RESUMEN
Methylglyoxal (MG) is a highly reactive dicarbonyl compound involved in the formation of advanced glycation endproducts (AGE). Levels of MG are elevated in patients with type-2 diabetes mellitus (T2DM), and AGE have been implicated in the progression of diabetic complications. The antihyperglycemic drug metformin (MF) has been suggested to be a scavenger of MG. The present work examined and characterized unequivocally the resulting scavenged product from the metformin-MG reaction. The primary product was characterized by (1)H, (13)C, 2D-HSQC, and HMBC NMR and tandem mass spectrometry. X-ray diffraction analysis determined the structure of the metformin and MG-derived imidazolinone compound as (E)-1,1-dimethyl-2-(5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl)guanidine (IMZ). A LC-MS/MS multiple reaction monitoring method was developed to detect and quantify the presence of IMZ in metformin-treated T2DM patients. Urine from >90 MF-treated T2DM patients was analyzed, with increased levels of MF directly correlating with elevations in IMZ. Urinary MF was detected in the range of 0.17 µM to 23.0 mM, and simultaneous measurement of IMZ concentrations were in the range of 18.8 nM to 4.3 µM. Since plasma concentrations of MG range from 40 nM to 4.5 µM, the level of IMZ production may be of therapeutic significance. Thus, in addition to lowering hepatic gluconeogenesis, metformin also scavenges the highly reactive MG in vivo, thereby reducing potentially detrimental MG protein adducts, with subsequent reductions in diabetic complications.
Asunto(s)
Hipoglucemiantes/metabolismo , Metformina/metabolismo , Piruvaldehído/química , Adulto , Anciano , Anciano de 80 o más Años , Cromatografía Líquida de Alta Presión , Cristalografía por Rayos X , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/patología , Femenino , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Imidazolinas/orina , Masculino , Metformina/química , Metformina/uso terapéutico , Persona de Mediana Edad , Conformación Molecular , Piruvaldehído/sangre , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
Dietary advanced glycation end products (AGE) formed during heating of food have gained interest as potential nutritional toxins with adverse effects on inflammation and glucose metabolism. In the present study, we investigated the short-term effects of high and low molecular weight (HMW and LMW) dietary AGE on insulin sensitivity, expression of the receptor for AGE (RAGE), the AGE receptor 1 (AGER1) and TNF-α, F2-isoprostaglandins, body composition and food intake. For 2 weeks, thirty-six Sprague-Dawley rats were fed a diet containing 20% milk powder with different proportions of this being given as heated milk powder (0, 40 or 100%), either native (HMW) or hydrolysed (LMW). Gene expression of RAGE and AGER1 in whole blood increased in the group receiving a high AGE LMW diet, which also had the highest urinary excretion of the AGE, methylglyoxal-derived hydroimidazolone 1 (MG-H1). Urinary excretion of N ε-carboxymethyl-lysine increased with increasing proportion of heat-treated milk powder in the HMW and LMW diets but was unrelated to gene expression. There was no difference in insulin sensitivity, F2-isoprostaglandins, food intake, water intake, body weight or body composition between the groups. In conclusion, RAGE and AGER1 expression can be influenced by a high AGE diet after only 2 weeks in proportion to MG-H1 excretion. No other short-term effects were observed.
Asunto(s)
Dieta/efectos adversos , Productos Finales de Glicación Avanzada/efectos adversos , Hexosiltransferasas/metabolismo , Receptor para Productos Finales de Glicación Avanzada/agonistas , Regulación hacia Arriba , Animales , Biomarcadores/sangre , Biomarcadores/orina , Ingestión de Energía , Productos Finales de Glicación Avanzada/administración & dosificación , Productos Finales de Glicación Avanzada/química , Productos Finales de Glicación Avanzada/orina , Hexosiltransferasas/sangre , Hexosiltransferasas/química , Hexosiltransferasas/genética , Calor/efectos adversos , Imidazoles/orina , Imidazolinas/orina , Lisina/análogos & derivados , Lisina/orina , Masculino , Proteínas de la Leche/administración & dosificación , Proteínas de la Leche/efectos adversos , Proteínas de la Leche/química , Peso Molecular , Proteolisis , Distribución Aleatoria , Ratas Sprague-Dawley , Receptor para Productos Finales de Glicación Avanzada/sangre , Receptor para Productos Finales de Glicación Avanzada/genética , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Eliminación Renal , Pruebas de Toxicidad Subaguda , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Tetrahydrozoline, a derivative of imidazoline, is widely used for the symptomatic relief of conjunctival and nasal congestion; however, intentional or unintentional high doses can result in toxicity manifested by hypotension, tachycardia, and CNS depression. The detection of the drug in blood and urine is helpful in the diagnosis and management of a toxic patient. For the analysis, plasma, serum, or urine is added to a tube containing alkaline buffer and organic extraction solvents, and tetrahydrozoline from the sample is extracted into the organic phase by gentle mixing. After centrifugation, the upper organic solvent layer containing the drug is removed and dried under stream of nitrogen at 40 degrees C. The residue is reconstituted in a hexane-ethanol mixture and analyzed using gas-chromatography-mass spectrometry. Quantitation of the drug is done by comparing responses of unknown sample to the responses of the calibrators using selected ion monitoring. Naphazoline is used as an internal standard.