Effects of Methylglyoxal on Rat Pancreatic β-Cells

Abstract

The addition of the α-ketoaldehyde methylglyoxal (0.5 or 1 mmol/L) to single isolated rat pancreatic β-cells caused a rapid, marked depolarization resulting in electrical activity. This effect of methylglyoxal on β-cell was reversible upon removal of the α-ketoaldehyde, and could be inhibited by the anion channel blockers 4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid (DIDS) and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB). Methylglyoxal also resulted in elevated cytosolic [Ca 2+] and an intracellular acidification in intact rat islets. In perifused islets, methylglyoxal provoked a modest, transient stimulation of secretion but inhibited glucose-induced insulin release. Incubation of islets with methylglyoxal resulted in the formation of large quantities of d-lactate, indicating metabolism of the α-ketoaldehyde via the glyoxalase pathway. The effects of methylglyoxal on β-cell membrane potential, cytosolic [Ca 2+] and intracellular pH were also observed in response to phenylglyoxal which is also effectively metabolized via the glyoxalase pathway. However, t-butylglyoxal which is poorly metabolized via the glyoxalase pathway, caused neither depolarization of the membrane potential nor intracellular acidification, but did inhibit glucose-induced insulin release. These findings suggests that the depolarization and acidification evoked by methyl- and phenylglyoxal are dependent upon their metabolism via the glyoxalase pathway. The possible mechanisms coupling α-ketoaldehyde metabolism via the glyoxalase pathway with membrane depolarization are discussed.