ABSTRACT

The aim of this dissertation has been to investigate the modulation of pancreatic islet cell secretion. In developing improved medication for diabetic patients, it is important to understand the basal signalling mechanisms in the islets.

In order to clarify some of the basic mechanisms acting during fusion of secretory granules, the role of phosphatidylinositol 4-kinase on insulin release was explored in β -cells. PI 4-K acts as a metabolic regulator of insulin secretion by modulating the fusion competence of the granules. Furthermore, secretory and cytoplasmic phospholipase A 2 plays an important role in regulation of insulin secretion. sPLA 2 is released from β -cells upon stimulation and hydrolyses phospholipids on membranes, producing lysophospholipids. Lyso-PC stimulates insulin release by closure of the K ATP channel. This suggests a role for sPLA 2 as an autocrine regulator. cPLA 2 stimulates insulin release, when applied directly into the cell. The effect of cPLA 2 involves priming and maturation of granules by modulating a granular chloride flux. Pharmacological regulation of insulin release was studied. Two new imidazoline compounds have been found to stimulate insulin release and inhibit glucagons release in a glucose-dependent manner. Rhes (Ras homologue expressed in striatum) has been reported to be involved in imidazoline-induced insulin secretion. To characterize Rhes, cells were stably transfected with full-length Rhes cDNA. Overexpression of Rhes strongly increases the glucose sensitivity of the cells. Capacitance measurements showed an increase in the exocytotic rate. Rhes transfectans contain larger insulin-containing granules and have a higher insulin content than untransfected cells, which fits well with the observed increase in insulin release.

These results can hopefully contribute to the understanding of the mechanisms underlying diabetes.