous to, but distinct from, the oxidative stress engendered by AGEs acting in part through specific cell-surface receptors for AGEs (4). Although the dynamics of these intermediates are less clearly understood than those of the end products, it is reasonable to expect that such molecules are present in elevated concentrations in proportion to ambient glycemia (3). Although AGEs have been linked with impairments in endothelial function (5–7), no analogous evidence documenting a relationship with the precursor intermediates is available in the literature. Of course, these intermediates have most likely been present in studies of hyperglycemia and endothelial function, including those specifically addressing AGEs, and they may well have contributed to the observed impairments in endothelial function. However, firm connection remains to be established between carbonyl compounds such as methylglyoxal and endothelial dysfunction.
Unfortunately, we were unable to quantitate either oxidative stress or any of these carbonyl compounds in conjunction with our therapy and cannot comment on the potential relationship to the improved vascular function. As detailed in the Discussion section of our paper (1), the mechanism of vascular benefit of metformin in our study remains unexplained. We agree that this potential mechanism for the vascular benefit of metformin warrants further investigation and may be of relevance in both type 1 and type 2 diabetes mellitus.
 |
References
|
|---|
1. 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]
2. Ruggiero-Lopez D, Lecomte M, Moinet G, Patereau G, Lagarde M, Wiernsperger N. 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]
3. 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]
4. Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes. 1999;48:1–9[Abstract]
5. Giugliano D, Ceriello A, Paolisso G, Cohen RA. Diabetes mellitus, hypertension, and cardiovascular disease: which role for oxidative stress? Prog Cardiovasc Dis. 1995;44:363–368
6. Galle J, Schneider R, Winner B, et al. Glycoxidized LDL impair endothelial function more potently than oxidized LDL: role of enhanced oxidative stress. Atherosclerosis. 1998;138:65–77[CrossRef][Medline]
7. Watts GF, Playford DA. Dyslipoproteinaemia and hyperoxidative stress in the pathogenesis of endothelial dysfunction in non-insulin-dependent diabetes mellitus: an hypothesis. Atherosclerosis. 1998;141:17–30[Medline]
Related Article
-
Improved endothelial function with metformin in type 2 diabetes mellitus
- N. Norman Chan
J. Am. Coll. Cardiol. 2001 38: 2131.
[Full Text]
[PDF]
|
Top
References