Role of KATP-channels in the control of glucagon secretion from human and rodent pancreatic islets. (360G-Wellcome-080170_Z_06_Z)

The control of glucagon secretion from the a-cells of the pancreatic islets ispoorly understood. Both paracrine (due to substances released from neighbouring cells) as well as intrinsic processes (i.e. within the a-cell itself) have been proposed to be of importance. Here we shall apply a combination of biochemical measurements of glucagon release, biophysical experiments (patch-clamp and capacitance measurements) and confocal [Ca2+]i-imaging to rodent and human pancreatic islets. We shall: 1) test the hypothesis that the intrinsic regulation of glucagon secretion depends on closure of a-cell KATP-channels; 2) establish the ion channel complement of the a-cell, which determines the electrical as well as secretory responses to the membrane depolarization resulting from closure of the KATP-channels; 3) assess the importance of the intrinsic mechanism(s) vs. paracrine processes inthe control of glucagon secretion by experimental interference with critical signalling pathways (e.g. insulin, somatostatin, Zn2+, GABA); and 4) investigate the relative roles of KATP-channels and the cAMP effector proteinsPKA and cAMP-GEFII in the modulation of glucagon secretion by adrenaline and GLP-1; both agonists acts by increasing cAMP and yet they have opposite effects (stimulation by adrenaline and inhibition by GLP-1) on glucagon secretion.