Phosphoinositides Turnover and Insulin Secretion in Pancreatic Islets

Cheng, Po‐Yuan; Yasuda, Hiroko; Katori, Tokue; Oka, Hiroshi

doi:10.1507/endocrj1954.34.189

Cited by 3 publications

(2 citation statements)

References 13 publications

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“…Thus, the absolute and relative (% of maximal) accelerations of 86Rb+ efflux by 0.1,IM-ACh were more than twice as large in the absence as in the presence of Ca2l. inositol and then perifused under conditions similar to ours is an index of phosphatidylinositol breakdown [26][27][28][29]. Our results show that the acceleration of 3H efflux by ACh was dose-dependent, and confirm that it is only partially inhibited by omission of extracellular Ca2+ [28].…”

Section: Discussionsupporting

confidence: 79%

“…3H efflux from islets preloaded with myo- [2-3H]inositol was measured in the same system by using batches of 50 islets for each experiment, after 2 h of loading with the tracer. Previous studies [26][27][28][29] have shown that the 3H-labelled products released from islets preloaded with myo-[2-3H]inositol consist of free inositol (> 70 %) and inositol phosphates. Those four studies concluded that the acceleration of 3H efflux brought about by several secretagogues, including muscarinic agonists [28], reflects phosphoinositide breakdown.…”

Section: Egtamentioning

confidence: 99%

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Glucose-, calcium- and concentration-dependence of acetylcholine stimulation of insulin release and ionic fluxes in mouse islets

García¹,

Hermans²,

Henquin³

1988

Biochemical Journal

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Mouse islets were used to define the glucose-dependence and extracellular Ca2+ requirement of muscarinic stimulation of pancreatic beta-cells. In the presence of a stimulatory concentration of glucose (10 mM) and of Ca2+, acetylcholine (0.1-100 microM) accelerated 3H efflux from islets preloaded with myo-[3H]inositol. It also stimulated 45Ca2+ influx and efflux, 86Rb+ efflux and insulin release. In the absence of Ca2+, only 10-100 microM-acetylcholine mobilized enough intracellular Ca2+ to trigger an early but brief peak of insulin release. At a non-stimulatory concentration of glucose (3 mM), 1 microM- and 100 microM-acetylcholine increased 45Ca2+ and 86Rb+ efflux in the presence and absence of extracellular Ca2+. However, only 100 microM-acetylcholine marginally increased 45Ca2+ influx and caused a small, delayed, stimulation of insulin release, which was abolished by omission of Ca2+. At a maximally effective concentration of glucose (30 mM), 1 microM- and 100 microM-acetylcholine increased 45Ca2+ influx and efflux only slightly, but markedly amplified insulin release. Again, only 100 microM-acetylcholine mobilized enough Ca2+ to trigger a peak of insulin release in the absence of Ca2+. The results thus show that only high concentrations of acetylcholine (greater than or equal to 10 microM) can induce release at low glucose or in a Ca2+-free medium. beta-Cells exhibit their highest sensitivity to acetylcholine in the presence of Ca2+ and stimulatory glucose. Under these physiological conditions, the large amplification of insulin release appears to be the result of combined effects of the neurotransmitter on Ca2+ influx, on intracellular Ca2+ stores and on the efficiency with which Ca2+ activates the releasing machinery.

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Section: Discussionsupporting

confidence: 79%

Section: Egtamentioning

confidence: 99%

Glucose-, calcium- and concentration-dependence of acetylcholine stimulation of insulin release and ionic fluxes in mouse islets

García¹,

Hermans²,

Henquin³

1988

Biochemical Journal

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Muscarinic Control of Pancreatic B Cell Function Involves Sodium-Dependent Depolarization and Calcium Influx*

et al. 1988

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Mouse pancreatic islets were used to investigate the mechanisms and functional significance of the B cell membrane depolarization by acetylcholine (ACh). At low glucose (3mM), ACh (20 microM) increased 22Na+ influx, and slightly depolarized the B cell membrane but did not induce electrical activity or stimulate 45Ca2+ influx. ACh also accelerated 86Rb+ and 45Ca2+ efflux and barely affected basal insulin release. At a stimulatory concentration of glucose (10 mM), ACh stimulated 22Na+ influx, depolarized the B cell membrane, increased glucose-induced electrical activity, and stimulated 45Ca2+ influx. ACh also accelerated 86Rb+ and 45Ca2+ efflux and strongly potentiated insulin release. Omission of extracellular Ca2+ did not impair ACh stimulation of 22Na+ influx or 86Rb+ efflux, slightly modified the acceleration of 45Ca2+ efflux, and almost completely suppressed the increase in insulin release. Na+ omission (with N-methyl-D-glucamine as substitute) prevented the B cell membrane depolarization and the stimulation of 45Ca2+ influx, largely inhibited the acceleration of 86Rb+ efflux and insulin release, and suppressed the late phase of 45Ca2+ efflux otherwise produced by ACh. On the other hand, ACh stimulation of 3H efflux from islets prelabeled with myo-[2-3H]inositol was not affected by Na+ omission. All effects of ACh were blocked by atropine and unaffected by nicotinic antagonists. It is concluded that activation of muscarinic receptors depolarized the B cell membrane by increasing its permeability to Na+. When the membrane is already depolarized by glucose, this further depolarization augments Ca2+ influx and, hence, potentiates insulin release.

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Membrane Phosphoinositides Control Insulin Secretion Through Their Effects on ATP-Sensitive K+ Channel Activity

et al. 2005

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ATP-sensitive K؉ channels (K ATP channels) of pancreatic ␤-cells play key roles in glucose-stimulated insulin secretion by linking metabolic signals to cell excitability. Membrane phosphoinositides, in particular phosphatidylinositol 4,5-bisphosphates (PIP 2 ), stimulate K ATP channels and decrease channel sensitivity to ATP inhibition; as such, they have been postulated as critical regulators of K ATP channels and hence of insulin secretion in ␤-cells. Here, we tested this hypothesis by manipulating the interactions between K ATP channels and membrane phospholipids in a ␤-cell line, INS-1, and assessing how the manipulations affect membrane excitability and insulin secretion. We demonstrate that disruption of channel interactions with PIP 2 by overexpressing PIP 2 -insensitive channel subunits leads to membrane depolarization and elevated basal level insulin secretion at low glucose concentrations. By contrast, facilitation of channel interactions with PIP 2 by upregulating PIP 2 levels via overexpression of a lipid kinase, phosphatidylinositol 4-phosphate 5 kinase, decreases the ATP sensitivity of endogenous K ATP channels by ϳ26-fold and renders INS-1 cells hyperpolarized, unable to secrete insulin properly in the face of high glucose. Our results establish an important role of the interaction between membrane phosphoinositides and K ATP channels in regulating insulin secretion. Diabetes 54:2852-2858, 2005 P ancreatic ␤-cells secrete insulin in response to glucose stimulus. The ATP-sensitive K ϩ (K ATP ) channel, a complex of four inwardly rectifying K ϩ channel Kir6.2 subunits and four sulfonylurea receptor 1 (SUR1) subunits, is a key component in this stimulus-secretion coupling process (1-3). The hallmark features of K ATP channels are their sensitivities to intracellular nucleotides ATP and ADP, the derivatives of glucose metabolism (1,2). ATP inhibits channel activity, whereas ADP, in complex with Mg 2ϩ , stimulates channel activity. It is now generally accepted that the physiological activity of K ATP channels is regulated primarily by the relative concentrations of ATP and ADP (1,4,5). As plasma glucose increases, ATP concentration increases and ADP concentration decreases, resulting in K ATP channel closure, membrane depolarization, Ca 2ϩ influx, and insulin release. Conversely, when glucose decreases, the concentration ratio of ATP to ADP decreases, leading to K ATP channel opening, membrane hyperpolarization, and termination of insulin secretion. The importance of ATP and ADP in regulating K ATP channels in vivo has been confirmed by the finding that mutations that reduce channel sensitivity to ATP or MgADP are causative in permanent neonatal diabetes or congenital hyperinsulinism, respectively (5-9).The discovery that membrane phosphoinositides, in particular the most abundant phosphoinositide phosphatidylinositol 4,5-bisphosphate (PIP 2 ) (10), stimulate K ATP channel activity and antagonize the inhibitory effect of ATP in isolated membrane patches (11,12) has led to the proposal that in addition ...

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Phosphoinositides Turnover and Insulin Secretion in Pancreatic Islets

Cited by 3 publications

References 13 publications

Glucose-, calcium- and concentration-dependence of acetylcholine stimulation of insulin release and ionic fluxes in mouse islets

Glucose-, calcium- and concentration-dependence of acetylcholine stimulation of insulin release and ionic fluxes in mouse islets

Muscarinic Control of Pancreatic B Cell Function Involves Sodium-Dependent Depolarization and Calcium Influx*

Membrane Phosphoinositides Control Insulin Secretion Through Their Effects on ATP-Sensitive K+ Channel Activity

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