Regulation of insulin secretion by CCK and glucose

A specific example of this type of control system is seen in the case of the interrelated roles of cholecystokinin 8-sulfate (CCK8S) and glucose in the regulation of insulin secretion from the beta cell of the Islets of Langerhans (Fig. 5). Each of these extracellular messengers stimulates insulin secretion under the appropriate conditions, but each does so by different mechanisms, allowing for a considerable range of responsiveness [28,29]. 

CCK8S acts in the beta cell as a typical Pi-linked agonist. Binding of CCK8S to its receptor leads to a breakdown of phosphatidylinositol 4,5-bisphosphate, with the generation of inositol 1,4,5-trisphosphate and diacylglycerol. The rise in inositol 1,4,5-trisphosphate concentration leads to the mobilization of an intracellular trig- 

If beta cells are incubated in media containing 2 mM glucose and then treated with forskolin and/or tolbutamide, there is a small transient increase in insulin secretion. The subsequent addition of CCK8S leads to a very marked first phase of insulin secretion, but causes no sustained increase or second phase of insulin secretion. These results mean that an increase in cAMP alters the Ca2+ sensitivity of the response elements underlying the first phase of secretion. These elements, presumed to be Ca2+-calmodulin-dependent processes including CaM-dependent protein kinases, become more sensitive to activation by Ca2+ either because cAMP acts to enhance the sensitivity of CaM-dependent kinases to Ca2+, or because cAMP inhibits, by an unknown mechanism, the activity of phosphoprotein phosphatases. 

The lesson is that in the case of hormones which act via the PI system, the two phases of the typical response can be modulated separately. The system need not behave in a single stereotyped fashion (see also Ref. 30). 

The example just discussed of the interrelated action of CCK8S and glucose in the regulation of insulin secretion is just one of many instances in which a particular response is controlled by multiple extracellular messengers. In fact, such an arrangement is the rule rather than the exception. 

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