Modeling of Glucose-Induced cAMP Oscillations in Pancreatic β Cells: cAMP Rocks when Metabolism Rolls

Abstract

Recent advances in imaging technology have revealed oscillations of cyclic adenosine monophosphate (cAMP) in insulin-secreting cells. These oscillations may be in phase with cytosolic calcium oscillations or out of phase. cAMP oscillations have previously been modeled as driven by oscillations in calcium, based on the known dependence of the enzymes that generate cAMP (adenylyl cyclase) and degrade it (phosphodiesterase). However, cAMP oscillations have also been reported to occur in the absence of calcium oscillations. Motivated by similarities between the properties of cAMP and metabolic oscillations in pancreatic β cells, we propose here that in addition to direct control by calcium, cAMP is controlled by metabolism. Specifically, we hypothesize that AMP inhibits adenylyl cyclase. We incorporate this hypothesis into the dual oscillator model for β cells, in which metabolic (glycolytic) oscillations cooperate with modulation of ion channels and metabolism by calcium. We show that the combination of oscillations in AMP and calcium in the dual oscillator model can account for the diverse oscillatory patterns that have been observed, as well as for experimental perturbations of those patterns. Predictions to further test the model are provided.

Spatially compartmentalized phase regulation of a Ca2+-cAMP-PKA oscillatory circuit

“…In particular, when the relative activity of PDE1 is greater than the activity of AC8, Ca 2+ -driven cAMP degradation dominates, resulting in an out-of-phase cAMP-Ca 2+ relationship. On the other hand, if the relative activity of AC8 is greater than that of PDE1, Ca 2+ -stimulated cAMP production is favored and an in-phase relationship is observed, consistent with previous modeling studies (Peercy et al 2015;Fridlyand et al 2007).…”

cAMP signalling in insulin and glucagon secretion

“…Also GLP‐1‐induced cAMP oscillations were in phase with those of [Ca 2+ ] i. The phase relationship is probably determined by the level of [Ca 2+ ] i together with the Ca 2+ sensitivity of the specific ACs and PDEs engaged by the stimulus, an assumption supported by mathematical modelling . However, the situation is probably even more complex because cAMP production is positively regulated also by cell metabolism, but ATP and Ca 2+ oscillations are synchronized in antiphase in β‐cells .…”

“…These isoforms are subject to multiple regulatory inputs but the stimulatory effect of glucose may simply reflect increased availability of ATP, the substrate for all ACs . However, since the ATP concentration is potentially saturating even under low glucose conditions, glucose may instead act via lowering of AMP to relieve its inhibitory effect on AC activity . As mentioned above, the soluble AC (sAC), has lower affinity for ATP and has been suggested to play a role in glucose sensing in INS‐1 cells and islets .…”

Upregulation of an inward rectifying K+ channel can rescue slow Ca2+ oscillations in K(ATP) channel deficient pancreatic islets

“…Equations for the dynamics of cAMP were recently added to an earlier version of the DOM [ 44 ] and it was shown that this version was capable of producing cAMP oscillations in model β-cells. We employed these equations, where the cAMP concentration is determined by the difference between its production by adenylyl cyclase ( V AC ) and degradation by phosphodiesterases ( V PDE ): where, where c is the cytosolic free Ca 2+ concentration, which stimulates both AC and PDE.…”

“…Since PKA activity is cAMP-dependent, changes in the cAMP concentration in the β-cell can in principle regulate Kir2.1 channel activity. Recent studies employing FRET-based sensors and TIRF microscopy showed that glucose induces cAMP oscillations in mouse β-cells [ 42 , 43 ], which may be accounted for by oscillations in metabolism [ 44 ]. It is therefore possible that, in KO cells, metabolic oscillations drive cAMP oscillations which in turn drive oscillations in Kir2.1 current, and this replaces oscillations in K(ATP) current as the mechanism for bursting electrical activity.…”