Cellular communication and heterogeneity in pancreatic islet insulin secretion dynamics

Abstract

Coordinated pulses of electrical activity and insulin secretion are a hallmark of the islet of Langerhans. These coordinated behaviors are lost when β cells are dissociated, which also leads to increased insulin secretion at low glucose levels. Islets without gap junctions exhibit asynchronous electrical activity similar to dispersed cells, but their secretion at low glucose levels is still clamped off, putatively by a juxtacrine mechanism. Mice lacking β cell gap junctions have near-normal average insulin levels, but are glucose intolerant due to reduced first-phase and pulsatile insulin secretion, illustrating the importance of temporal dynamics. Here, we review the quantitative data on islet synchronization and the current mathematical models that have been developed to explain these behaviors and generate greater understanding of the underlying mechanisms.

Keywords: calcium waves; computer modeling; fluorescence; islet of Langerhans; microscopy.

Figure 1. Experimental dependence of [Ca²⁺]_i dynamics of gap junction coupling

Representative oscillations of [Ca²⁺]_i in 4 cells of an islet, together with phase map of [Ca²⁺]_i oscillations, where colored cells show oscillations that are synchronized with other colored cells, whereas uncolored (grey) cells show poorly synchronized oscillations or absence of oscillations. Oscillations and phase map are displayed for a wild-type islet with normal gap junction coupling (left, Cx36, 100%); an islet from a mouse with a heterozygous knockout of Cx36 which has ~50% gap junction conductance (middle, Cx36+/−, 50%); and an islet from a mouse with a homozygous knockout of Cx36 which has ~0% gap junction conductance (right, Cx36−/−, 50%). Note the transition between regular, near-fully synchronized oscillations, and heterogeneous irregular an uncoordinated oscillations as Cx36 is reduced. Figure adapted from [37].

Figure 2. Schematic of cellular interactions that regulate insulin release

Two representative heterogeneous cells in an islet that have different threshold for glucose activation of Ca²⁺-signaling which may arise for many reasons but here is indicated as different K_ATP activation. At basal glucose levels, one cell (upper, green shaded) is more excitable and in isolation would depolarize and fire action potentials, whereas the other cell (lower, grey shaded) is less excitable and would remain quiescent. Cx36 gap junction coupling mediates a hyperpolarizing current (I_K) to the more excitable cell, preventing transient depolarization, voltage-gated calcium channel activation, and suppressing [Ca²⁺]_i elevations and Ca²⁺-triggering of insulin secretion in the more excitable cell. In the absence of Cx36 the more excitable cell can depolarize and elevate [Ca²⁺]_i. Distally, other juxtacrine mechanisms, putatively including EphA forward signaling and NCAM signaling, also suppress insulin granule trafficking and/or exocytosis to additionally suppress insulin secretion. cAMP acting via PKA overcomes the effect of other suppressive juxtacrine mechanisms, but only when gap junction coupling is also inhibited will the more excitable cell show elevated Ca²⁺-triggering and elevated basal insulin secretion, as in isolated cells.

Figure 3. Modelled multicellular islet [Ca²⁺]_i

A: Representative oscillations of [Ca²⁺]_i in 3 heterogeneous cells of a modelled multicellular islet, in the presence of full electrical coupling (left) and absence of electrical coupling (right). B: Dependence of the synchronization of [Ca²⁺]_i oscillations measured experimentally (grey diamonds) and form modelled islet (black squares) as a function of electrical coupling, normalized to that of wild-type islet or modeled islet showing wild-type behavior. C: representative phase maps of modelled islets as the level of electrical coupling is progressively decreased. Presence of color indicates cell is synchronized, absence of color (grey) indicates cell is desynchronized with the rest of the islet. Figure adapted from [37].

Figure 4. Modelling [Ca²⁺]_i upon glucose gradient

Map of [Ca²⁺]_i elevation upon a gradient of glucose metabolism, with [Ca²⁺]_i time courses from indicated cells. Time courses are offset for clarity, with vertical bar indicating change of 0.1μM. Small amount of excitation bleed through is circled which is experimentally measured. Otherwise, a sharp transition between an area of coordinated excitability and quiescent behavior can be seen. Figure adapted from [54].