Cyclic AMP Phosphodiesterases of Human and Rat Islets of Langerhans: Contributions of Types III and IV to the Modulation of Insulin Secretion

Parker, Janice C.; Vanvolkenburg, Maria A.; Ketchum, R.J.; Brayman, Kenneth L.; Andrews, Kim

doi:10.1006/bbrc.1995.2858

Cited by 53 publications

(55 citation statements)

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“…Effects of Overexpression of PDE3B on Glucose-stimulated Insulin Secretion-Previous work has indicated that inhibition of PDE3 activity does not affect basal insulin release from islets kept in non-stimulatory (3 mM) glucose concentration, although it enhances insulin release in the presence of high (8 mM) glucose (34). We therefore initially examined, in static incubations, the effects of PDE3B overexpression on glucose-induced insulin secretion.…”

Section: Resultsmentioning

confidence: 99%

Important Role of Phosphodiesterase 3B for the Stimulatory Action of cAMP on Pancreatic β-Cell Exocytosis and Release of Insulin

Härndahl¹,

Jing²,

Ivarsson³

et al. 2002

Journal of Biological Chemistry

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Cyclic AMP potentiates glucose-stimulated insulin release and mediates the stimulatory effects of hormones such as glucagon-like peptide 1 (GLP-1) on pancreatic ␤-cells. By inhibition of cAMP-degrading phosphodiesterase (PDE) and, in particular, selective inhibition of PDE3 activity, stimulatory effects on insulin secretion have been observed. Molecular and functional information on ␤-cell PDE3 is, however, scarce. To provide such information, we have studied the specific effects of the PDE3B isoform by adenovirus-mediated overexpression. In rat islets and rat insulinoma cells, approximate 10-fold overexpression of PDE3B was accompanied by a 6 -8-fold increase in membrane-associated PDE3B activity. The cAMP concentration was significantly lowered in transduced cells (INS-1(832/13)), and insulin secretion in response to stimulation with high glucose (11.1 mM) was reduced by 40% (islets) and 50% (INS-1). Further, the ability of GLP-1 (100 nM) to augment glucose-stimulated insulin secretion was inhibited by ϳ30% (islets) and 70% (INS-1). Accordingly, when stimulating with cAMP, a substantial decrease (65%) in exocytotic capacity was demonstrated in patch-clamped single ␤-cells. In untransduced insulinoma cells, application of the PDE3-selective inhibitor OPC3911 (10 M) was shown to increase glucose-stimulated insulin release as well as cAMP-enhanced exocytosis. The findings suggest a significant role of PDE3B as an important regulator of insulin secretory processes.

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Section: Resultsmentioning

confidence: 99%

Important Role of Phosphodiesterase 3B for the Stimulatory Action of cAMP on Pancreatic β-Cell Exocytosis and Release of Insulin

Härndahl¹,

Jing²,

Ivarsson³

et al. 2002

Journal of Biological Chemistry

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“…Tissue-specific expression of 11 families of phosphodiesterase isozymes has been reported [47]. Pancreatic beta cells predominantly express phosphodiesterase 3 and phosphodiesterase 4 [48]. Therefore we used cilostamide and rolipram, inhibitors of phosphodiesterase 3 and 4 respectively, to sustain exendin-4-mediated cyclic AMP levels (Fig.…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

et al. 2010

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Aims/hypothesis Exendin-4, a glucagon-like peptide-1 (GLP-1) analogue, is reported to have modest antiinflammatory effects in addition to that of improving beta cell survival. We therefore sought to determine whether exendin-4 decreases expression of the gene encoding chemokine (C-X-C motif) ligand (CXCL)10, which plays a role in initiating insulitis in type 1 diabetes. Methods The expression of CXCL10 in human islets was determined at the mRNA level by real-time RT-PCR analysis and at the protein level by western blotting. The level of CXCL10 in culture medium was measured by ELISA. Pathway-specific gene expression profiling was carried out to determine the expression of a panel of genes encoding chemokines and cytokines in human islets exposed to cytokines. Results IFN-γ induced expression of CXCL10 through activation of signal transducer and activator of transcription-1 (STAT-1). A combination of cytokines (IL-1β, TNF-α and IFN-γ) showed strong synergy in the induction of numerous chemokines and cytokines through nuclear factor kappa B and STAT-1. Exendin-4 suppressed basal expression of several inflammatory mediators. In combination with phosphodiesterase inhibitors, exendin-4 also decreased IFN-γ-induced CXCL10 expression in human islets and in MIN6 cells (a mouse beta cell line), and its secretion into the culture medium. Exendin-4 action was mimicked by forskolin, an activator of adenylyl cyclase, and by dibutyryl cyclic AMP. Protein kinase A was not involved in mediating exendin-4 action on CXCL10. The mechanism of exendin-4's anti-inflammatory action involved decreases in STAT-1 levels. Conclusions/interpretation These findings suggest that the GLP-1-cyclic AMP pathway decreases islet inflammation in addition to its known effects on beta cell survival.

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“…The anti-insulin monoclonal antibody was from Sigma. The anti-IGF-1 receptor and anti-insulin receptor antibodies were from Santa Cruz Biotechnology; both antibodies were raised against the N-terminal unique sequences (amino acids [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] of the corresponding receptor. IGF-1 was from Becton Dickinson or GIBCO͞BRL.…”

Section: Methodsmentioning

confidence: 99%

“…13). Interestingly though, only the specific pharmacological inhibitors for PDE3 will actually potentiate insulin secretion (12,14). These data suggest a possible functional importance for a PDE3 isozyme in the regulation of insulin secretion from pancreatic islets.…”

mentioning

confidence: 96%

Attenuation of insulin secretion by insulin-like growth factor 1 is mediated through activation of phosphodiesterase 3B

Zhao

Teague

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

138

115

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Both insulin and insulin-like growth factor 1 (IGF-1) are known to reduce glucose-dependent insulin secretion from the ␤ cells of pancreatic islets. In this paper we show that the mechanism by which IGF-1 mediates this effect is in large part through activation of a specific cyclic nucleotide phosphodiesterase, phosphodiesterase 3B (PDE3B). More specifically, in both isolated pancreatic islets and insulin-secreting HIT-T15 cells, IGF-1 inhibits insulin secretion that has been increased by glucose and glucagonlike peptide 1 (GLP-1). Moreover, IGF-1 decreases cAMP levels in parallel to the reduction of insulin secretion. Insulin secretion stimulated by cAMP analogs that activate protein kinase A and also are substrates for PDE3B is also inhibited by IGF-1. However, IGF-1 does not inhibit insulin secretion stimulated by nonhydrolyzable cAMP analogs. In addition, selective inhibitors of PDE3B completely block the ability of IGF-1 to inhibit insulin secretion. Finally, PDE3B activity measured in vitro after immunoprecipitation from cells treated with IGF-1 is higher than the activity from control cells. Taken together with the fact that pancreatic ␤ cells express little or no insulin receptor but large amounts of IGF-1 receptor, these data strongly suggest a new regulatory feedback loop model for the control of insulin secretion. In this model, increased insulin secretion in vivo will stimulate IGF-1 synthesis by the liver, and the secreted IGF-1 in turn feedback inhibits insulin secretion from the ␤ cells through an IGF-1 receptormediated pathway. This pathway is likely to be particularly important when levels of both glucose and secretagogues such as GLP-1 are elevated.

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Cyclic AMP Phosphodiesterases of Human and Rat Islets of Langerhans: Contributions of Types III and IV to the Modulation of Insulin Secretion

Cited by 53 publications

References 0 publications

Important Role of Phosphodiesterase 3B for the Stimulatory Action of cAMP on Pancreatic β-Cell Exocytosis and Release of Insulin

Important Role of Phosphodiesterase 3B for the Stimulatory Action of cAMP on Pancreatic β-Cell Exocytosis and Release of Insulin

Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

Attenuation of insulin secretion by insulin-like growth factor 1 is mediated through activation of phosphodiesterase 3B

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