Phosphatidylinositol 3-Kinase Suppresses Glucose-Stimulated Insulin Secretion by Affecting Post-Cytosolic [Ca2+] Elevation Signals

Eto, Kazuhiro; Yamashita, Tetsuo; Tsubamoto, Yoshiharu; Terauchi, Yasuo; Hirose, Kenzo; Kubota, Naoto; Yamashita, Satoshi; Taka, Junko; Satoh, Shinobu; Sekihara, Hisahiko; Tobe, Kazuyuki; Iino, Masamitsu; Noda, Mitsuhiko; Kimura, Satoshi; Kadowaki, Takashi

doi:10.2337/diabetes.51.1.87

Cited by 74 publications

(73 citation statements)

References 81 publications

(93 reference statements)

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“…While -cell hyperplasia undoubtedly contributes to hyperinsulinemia in these genetically altered mice, this effect is variable and does not always correlate with the degree of hyperinsulinemia (Brüning et al 1997, Kido et al 2000. Most recently, Eto et al (2002) reported that islets isolated from mice deficient in the p85 regulatory subunit of PI3K exhibit augmented insulin secretory responses to glucose stimulation. These findings and the present studies suggest that a reduction in the negative feedback effect that insulin exerts upon its own secretion from the -cell (Iversen & Miles 1971, Ammon & Verspohl 1976, Liljenquist et al 1978, Ammon et al 1991 may play a role in their in vitro hypersensitivity to glucose and their in vivo development of hyperinsulinemia.…”

Section: Discussionmentioning

confidence: 99%

Inhibitors of phosphatidylinositol 3-kinase amplify insulin release from islets of lean but not obese mice

Zawalich

Tesz²,

Zawalich³

2002

Journal of Endocrinology

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We examined the effects of phosphatidylinositol 3-kinase (PI3K) inhibition by wortmannin or LY294002 on glucose-induced secretion from mouse islets. Islets were collagenase isolated and perifused or subjected to Western blot analyses and probed for insulin receptor-signaling components. In agreement with previous studies, mouse islets, when compared with rat islets, were minimally responsive to 10 mM glucose stimulation. The inclusion of 50 nM wortmannin or 10 µM LY294002 significantly amplified 10 mM glucose-induced release from mouse islets. The effect of wortmannin was abolished by the calcium channel antagonist nitrendipine or by lowering the glucose level to 3 mM. Wortmannin had no effect on 10 mM -ketoisocaproate-induced secretion. In contrast to its potentiating effect on islets from CD-1 mice, wortmannin had no effect on 10 mM glucose-induced release from ob/ob mouse islets. Western blot analyses revealed the presence of the insulin receptor, insulin receptor substrate proteins 1 and 2 and PI3K in CD-1 islets. These results support the concept that a PI3K-dependent signaling pathway exists in -cells and that it may function to restrain glucose-induced insulin secretion from -cells. They also suggest that, as insulin resistance develops in peripheral tissues, a potential result of impaired PI3K activation, the same biochemical anomaly in -cells promotes a linked increase in insulin secretion to maintain glucose homeostasis.

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Section: Discussionmentioning

confidence: 99%

Inhibitors of phosphatidylinositol 3-kinase amplify insulin release from islets of lean but not obese mice

Zawalich

Tesz²,

Zawalich³

2002

Journal of Endocrinology

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“…This hypothesis is consistent with findings made using knockout mice where insulin signaling has been disrupted and by pharmacologic inhibition of kinases thought to be involved in insulin signaling. For example, islets deficient in the insulin receptor substrate-2 protein or the p85␣ regulatory subunit of phosphatidylinositol 3-kinase hyper-respond to glucose stimulation (41,44). Of particular physiologic significance, perhaps, is the observation that basal secretion is not augmented from these ␤-cells.…”

Section: Discussionmentioning

confidence: 99%

Effects of Glucose, Exogenous Insulin, and Carbachol on C-peptide and Insulin Secretion from Isolated Perifused Rat Islets

Zawalich

2002

Journal of Biological Chemistry

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Isolated perifused rat islets were stimulated with glucose, exogenous insulin, or carbachol. C-peptide and, where possible, insulin secretory rates were measured. Glucose (8 -10 mM) induced dose-dependent and kinetically similar patterns of C-peptide and insulin secretion. The addition of 100 nM bovine insulin had no effect on C-peptide release in response to 8 -10 mM glucose stimulation. The addition of 100 nM bovine insulin or 500 nM human insulin together with 3 mM glucose had no stimulatory effect on C-peptide secretion rates from perifused rat islets. Stimulation with carbachol plus 7 mM glucose enhanced both C-peptide and insulin secretion, and the further addition of 100 nM bovine insulin had no inhibitory effect on C-peptide secretory rates under this condition. Perifusion studies using pharmacologic inhibitors (genistein and wortmannin) of the kinases thought to be involved in insulin signaling potentiated 10 mM glucose-induced secretion. The results support the following conclusions. 1) C-peptide release rates accurately reflect insulin secretion rates from collagenase-isolated, perifused rat islets. 2) Exogenously added bovine insulin exerts no inhibitory effect on release to several agonists including glucose. 3) In the presence of 3 mM glucose, exogenously added bovine or human insulin do not stimulate endogenous insulin secretion.Insulin secretion from the pancreatic ␤-cell is tightly regulated by stimulatory signals generated during the intracellular metabolism of glucose and by neurohumoral agonists operative at the cell membrane (1-5). Most recently an additional layer of complexity has been added by reports suggesting that insulin exerts an autocrine stimulatory effect on insulin secretion from the ␤-cell (6, 7). This concept was based primarily on amperometric measurements using ␤-cells preincubated in 5-hydroxytryptamine (5HT).1 Because 5HT exposure exerts inhibitory effects on insulin release (8 -10), the precise physiologic significance of findings made with 5HT-preloaded ␤-cells is unclear. Moreover, previous studies exploring the potential role of insulin on stimulated secretion showed no effect (11) or supported the concept that insulin exerts a negative, not positive, feedback on its own secretion (12-15).There are at least three major issues that must be addressed in attempting to establish the impact of exogenously added insulin on endogenous insulin secretory rates. The first is technical; it is difficult to accurately measure endogenous insulin release rates in the presence of exogenous insulin. The second relates to concentration of insulin necessary to establish an effect of exogenously added hormone on the ␤-cell. Considering that the ␤-cell continually releases insulin into a small volume of interstitial fluid, the level of insulin bathing the ␤-cell may be quite high. For example, calculations based on islet cell volume, the insulin diffusion constant and insulin secretory rates, suggest that these levels may exceed 100 nM during glucose stimulation (16). Even at rest, levels o...

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“…For example the ␤IRKO and IRS-2 Ϫ/Ϫ mouse models developed diminished islet insulin content (11,16,18,20). Similarly, PI3-kinase regulatory subunit-deficient mouse islets also exhibited diminished insulin content (10). Several studies of insulinoma cells as well as primary islet cultures reported that insulin content was positively regulated by insulin signaling (6,43,(55)(56)(57)(58).…”

Section: Con(e)mentioning

confidence: 99%

Reduced Expression of the Insulin Receptor in Mouse Insulinoma (MIN6) Cells Reveals Multiple Roles of Insulin Signaling in Gene Expression, Proliferation, Insulin Content, and Secretion

Ohsugi

Cras-Méneur

Zhou

et al. 2005

Journal of Biological Chemistry

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The role of insulin signaling in pancreatic ␤ cells has become increasingly apparent. Stably transformed insulinoma cell lines (MIN6) were created with small interfering RNA resulting in the reduction of insulin receptor (IR) expression up to 80% (insulin receptor knockdown, IRKD⌬80). Functionally perturbed IR signaling was confirmed with the absence of insulin-stimulated insulin receptor substrate 1 tyrosine phosphorylation. Additionally, Akt phosphorylation was reduced and responded poorly to glucose stimulation. Gene expression profiling revealed that reduced IR expression was associated with alterations in expression of >1,500 genes with diverse functions. IRKD cells exhibited low rate of proliferation due to delay in transition from G 0 /G 1 to S phase, whereas susceptibility to apoptosis did not differ from that of control cells. Insulin content was reduced in proportion to the reduction of IR. IRKD cells maintained glucose responsiveness as measured by NAD(P)H generation, whereas Ca 2؉ responses and insulin secretion were enhanced. IRKD⌬80 and control cells were treated with glucose (25 mM) or insulin (100 nM) for 45 min, and gene expression profiles were assessed. Transcriptional activation of several hundred early response genes common to both glucose and insulin stimulation was observed in control cells. In IRKD⌬80 cells, insulin failed to activate any genes as anticipated. Importantly, glucose stimulation of gene expression in IRKD⌬80 cells showed that most genes previously activated by glucose were no longer activated, suggesting a major autocrine/paracrine effect of insulin on glucoseregulated gene expression. On the other hand, there were a number of glucose-regulated genes in the IRKD⌬80 cells that were not previously observed in control cells, suggesting a feedback regulation of insulin signaling on glucose-regulated gene expression. These results demonstrate important roles of the insulin receptor in islet ␤ cell gene expression and function and may serve to elucidate molecular defects in animal models with diminished ␤ cell insulin signaling.Pancreatic ␤ cells dynamically adapt to their environment (1, 2). Changes in plasma glucose concentration along with various hormones and growth factors have been shown to be major determinants of insulin secretion, biosynthesis, and islet mass (3, 4). The islet ␤ cell responds to these changes in its environment by altering its transcriptional responses, and these changes in gene expression ultimately result in altered mass and function. However, the signaling pathways activated by these environmental changes and the ensuing transcriptional events that mediate these biological responses are only beginning to be elucidated. Specifically, the relationships between the signaling pathways activated by glucose and those activated by growth factors such as insulin remain unclear.The roles of insulin as a growth factor in the modulation of ␤ cell mass and function have been implied by the results of recent experiments. Glucose stimulation of ␤ cells in culture ha...

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Phosphatidylinositol 3-Kinase Suppresses Glucose-Stimulated Insulin Secretion by Affecting Post-Cytosolic [Ca2+] Elevation Signals

Cited by 74 publications

References 81 publications

Inhibitors of phosphatidylinositol 3-kinase amplify insulin release from islets of lean but not obese mice

Inhibitors of phosphatidylinositol 3-kinase amplify insulin release from islets of lean but not obese mice

Effects of Glucose, Exogenous Insulin, and Carbachol on C-peptide and Insulin Secretion from Isolated Perifused Rat Islets

Reduced Expression of the Insulin Receptor in Mouse Insulinoma (MIN6) Cells Reveals Multiple Roles of Insulin Signaling in Gene Expression, Proliferation, Insulin Content, and Secretion

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