Methylglyoxal causes swelling and activation of a volume-sensitive anion conductance in rat pancreatic beta-cells.

Membrane potential and whole-cell current were studied in rat pancreatic beta-cells using the 'perforated patch' technique and cell volume measured by a video-imaging method. Exposure of beta-cells to the alpha-ketoaldehyde methylglyoxal (1 mM) resulted in depolarization and electrical activity. In cells voltage-clamped at -70 mV, this effect was accompanied by the development of inward current noise. In voltage-pulse experiments, methylglyoxal activated an outwardly rectifying conductance which was virtually identical to the volume-sensitive anion conductance previously described in these cells. Two inhibitors of this conductance, 4,4'-dithiocyanatostilbene-2,2'-disulfonic acid (DIDS) and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), also inhibited the depolarization and inward current evoked by methylglyoxal. Methylglyoxal increased beta-cell volume to a relative value of 1.33 after 10 min with a gradual return towards basal levels following withdrawal of the alpha-ketoaldehyde. None of the effects of methylglyoxal was observed in response to t-butylglyoxal which, unlike methylglyoxal, is a poor substrate for the glyoxalase pathway. Methylglyoxal had no apparent effect on beta-cell K+ channel activity. It is suggested that the metabolism of methylglyoxal to D-lactate causes beta-cell swelling and activation of the volume-sensitive anion channel, leading to depolarization. These findings could be relevant to the stimulatory action of D-glucose, the metabolism of which generates significant quantities of L-lactate.