Electrophysiology of stimulus-secretion coupling in human beta-cells. Diabetes 41:1221–1228

Herein, we review the applicability to human @cells of an electrophyslologlcally based hypothesis of the coupllng of glucose metabolism to insulin secretion. According to this hypothesis, glucose metabolism leads to the generation of lntracellular Intermediates (Including ATP), which leads to closure of ATP-sensitive K+ channels. Channel closure results in membrane depolarizatlon, the onset of electrical activity, and voltage-dependent Ca2+ entry. The resultant rise In cytosollc Ca2+ leads to Ca2+-dependent exocytosls of Insulin granules. We found that most of the publlshed experimental evldence for human @cells supports this hypothesis. In addltlon, we present three other emerging lines of evldence in support of thls hypothesis for human islet p-cells: 1) the effects of pH,-altering maneuvers on Insulin secretion and electrlcal activity; 2) prellmlnary ldentlflcation of LVA and HVA single Ca2+ channel currents; and 3) valldatlon of the feasibility of C, measurements to track insulln granule exocytosis. On the basls of thls last new line of evidence, we suggest that comblnatlons of C,,, measurements and electrical activitylmembrane current measurements may help define the roles of diverse electrical activity patterns, dlsplayed by human @-cells, in stimulus-induced insulln secretion