Paracrine regulation of glucagon secretion: the β/α/δ model

Abstract

The regulation of glucagon secretion in the pancreatic α-cell is not well understood. It has been proposed that glucose suppresses glucagon secretion either directly through an intrinsic mechanism within the α-cell or indirectly through an extrinsic mechanism. Previously, we described a mathematical model for isolated pancreatic α-cells and used it to investigate possible intrinsic mechanisms of regulating glucagon secretion. We demonstrated that glucose can suppress glucagon secretion through both ATP-dependent potassium channels (K) and a store-operated current (SOC). We have now developed an islet model that combines previously published mathematical models of α- and β-cells with a new model of δ-cells and use it to explore the effects of insulin and somatostatin on glucagon secretion. We show that the model can reproduce experimental observations that the inhibitory effect of glucose remains even when paracrine modulators are no longer acting on the α-cell. We demonstrate how paracrine interactions can either synchronize α- and δ-cells to produce pulsatile oscillations in glucagon and somatostatin secretion or fail to do so. The model can also account for the paradoxical observation that glucagon can be out of phase with insulin, whereas α-cell calcium is in phase with insulin. We conclude that both paracrine interactions and the α-cell's intrinsic mechanisms are needed to explain the response of glucagon secretion to glucose.

Functional identification of islet cell types by electrophysiological fingerprinting

“…We used our large dataset to improve the fit of a conductance-based model of a δ-cell to the experimental data. The δ-cell model of Watts et al [75] was used as the starting model. ( a ) The model was simulated under a Na + current inactivation voltage-step protocol ( V cond = −180 to 20 mV followed by a test pulse to 0 mV), and the evoked Na + current in the model (solid) was compared with the inward current experimentally recorded from a δ-cell under the same protocol (dashed).…”

“…The currents shown are in response to V cond = −150, −100, −60 and −20 mV. ( b ) Spiking behaviour generated by the model of Watts et al [75] with the reparametrized Na + current model (as shown in a ) and C cell = 4 pF was compared with the original, unaltered δ-cell model by Watts et al [75]. Note that action potentials evoked in the improved model overshoot 0 mV, have short duration and also have a pronounced after-hyperpolarization (arrows; owing to the A-type K + current), as seen in the experimental action potentials recorded from a δ-cell under the perforated patch-clamp configuration ( c ).…”

“…Conductance-based mathematical models of the electrical activity of α-cells have provided us with invaluable insights into the mechanisms regulating glucagon secretion [72–75]. However, parameters used in these models were based on presumptive α-cells identified by traditional electrophysiological criteria [3,29,31,35,38,46], which we have shown here to be inaccurate.…”

“…Recently, Watts et al [75] generated a conductance-based model of a δ-cell for studying the dynamical interactions between cell types, but this was a modified version of an α-cell model [75]. We therefore developed a model of δ-cell electrical activity, constrained to our experimental data for δ-cells (figure 10 and appendix C).…”

Postprandial Suppression of Glucagon Secretion: A Puzzlement

“…1-Some controls of glucagon secretion that may be involved in glucagon nonsuppression or tonically increased fasting glucagon levels in insulin resistance or diabetes (note that receptor mechanisms are not shown). As reviewed in detail elsewhere (1)(2)(3)(4)(5)(26)(27)(28), nutrient, neural, endocrine, paracrine, and autocrine effects control glucagon secretion. The dynamic interactions among these controls are poorly understood.…”