Metabolic amplifying pathway increases both phases of insulin secretion independently of β-cell actin microfilaments

Abstract

]c was elevated and controlled by KCl or tolbutamide, the amplifying action of glucose was facilitated by actin depolymerization and unaffected by polymerization. Both phases of IS were larger in response to high-glucose than to tolbutamide in low-glucose, although triggering [Ca 2ϩ ]c was lower. This difference in IS, due to amplification, persisted when the IS rate was doubled by actin depolymerization or polymerization. In conclusion, metabolic amplification is rapid and influences the first as well as the second phase of IS. It is a late step of stimulus-secretion coupling, which does not require functional actin microfilaments and could correspond to acceleration of the priming process conferring release competence to insulin granules. biphasic insulin release; cytosolic calcium; exocytosis; insulin granules; pancreatic islets THE RATE OF INSULIN SECRETION by pancreatic ␤-cells is controlled by a hierarchical interaction among circulating nutrients, hormones, and neurotransmitters. The preeminent influence of glucose itself is exerted via two signaling pathways that both require metabolism of the sugar in ␤-cells (1, 11, 39). In the triggering pathway, closure of ATP-sensitive potassium (K ATP ) channels by adenine nucleotides permits membrane depolarization, which leads to Ca 2ϩ influx through voltagegated calcium channels and results in an increase in the cytosolic free Ca 2ϩ concentration ([Ca 2ϩ ] c ) that eventually triggers exocytosis of insulin granules. Simultaneously, glucose activates a metabolic amplifying pathway that does not involve additional action on K ATP channels or further rise in [Ca 2ϩ ] c but that augments the secretory response to the triggering Ca 2ϩ signal (14). The cellular mechanisms and effectors of this amplification have not yet been identified.During a hyperglycemic clamp, the increase in plasma insulin concentration is biphasic in humans (4) and rodents (13,29). In vitro, when a perfused pancreas or perifused isolated islets are challenged by an abrupt and steady increase in the glucose concentration, the acceleration of insulin secretion follows a biphasic pattern with a prominent rapid first phase and a sustained second phase (6,12,13,39,54). The mechanisms underlying the biphasic kinetics of insulin secretion are incompletely elucidated and probably involve both the time course of intracellular signals and the distribution of insulin granules in distinct pools (12,27,30,35,41,50). The first phase is commonly attributed to Ca 2ϩ -induced exocytosis of insulin granules from a limited pool of docked (tethered to the plasma membrane) and primed (release competent) granules. In contrast, the second phase is thought to involve functional recruitment or physical translocation of granules to the exocytotic sites. The characteristics and localization of this or these reserve pool(s) are still disputed (3,16,19,31,35,38). However, the general view holds that the amplifying action of glucose is necessary for the second phase but not involved in the first phase.Most actin micro...

Actin Dynamics Regulated by the Balance of Neuronal Wiskott-Aldrich Syndrome Protein (N-WASP) and Cofilin Activities Determines the Biphasic Response of Glucose-induced Insulin Secretion

“…This may account for the characteristic dynamics of first phase of GIIS, which occurs rapidly, massively, and transiently. Indeed, actin-depolymerizing agents such as cytochalasin B and latrunculin B sustain massive insulin secretion from perifused pancreatic islets during application (23,45,57). It is also established that insulin is immediately, massively, and transiently secreted by K ϩ stimulation (6,8).…”

“…It was also reported that cytochalasin E and Clostridium botulinum C2 toxin, which are F-actin-depolymerizing agents, decrease insulin secretion (22). More recently, latrunculin B, which binds to G-actin and leads to F-actin depolymerization, was shown to potentiate GIIS (23). It was also reported that F-actin is not essential in the metabolic amplifying pathway of GIIS, using cytochalasin B, latrunculin B, and jasplakinolide (23).…”

“…More recently, latrunculin B, which binds to G-actin and leads to F-actin depolymerization, was shown to potentiate GIIS (23). It was also reported that F-actin is not essential in the metabolic amplifying pathway of GIIS, using cytochalasin B, latrunculin B, and jasplakinolide (23). These disparate findings on the role of F-actin in insulin secretion may partly be due to limitation of the pharmacological approach.…”

Monoacylglycerol as a Metabolic Coupling Factor in Glucose-Stimulated Insulin Secretion

“…F-actin negatively regulates exocytosis via binding and blocking Syntaxin 4 accessibility (Jewell et al, 2008). But further studies indicate that metabolic amplifying pathway increases both phases of insulin secretion and is independent on actin microfilaments (Mourad et al, 2010).…”

Involvement of actin filament in the generation of Ca2+mobilizing messengers in glucose-induced Ca2+signaling in pancreatic β-cells

“…[26][27][28] An experiment using intact islets shows that the increase in insulin secretion produced by actin (de)polymerizing drugs was not accompanied by an increase in [Ca 2+ ] i . 29 These findings suggest that actin remodeling affects insulin secretion by mechanisms dissociated from the rise in [Ca 2+ ] i .…”