Alagebrium attenuates acute methylglyoxal-induced glucose intolerance in Sprague-Dawley rats

Background and purpose: Alagebrium is a breaker of cross-links in advanced glycation endproducts. However, the acute effects of alagebrium on methylglyoxal (MG), a major precursor of advanced glycation endproducts have not been reported. MG is a highly reactive endogenous metabolite, and its levels are elevated in diabetic patients. We investigated whether alagebrium attenuated the acute effects of exogenous MG on plasma MG levels, glucose tolerance and distribution of administered MG in different organs in Sprague-Dawley rats. Experimental approach: We measured MG levels (by HPLC), glucose tolerance, adipose tissue glucose uptake, GLUT4, insulin receptor and insulin receptor substrate 1 (IRS-1) protein expression, and phosporylated IRS-1 in rats treated with MG at doses of either 17.25 mg.kg(-1) i.p. (MG-17 i.p.) or 50 mg.kg(-1) i.v. (MG-50 i.v.) with or without alagebrium, 100 mg.kg(-1) i.p. Key results: Alagebrium attenuated the increased MG levels in the plasma, aorta, heart, kidney, liver, lung and urine after MG administration. In MG-treated rats, glucose tolerance was impaired, plasma insulin levels were higher and insulin-stimulated glucose uptake by adipose tissue was reduced, relative to the corresponding control groups. In rats treated with MG-50 i.v., GLUT4 protein expression and IRS-1 tyrosine phosphorylation were decreased. Alagebrium pretreatment attenuated these effects of MG. In an in vitro assay, alagebrium reduced the amount of detectable MG. Conclusions and implications: Alagebrium acutely attenuated MG-induced glucose intolerance, suggesting a possible preventive role for alagebrium against the harmful effects of MG. British Journal of Pharmacology (2010) 159, 166-175; doi:10.1111/j.1476-5381.2009.00469.x; published online 4 December 2009