Interaction of sulfonylurea with the pancreatic B-cell

Sulfonylureas have a variety of effects on pancreatic B-cells. In the present review an attempt has been made to identify those that appear fundamental from a mechanistic point of view and in that sense common to all hypoglycemic drugs tested. On several points the available able experimental information is limited. With this reservation in mind, the following general hypothesis is presented for the insulin-releasing action of this class of drugs. Hypoglycemic sulfonylureas and related [(acylamino)alkyl]benzoic acids bind to the B-cell plasma membrane, a step in which hydrophobic anchoring is essential. Dissociated acidic COOH or SO2NHCO groups in the drugs are thus presented to an ion-gating protein in the plasma membrane, possibly in the vicinity of a pair of sulfur atoms. The reduced state of these sulfurs is promoted, preventing the formation of a disulfide bridge. K+ permeability is thereby decreased, favoring depolarization of the B-cell and Ca2+ influx through voltage-dependent channels. Finally, Ca2+ triggers the physiological apparatus for discharge of the insulin secretory granules. The effect of this insulinreleasing signal chain is amplified by cyclic AMP which increases in the B-cell as a consequence of depolarization and Ca2+ influx. This hypothesis does not attribute an ionophoretic role to the sulfonylureas per sebecause various experiments with cells and artificial membrane systems render such an idea apparently less tenable.