Insulin inhibits its own secretion from isolated, perifused human pancreatic islets

Marchetti, Piero; Dw, Scharp; Mclear, M.; Finke, Edward H.; Olack, Barbara; Swanson, C. J.; Giannarelli, R; Navalesi, Renzo; Pe, Lacy

doi:10.1007/bf00569560

Cited by 16 publications

(10 citation statements)

References 15 publications

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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%

“…When infused into normal healthy human subjects at a dose not causing hypoglycemia, IGF-1 can decrease the circulating insulin level (2) and IGF-1 can directly attenuate insulin secretion from isolated primary rat pancreatic ␤ cells (3). Insulin itself has been postulated to exert a negative-feedback control of its own secretion (4,5). However, as this effect of insulin requires high concentrations [ranging from 200 to 1,000 microunits ( U)͞ml] it is also possible that this effect of insulin may be mediated through ␤ cell IGF-1 receptors that have low affinity for insulin (4)(5)(6)(7).…”

mentioning

confidence: 99%

“…Insulin itself has been postulated to exert a negative-feedback control of its own secretion (4,5). However, as this effect of insulin requires high concentrations [ranging from 200 to 1,000 microunits ( U)͞ml] it is also possible that this effect of insulin may be mediated through ␤ cell IGF-1 receptors that have low affinity for insulin (4)(5)(6)(7).…”

mentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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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

View full text Add to dashboard Cite

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“…Insulin receptors have been observed on the beta cell [77] and insulin was shown in some studies to inhibit its own release [77,78,79]. Thus this inhibition could be achieved by insulin-mediated activation of beta-cell PDE3 and consequent reduction in beta-cell cyclic AMP concentrations.…”

Section: Insulin and Insulin-like Growth Factor-1 (Igf-1)mentioning

confidence: 99%

Cyclic nucleotide phosphodiesterases in pancreatic islets

Pyne

Furman

2003

Diabetologia

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Cyclic nucleotide phosphodiesterases (PDEs) comprise a family of enzymes (PDE1-PDE11) which hydrolyse cyclic AMP and cyclic GMP to their biologically inactive 5′ derivatives. Cyclic AMP is an important physiological amplifier of glucose-induced insulin secretion. As PDEs are the only known mechanism for inactivating cyclic nucleotides, it is important to characterise the PDEs present in the pancreatic islet beta cells. Several studies have shown pancreatic islets or beta cells to contain PDE1C, PDE3B and PDE4, with some evidence for PDE10A. Most evidence suggests that PDE3B is the most important in relation to the regulation of insulin release, although PDE1C could have a role. PDE3-selective inhibitors augment glucose-induced insulin secretion. In contrast, activation of beta-cell PDE3B could mediate the inhibitory effect of IGF-1 and leptin on insulin secretion. In vivo, although PDE3 inhibitors augment glucose-induced insulin secretion, concomitant inhibition of PDE3B in liver and adipose tissue induce insulin resistance and PDE3 inhibitors do not induce hypoglycaemia. The development of PDE3 inhibitors as anti-diabetic agents would require differentiation between PDE3B in the beta cell and that in hepatocytes and adipocytes. Through their effects in regulating beta-cell cyclic nucleotide concentrations, PDEs could modulate beta-cell growth, differentiation and survival; some work has shown that selective inhibition of PDE4 prevents diabetes in NOD mice and that selective PDE3 inhibition blocks cytokine-induced nitric oxide production in islet cells. Further work is required to understand the mechanism of regulation and role of the various PDEs in islet-cell function and to validate them as targets for drugs to treat and prevent diabetes. [Diabetologia (2003[Diabetologia ( ) 46:1179[Diabetologia ( -1189

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“…Delivery of this product into the surrounding buffer could entrain surrounding islets. Both insulin (43) and islet amyloid polypeptide (44) could meet this criteria. Alternatively, there might be some degree of electrophysiological coupling of islets compacted together in an ionic solution.…”

Section: Discussionmentioning

confidence: 99%

Pulsatile Insulin Secretion by Human Pancreatic Islets

Song

Kjems

Ritzel

et al. 2002

The Journal of Clinical Endocrinology & Metabolism

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Insulin is secreted in discrete bursts. These pulses are also present when individual or groups of islets are perifused. Interpretation of the measured frequency and magnitude of pulsatile hormone secretion requires an examination of the sensitivity and specificity of the methods for pulse detection and validation of these for the experimental apparatus and hormone assay in which they are applied. In the present study we achieve these aims for a perfusion method for measurement of pulsatile insulin release by human islets. A deconvolution technique previously developed for measurement of pulsatile hormone secretion in vivo was specifically validated for in vitro pulse detection in the present study. Deconvolution analysis reliably (>90%) detected insulin pulses with an amplitude 20% or more above baseline and recovered quantitatively the insulin secretion profile, insulin secretion rate, and insulin pulse mass from single as well as multiple perifused islets. Cluster analysis was less sensitive, but was able to detect most (>80%) pulses with an amplitude of 40% or more above baseline. With this limitation, cluster analysis is potentially useful for groups, but not single perifused human islets. Analysis of single human islets showed that enhanced insulin secretion by increased glucose concentrations in the perfusate is achieved by enhancing insulin pulse mass with no change in pulse frequency. Perfused single or groups of human islets exhibited an interpulse interval (ϳ6 -8 min) comparable to that observed in humans in vivo. IINSULIN IS SECRETED in a pulsatile manner (1-5). These pulses can be detected in vivo as well as in vitro in perifused islets of Langerhans (1, 6 -11). Reliable detection and quantification of pulsatile hormone secretion require statistical methods that have been validated for the conditions in which they will be used. We previously validated the use of a deconvolution technique developed by Johnson and Veldhuis (12) for detection and quantification of pulsatile insulin secretion in vivo (5). In the present study we sought to extend this approach for the quantification of pulsatile insulin secretion by perifused human islets of Langerhans. Perifusion studies have the advantage that they allow analysis of the mechanisms that regulate insulin secretion in the absence of the complexities of feedback control (for example, by the changes in plasma glucose concentration). They also allow mechanistic studies of the factors that generate pulsatile insulin secretion (pacemaker activity) as well as coordinate this signal between islets (coordination).In the present study we appraised the sensitivity and specificity of two statistically independent methods for pulse detection, cluster analysis (13) and deconvolution analysis (12). Cluster analysis was selected as a typical example of the most commonly used statistical algorithms for pulse detection. The deconvolution method used was selected because it provides a statistically based measure of pulse location as well as yields information on secretion...

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Insulin inhibits its own secretion from isolated, perifused human pancreatic islets

Cited by 16 publications

References 15 publications

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

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

Cyclic nucleotide phosphodiesterases in pancreatic islets

Pulsatile Insulin Secretion by Human Pancreatic Islets

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