The Effect of cAMP and the Role of Epac2A During Activation, Activity, and Deactivation of Beta Cell Networks

Abstract

Beta cells couple stimulation by glucose with insulin secretion and impairments in this coupling play a central role in diabetes mellitus. To clarify the effect of cAMP and the role of Epac2A in intracellular calcium signals and intercellular coupling, we performed functional multicellular calcium imaging in beta cells in mouse pancreas tissue slices after stimulation with glucose and forskolin in wild-type and Epac2A knock-out mice. Increased cAMP evoked calcium signals in otherwise sub-stimulatory glucose and beta cells from Epac2A knock-out mice displayed a faster activation. During the plateau phase, beta cells from Epac2A knock-out mice displayed a slightly higher active time in response to glucose compared with wild-type littermates, and increased cAMP increased the active time via a large increase in oscillation frequency and small decrease in oscillation duration in both Epac2A knock-out and wild-type mice. Functional network properties during stimulation with glucose did not differ in Epac2A knock-out mice, but the presence of Epac2A was crucial for the protective effect of increased cAMP in preventing a decline in beta cell functional connectivity with time. Finally, increased cAMP prolonged beta cell activity during deactivation in an Epac2A-independent manner.

The Role of cAMP in Beta Cell Stimulus–Secretion and Intercellular Coupling

“…The results presented in Figure 3G,H indicate that increased levels of cAMP led to a denser and a more integral network (Figure 3H), thereby signifying a higher degree of synchronization between beta cells when compared to glucose stimulation only (Figure 3G). This is well in agreement with our previous results, where, in control experiments with prolonged glucose stimulation only, synchronized behavior diminished with time, but the activation of cAMP prevented this effect and enhanced the degree of beta cell synchronicity [199]. Most importantly, performing the same set of experiments with Epac2A KO mice, stimulation with forskolin restored the functional network integrity only partly.…”

“…Finally, in our very recent study, we investigated explicitly how cAMP-mediated amplification affected the collective beta cell activity within the islets [199]. Our results showed that the activation of cAMP signaling did not only profoundly increase beta cell activity but also enhanced synchronicity and the coordination of intercellular signals.…”

The Role of cAMP in Beta Cell Stimulus-Secretion and Inter-cellular Coupling

“…Clearly, in the latter case, the network is characterized by more functional connections resulting in a more integral network, which indicates a higher degree of synchronization between beta cells. This is well in agreement with our previous results, where in control experiments with prolonged glucose stimulation only, synchronized behavior diminished with time, but the activation of cAMP prevented this effect and enhanced the degree of beta cell synchronicity [183]. Most importantly, performing the same set of experiments with Epac2A KO mice, stimulation with forskolin restored the functional network integrity only partly.…”

“…Finally, in our very recent study we investigated explicitly how cAMP-mediated amplification affected the collective beta cell activity within the islets [183]. Our results have shown that the activation of cAMP signaling did not only profoundly increase beta cell activity but also enhanced synchronicity and the coordination of intercellular signals.…”

Exendin-4 affects calcium signalling predominantly during activation and activity of beta cell networks in acute mouse pancreas tissue slices

“…Therefore, the influence of GLP-1RAs on beta cell activation and deactivation phases, which probably play a significant role during the first phase of insulin secretion and can help assess the risk of hypoglycaemia, respectively, remain to be explored (67)(68)(69). Additionally, modulation of [Ca 2+ ] IC dynamics by GLP-1RAs, particularly with respect to [Ca 2+ ] IC oscillation properties and functional connectivity during the plateau phase, are inadequately explored in the existing literature (70).…”