Signaling Underlying Pulsatile Insulin Secretion

Gylfe, Erik; Ahmed, Manzur; Bergsten, Peter; Dansk, Heléne; Dyachok, Oleg; Eberhardson, Michael; Grapengiesser, Eva; Hellman, Bo; Jm, Lin; Sundsten, Tea; Tengholm, Anders; Vieira, Elaine; Westerlund, Johanna

doi:10.1517/03009734000000054

Cited by 20 publications

(21 citation statements)

References 81 publications

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“…Insulin released from the pancreas (33) and from individual islets is pulsatile (2). Measurements of [Ca 2ϩ ] i (34) and of Zn 2ϩ co-released from the insulin secretory granules (35) indicate that isolated ␤-cells also show pulsatile secretory activity.…”

Section: Discussionmentioning

confidence: 99%

“…: 46-18-4714481; Fax: 46-18-4714059; E-mail: anders.tengholm@mcb.uu.se. 2 The abbreviations used are: [Ca 2ϩ ] i , cytoplasmic Ca 2ϩ concentration; PI3-kinase, phosphatidylinositol 3Ј-OH-kinase; PIP 3 , phosphatidylinositol 3,4,5-trisphosphate; PH, pleckstrin homology; GFP, green fluorescent protein; GFP-PH Akt , pleckstrin homology domain from Akt fused to GFP; GRP1, general receptor for phosphoinositides-isoform 1. …”

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confidence: 99%

“…The resulting depolarization activates voltage-dependent Ca 2ϩ influx, which triggers exocytosis of the insulin secretory granules (1). The elevation of the cytoplasmic Ca 2ϩ concentration ([Ca 2ϩ ] i ) 2 is often periodic, and coordination of [Ca 2ϩ ] i oscillations among ␤-cells is considered to account for the pulsatile release of insulin observed in healthy subjects (2).…”

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Glucose and Insulin Synergistically Activate Phosphatidylinositol 3-Kinase to Trigger Oscillations of Phosphatidylinositol 3,4,5-Trisphosphate in β-Cells

Idevall‐Hagren

Tengholm

2006

Journal of Biological Chemistry

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In insulin-secreting ␤-cells, activation of phosphatidylinositol 3-OH-kinase with resulting formation of phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) has been implicated in the regulation of ion channels, insulin secretion, and gene transcription as well as in cell growth and survival, but the kinetics of PIP 3 signals following physiological stimulation of insulin secretion is unknown. Using evanescent wave microscopy and a green fluorescent protein-tagged PIP 3 -binding protein domain for real-time monitoring of plasma membrane PIP 3 concentration in single MIN6 ␤-cells, we now demonstrate that glucose stimulation of insulin secretion results in pronounced PIP 3 oscillations via autocrine stimulation of insulin receptors. Glucose lacked effect when insulin secretion was prevented with the hyperpolarizing agent diazoxide, but the sugar dose dependently enhanced the PIP 3 response to maximal insulin stimulation without affecting the rate of PIP 3 degradation. We conclude that glucose is an important co-activator of phosphatidylinositol-3-OH-kinase and that the plasma membrane PIP 3 concentration in ␤-cells undergoes oscillations due to pulsatile release of insulin.Insulin is secreted from pancreatic ␤-cells in response to an elevation of the plasma glucose concentration. The rapid uptake and metabolism of the sugar leads to an increase of the ATP/ADP ratio and closure of ATP-sensitive K ϩ channels in the plasma membrane. The resulting depolarization activates voltage-dependent Ca 2ϩ influx, which triggers exocytosis of the insulin secretory granules (1). The elevation of the cytoplasmic Ca 2ϩ concentration ([Ca 2ϩ ] i ) 2 is often periodic, and coordination of [Ca 2ϩ ] i oscillations among ␤-cells is considered to account for the pulsatile release of insulin observed in healthy subjects (2).In addition to endocrine stimulation of glucose uptake and storage in liver, muscle, and adipose tissue, insulin has autocrine effects on ␤-cells, regulating proliferation, survival, insulin synthesis, and secretion. Insulin has been reported to have both stimulatory (3-7) and inhibitory (8 -12) feedback effects on ␤-cells. Because some of the discordant observations may depend on different times allowed for insulin action, it is important to characterize the kinetics of insulin receptor-induced signaling events.Binding of insulin to its receptor is associated with receptor autophosphorylation and tyrosine phosphorylation of insulinreceptor substrate (IRS) proteins and other adapter molecules (13-15), which in turn leads to activation of the phosphatidylinositol 3Ј-OH-kinase (PI3-kinase) (16) and Ras-mitogen-activated protein kinase (17) pathways. PI3-kinase catalyzes formation of the membrane phospholipid phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ), which is an important regulator of ion channels (18), protein kinases, and guanine nucleotide exchange factors (19,20).Glucose is known to activate PI3-kinase in ␤-cells, an effect that has been attributed to autocrine activation of insulin receptors by secreted in...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Glucose and Insulin Synergistically Activate Phosphatidylinositol 3-Kinase to Trigger Oscillations of Phosphatidylinositol 3,4,5-Trisphosphate in β-Cells

Idevall‐Hagren

Tengholm

2006

Journal of Biological Chemistry

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“…First, although [Ca 2ϩ ] i was found to oscillate in individual ␤-cells from Cx36 Ϫ/Ϫ mice, the islets of these animals no longer showed the synchronous oscillations of [Ca 2ϩ ] i that normally occur during glucose stimulation (17)(18)(19)(20)(21)(22). These oscillations are caused by a depolarizationmediated, periodic influx of Ca 2ϩ into ␤-cells (22,23), as shown by their temporal relation with membrane potential changes (17,21) and their abolition by the omission of extracellular Ca 2ϩ , blockers of L-type Ca 2ϩ channels, or membrane repolarization (17,22). Synchronization of glucose-induced oscillations of membrane potential (4), and hence of [Ca 2ϩ ] i oscillations (17,23), has been attributed to the electrical coupling of ␤-cells connected by gap junctions.…”

Section: Gap Junctions and ␤-Cellsmentioning

confidence: 99%

Loss of Connexin36 Channels Alters β-Cell Coupling, Islet Synchronization of Glucose-Induced Ca2+ and Insulin Oscillations, and Basal Insulin Release

Ravier¹,

Güldenagel

Charollais³

et al. 2005

Diabetes

345

444

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“…Since this coordination occurs in the absence of external neuronal input to the pancreas but can be temporarily disrupted by neurotransmitters, it was early suggested to involve coordination by intrapancreatic neurons (Stagner et al, 1980). Later experiments confirmed that pulsatile secretion is prevented by neural blockade (Stagner and Samols, 1985a;Gylfe et al, 2000). However, the neurons involved do not seem to be adrenergic or cholinergic (Stagner and Samols, 1985b).…”

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Oscillatory control of insulin secretion

Tengholm

Gylfe

2009

Molecular and Cellular Endocrinology

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163

169

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Pulsatile insulin secretionSince insulin is the only blood glucose-lowering hormone, its secretion is essential for glucose homeostasis, and disturbances are associated with glucose intolerance and diabetes.Glucose is the major stimulus for insulin release but secretion is enhanced also by other nutrients and is under stimulatory and inhibitory control by hormones and neurotransmitters.Although the external factors are essential determinants of insulin secretion, there are also input-independent variations in hormone release. Regular oscillations of the circulating insulin concentrations in normal subjects consequently occur without accompanying changes

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Signaling Underlying Pulsatile Insulin Secretion

Cited by 20 publications

References 81 publications

Glucose and Insulin Synergistically Activate Phosphatidylinositol 3-Kinase to Trigger Oscillations of Phosphatidylinositol 3,4,5-Trisphosphate in β-Cells

Glucose and Insulin Synergistically Activate Phosphatidylinositol 3-Kinase to Trigger Oscillations of Phosphatidylinositol 3,4,5-Trisphosphate in β-Cells

Loss of Connexin36 Channels Alters β-Cell Coupling, Islet Synchronization of Glucose-Induced Ca2+ and Insulin Oscillations, and Basal Insulin Release

Oscillatory control of insulin secretion

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