We investigated the stimulatory effect of
M16209 (1-(3-bromobenzo[b]
furan-2-yl-sulfonyl)
hydantoin), a novel
aldose reductase inhibitor, on insulin secretion using isolated, perfused pancreases of rats. In the pancreases from normal rats,
M16209 (100 microM) greatly augmented
glucose-stimulated insulin secretion, but showed no effect on unstimulated insulin secretion at 2.8 mM
glucose. In contrast,
gliclazide (10 microM), a sulfonylurea, strongly enhanced both
glucose-stimulated and unstimulated insulin secretion.
Sorbinil and
epalrestat, potent
aldose reductase inhibitors, had no stimulatory effect on insulin secretion.
M16209 (100 microM) improved appreciably the decreased
insulin response to 22.2 mM
glucose and enhanced slightly unstimulated insulin secretion in the pancreases of rats with neonatally
streptozotocin-induced,
non-insulin-dependent diabetes mellitus (
NIDDM).
Gliclazide (10 microM), however, failed to affect the pancreases of
NIDDM rats. Furthermore,
M16209 showed no appreciable effect on
ATP-sensitive K(+)-channels in pancreatic beta-cells. These results suggest that
M16209, unlike sulfonylureas, selectively enhances
glucose-stimulated insulin secretion in both normal and
NIDDM rats through a direct action on the pancreas. The site of action remains unknown, but the inhibition of
aldose reductase or the
ATP-sensitive K+ channels is unlikely to be involved.