On Cholecystokinin and Phospholipase A2 in Insulin Secretion - an Experimental Study With Reference to the Development of Diabetes
Abstract: In view of unsolved issues regarding cellular events underlying the adaptation of insulin secretion to insulin resistance, together with the observation that insulin secretion induced by the gastrointestinal hormone and neuropeptide cholecystokinin (CCK) is not solely explained by phospholipase C-protein kinase C (PLC-PKC) pathway activation, this study aimed at delineate mechanisms responsible for the hyperinsulinemia in insulin resistance, with particular attention paid to the action of glucose vs. non-glucose secretagogues, such as CCK. In glucose-intolerant and insulin-resistant high-fat diet-fed C57BL/6J mice, glucose-stimulated insulin secretion was impaired both in vivo and in vitro, whereas non-glucose-stimulated insulin secretion, by CCK or carbachol, was potentiated, revealing an important role of non-glucose secretagogues in islet adaptation to insulin resistance. Furthermore, in isolated rat islets, CCK induced activation of phospholipase A2 (PLA2), both in the presence and absence of extracellular Ca2+, indicating that CCK activates both the Ca2+-dependent and the Ca2+-independent forms of PLA2. This ability differed from that of the cholinergic agonist carbachol, which was unable to stimulate PLA2 in the absence of Ca2+. Moreover, the PLA2-activating capacity of CCK was partially dependent on PKC, whereas it was independent of the cyclooxygenase and lipoxygenase pathways. In addition, the CCK-stimulated PLA2 stimulation was decreased by activation of the cyclic AMP-protein kinase A (cAMP-PKA) pathway, which also reduced an expected CCK-induced potentiation of insulin secretion. Finally, in islets from high-fat diet-fed C57BL/6J mice, CCK-induced activation of PLA2 was exaggerated. Thus, in conclusion, these studies suggest that (i) insulin resistance increases the islet sensitivity to non-glucose stimuli. such as CCK, (ii) that the islet PLA2 signalling pathway is involved in the insulinotropic action of CCK, and (iii) that insulin resistance causes an enhanced CCK-induced activation of islet PLA2 signalling.
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