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Electrophysiology of secretion modulation by various neuroendocrine cells of clinical importance: the pancreatic â-cell and enteroendocrine L and K cells

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Electrophysiology of secretion modulation by various neuroendocrine cells of clinical importance: the pancreatic �-cell and enteroendocrine L and K cells I. Introduction The prospect of using gene therapy to treat type 1, or insulin-dependent diabetes (IDD) has caused considerable excitement in the area of diabetes research. In patients with IDD, autoimmune attack has destroyed the �-cells that normally reside in the pancreatic islets and mediate glucose homeostasis by secreting insulin. Treatment of IDD by islet transplantation of cadaver tissue or xenogenic islets has been unsuccessful due to immune rejection either by the recognition of �-cell-specific antigens (that led to the initial development of IDD) or of foreign antigens. Another challenge to islet transplantation is the highly limited number of donor pancreases. To circumvent these hurdles, tissue engineers must look toward autologous, non-�-cell sources as targets for gene therapy. The precise dynamic control of secretion from any cell-engineered solution is crucial to achieving the fine control required to maintain homeostasis. The �-cell responds within minutes to increases in plasma glucose levels and is equally as efficient at down-regulating this process once euglycemia has been reached. This signature function of regulated secretion in response to nutrient-sensing has also been demonstrated in enteroendocrine cells[1], specialized cells of the gut epithelium, making enteroendocrine cells the subject of intense current research. Expressing insulin in these surrogate �-cells has shown promise but the dynamics of the insulin response have been sluggish and poorly characterized in comparison with the quintessential �-cell[2]. Thus, in trying to reproduce this superb glucose control system, a clear understanding of how the molecular properties of its ion channels and the cellular processes are involved in the generation and control of insulin secretion. ...read more.


This is close to the equilibrium potential for K+ and, as expected ion substitutions revealed that K+ permeability through metabolically-sensitive K channels governs the maintenance of resting membrane potential and the initiation of depolarization. Experimental evidence showed a reduced 42K+ efflux from isolated islets stimulated with glucose which corresponded to an increase in membrane resistance and increased secretion (Howell & Taylor, 1968). Three lines of evidence established the underlying role of metabolism in glucose sensitivity (presumably of K channels). First, Na azide and 2,4-dinitrophenol (known metabolic uncouplers) caused hyperpolarization and ended insulin secretion. Non-metabolized glucose derivatives could not induce depolarization. Finally, non-glucose metabolic intermediates (i.e. leucine and ?-ketoisocaproate) could induce electric activity[9]. Action Potential Generation Biphasic electrical responses were induced by a step increase in glucose concentrations from 2.8 to 11mM causing depolarization to the -50 mV threshold. The first phase was a prolonged period of action potential firing at a plateau of -35 mV. Then, steady-state activity, known as bursting, takes over in which membrane potential oscillates between a silent phase (membrane potential just below threshold) and active phase with typical magnitude of spikes between 10 to 20 mV in magnitude. Varying glucose concentrations can alter the relative lengths of the active plateaus and silent phases. Although the mechanism underlying bursting remains controversial, it is clear that a number of coordinated interactions between �-cell ion channels are required. The electrophysiological components so far identified in the �-cell include a number of different channels that maintain the balance of outward and inward currents of the K+, Ca2+, and other physiologically relevant ions. ...read more.


Increasing concentrations between 0-20 mmol/l decreased the membrane conductance, caused membrane depolarization, and triggered the generation of action potentials[14]. Action potentials were also triggered by tolbutamide (500umol/l) and suppressed by diazoxide (340umol.l) or the metabolic inhibitor azide (3 mmol/l), suggesting the involvement of KATP channels. Development of large tolbutamide-sensitive washout currents in whole cell recordings confirms the presence of KATP channels[14]. Due to the large number of similarity, the authors suggested that the stimulus-secretion pathways in L-cells and B-cells share common glucose-sensing machinery. Although it is unlikely that glucose normally acts on L cells and so must activate the release of GLP-1 by means other than a direct effect. Fatty acids, on the other hand, may act directly on the L cells [15]. Far less is known about the enteroendocrine K cells which produce glucose-dependent insulinotropic peptide (GIP) due to difficulties in isolating large numbers of pure K cells. K cells are located primarily in the duodenum an ideal place for regulation by nutrients. Indeed GIP is released rapidly in response to ingestion of nutrients which are thought to act directly on the K cells[15]. It has been suggested that many of the factors regulating hormone production and secretion, as well as timing of the peptide release are remarkably similar to those of �-cells[16]. Glyceraldehyde and methyl-pyruvate were secretagogues, indicating cells depolarized in response to changes in intracellular metabolite level[16]. Interestingly, K channel-opening drugs and sulphonylureas had little effect on insulin secretion by K cells suggesting that secretion is independent of KATP channels[16]. Obvious promise exists in using these cell types for therapies of diabetes yet much work remains to be done in characterizing their electrical behavior and stimulus-secretion mechanism and dynamics. ...read more.

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