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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. Metformin was incubated at pH 7.4 and 37 degrees in the presence of either methylglyoxal or glyoxal and reaction products analysed by HPLC coupled to mass tandem spectrometry. AGE formation on albumin by methylglyoxal and glyoxal in the presence or absence of metformin was also studied by measuring the fluorescence at 370/440 nm after albumin-AGE isolation by ultrafiltration. As a standard for mass spectra analysis, a metformin-methylglyoxal adduct was chemically synthesised and characterised as a triazepinone (2-amino-4-(dimethyl-amino)-7-methyl-5,7-dihydro-6H-[1,3,5]triazepin+ ++-6-one). The results obtained showed that metformin strongly reacted with methylglyoxal and glyoxal, forming original guanidine-dicarbonyl adducts. Reaction kinetic studies as well as mass fragmentation spectra of the reaction products were compatible with the presence of triazepinone derivatives. In the presence of metformin, AGE-related fluorescence after albumin incubation with either glyoxal or methylglyoxal was decreased by 37% and 45%, respectively. These results suggest that besides its known antihyperglycemic effect, metformin could also decrease AGE formation by reacting with alpha-dicarbonyl compounds. This is relevant to a potential clinical use of metformin in the prevention of diabetic complications by inhibition of carbonyl stress.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10571251&dopt=Abstract
Vnitr Lek. 2002 Mar;48(3):192-6.
[Hyperinsulinemia and disorders of the menstrual cycle]
[Article in Slovak]
Dravecka I, Lazurova I, Kraus V, Petrovicova J, Palko M.
II. interna klinika Lekarskej fakulty UPJS a FNsP Kosice, Slovenska republika.
Hyperinsulinaemia and insulin resistance are usually associated phenomena of obesity and the polycystic ovary syndrome (PCO syndrome). On the other hand the PCO syndrome and obesity are often associated with disorders of the menstrual cycle and/or sterility. The authors examined 35 women aged 21 to 38 years (x = 27 +/- 4.4) with a history of anovulation cycles and/or sterility. 24 of them (68.6%) suffered from PCO syndrome. Their mean BMI was 28.95 kg/m2. 11 patients had a normal body weight, 6 were overweight and 18 were obese. The authors used the oral glucose tolerance test (oGTT) and during minute 0 and 120 blood samples were collected for assessment of the blood sugar and plasma insulin. Insulin levels in minute 0 (Io above 20 and in minute 120 (I120) above 65 uIU/ml were classified as hyperinsulinaemia. In the follicular stage of the anovulation cycle the authors assessed FSH, LH, testosterone, progesterone and prolactin. Hyperinsulinaemia ws recorded in 16 of 35 women. The mean insulin level at minute 0 was 11.9 +/- 1.3 and during minute 120 54.2 +/- 8.1 uIU/ml. The authors found significant differences in levels of I0 (6.4 +/- 1.2 vs. 16.1 +/- 1.9 uIU/ml, p < 0.01) and I120 (17.5 +/- 3 vs. 71.3 +/- 10.3 uIU/ml, p < 0.01) between obese and non-obese patients, Also in patients with the PCO there was a statistically significant difference in insulin levels of slim (BMI less than 25) as compared with obese women (BMI more than 30) (p < 0.01). A positive correlation was found between insulin levels and BMI (p < 0.01) and a liminal correlation between insulin and testosterone (p = 0.05). Patients with hyperinsulinaemia were treated with oral antidiabetics from the group of biguanides--metformin for a period of three months. During metformin treatment the insulin level declined and subsequently the menstrual cycle became normal in 11 of 16 patients with hyperinsulinaeia (68.7%), incl. two women who became pregnant. The results indicate a possible new indication of metformin in the treatment of ovarian hyperandrogenism in insulin resistant patients.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11968579&dopt=Abstract
Diabete Metab. 1994 Nov-Dec;20(6):532-9.
Metabolic and drug distribution studies do not support direct inhibitory effects of metformin on intestinal glucose absorption.
Cuber JC, Bosshard A, Vidal H, Vega F, Wiernsperger N, Rapin JR.
INSERM U45, Hopital E. Herriot, Lyon.
In an attempt to clarify the question of an involvement of the inhibition of intestinal glucose absorption in the mechanism of action of Metformin, we used several experimental approaches: 1 glucose/lactate measurement in rat portal blood in vivo and 2 in the venous effluent of an isolated perfused rat intestinal segment; 3 metabolism of freshly isolated enterocytes in vitro and tissue distribution of 3H-labeled Metformin was investigated both in vivo and in vitro. Metformin applied intraluminally had no significant effect on portal glycaemia after a glucose load, but lactate increased, whereas in vivo only a high Metformin dosage reduced portal glucose appearance significantly. Although high Metformin concentrations were found in gut biopsies, precise histological analysis in the isolated intestine revealed that it was absent from enterocytes; however the drug accumulated in villous lacteals. Intrarterially applied Metformin decreased glucose absorption in the isolated perfused ileo-jejunal segment. These data suggested that vascular Metformin boosted intestinal anaerobic glucose metabolism. Biochemical measurements performed on freshly isolated enterocytes showed that even high Metformin levels did not interfere with cell respiration or with Na+/K+ ATPase activity. Thus, our data agree with other recent reports, suggesting that even at nontherapeutic concentrations Metformin has no relevant inhibitory effect on intestinal glucose absorption. The data are discussed in the frame of previous divergent observations. The results suggest however that Metformin of vascular origin stimulates glucose consumption by the intestine, which then increases lactate output from the gut.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7713276&dopt=Abstract
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