Wortmannin, a PI3-Kinase Inhibitor: Promoting Effect on Insulin Secretion from Pancreatic β Cells through a cAMP-Dependent Pathway

Nunoi, Kumiko; Yasuda, Koichiro; Tanaka, Hisako; Kubota, Akira; Okamoto, Yoshimasa; Adachi, Tomohiko; Shihara, Nobuyuki; Uno, Masatoshi; Xu, Li; Kagimoto, Shinji; Seino, Yutaka; Yamada, Yoshio; Tsuda, Kinsuke

doi:10.1006/bbrc.2000.2514

Cited by 29 publications

(32 citation statements)

References 32 publications

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“…Our findings with isolated perifused rat islets confirm the observations made using mouse islets (38) or neonatal cultured rat islets (39): genistein is a potentiator of glucose-induced secretion. Furthermore, our findings also confirm previous studies in both rat (23,40) and mouse (41) islets as well as in MIN cells (42); wortmannin is a potentiator of glucose-induced secretion. Although it is known that these compounds may interfere with kinases not involved with insulin signaling and that these effects may complicate the interpretation of the data, the main point to be made is that these compounds significantly potentiated glucose-induced release.…”

Section: Discussionsupporting

confidence: 92%

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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Section: Discussionsupporting

confidence: 92%

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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“…Essentially identical consequences that wortmannin potentiated glucose-stimulated insulin secretion at intermediate glucose concentrations can be extracted from data by us and others (29,34,35). Wortmannin at 100 nmol/l potentiated 15-25 mmol/l glucose-stimulated insulin secretion by ϳ100% in MIN6 cells (29), which was in good agreement with our results.…”

Section: Discussionsupporting

confidence: 91%

“…Nevertheless, glucose-stimulated insulin release from ␤-cells was significantly increased at higher glucose concentrations. Wortmannin and another structurally distinct PI 3-kinase inhibitor, LY294002, also exhibited marked potentiation of glucose-stimulated insulin secretion at higher glucose concentrations, as was consistent with previous reports (29,34,35). Our data indicated that inhibition of PI 3-kinase activity did not interfere with the secretion-triggering pathway, including the increase in glucose oxidation, ATP content, or cytosolic [Ca 2ϩ ] in response to glucose, but it did exert its potentiating effect distal to cytosolic [Ca 2ϩ ] elevation, presumably through pathways that amplified efficacy of Ca 2ϩ in the presence of glucose metabolism.…”

supporting

confidence: 91%

“…To address these issues, we performed complementary experiments to analyze the effect of pharmacological inhibition of PI 3-kinase with wortmannin on glucosestimulated insulin secretion in wild-type islets, resulting in confirmation of previous reports (29,34,35). We first confirmed that wortmannin dose-dependently suppressed PI 3-kinase activities in wild-type islet homogenates (Fig.…”

Section: Moreover P85␣supporting

confidence: 80%

“…Thus, 100 nmol/l wortmannin had no effect on insulin secretion induced by basal concentration of glucose in HIT-T15 cells (33), and 50 -100 nmol/l wortmannin potentiated glucose-stimulated insulin secretion at higher glucose ranges in MIN6 cells (29); the same concentrations of wortmannin seemed to show no effect on secretion induced by glucose plus carbamyl choline in rat islets or ␤-TC3 cells (30). Very recently, two articles reported wortmannin's potentiating effect on glucose-stimulated insulin secretion at 8 -16.7 mmol/l glucose in rat islets (34,35). However, the mechanism of the potentiation has been elusive and a few experiments only suggested that inositol phosphate accumulation or protein kinase C activity in islets was not correlated with the phenomenon (35).…”

mentioning

confidence: 99%

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

et al. 2002

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The role of phosphatidylinositol (PI) 3-kinase in the regulation of pancreatic ␤-cell function was investigated. PI 3-kinase activity in p85␣ regulatory subunitdeficient (p85␣ ؊/؊ ) islets was decreased to ϳ20% of that in wild-type controls. Insulin content and mass of rough endoplasmic reticula were decreased in ␤-cells from p85␣؊/؊ mice with increased insulin sensitivity. However, p85␣؊/؊ ␤-cells exhibited a marked increase in the insulin secretory response to higher concentrations of glucose. When PI 3-kinase in wild-type islets was suppressed by wortmannin or LY294002, the secretion was also substantially potentiated. Wortmannin's potentiating effect was not due to augmentation in glucose metabolism or cytosolic [Ca 2؉ ] elevation. Results of p85␣ ؊/؊ islets and wortmannin-treated wildtype islets stimulated with diazoxide and KCl showed that inhibition of PI 3-kinase activity exerted its effect on secretion, at least in part, distal to a cytosolic [Ca 2؉ ] elevation. These results suggest that PI 3-kinase activity normally plays a crucial role in the suppression of glucose-stimulated insulin secretion. Diabetes 51: 87-97, 2002

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Role of Hypoxia-Inducible Factor (HIF) in the Initiation of Cancer and Its Therapeutic Inhibitors

Eda

Vadde

Rajeswari

2017

Role of Transcription Factors in Gastrointestinal Malignancies

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Wortmannin, a PI3-Kinase Inhibitor: Promoting Effect on Insulin Secretion from Pancreatic β Cells through a cAMP-Dependent Pathway

Cited by 29 publications

References 32 publications

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

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

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

Role of Hypoxia-Inducible Factor (HIF) in the Initiation of Cancer and Its Therapeutic Inhibitors

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