Prior in vitro exposure to GLP-1 with or without GIP can influence the subsequent beta cell responsiveness

Delmeire, Dominique; Flamez, Daisy; Moens, Karen; Hinke, Simon A.; Schravendijk, Christiaan Van; Pipeleers, Daniël; Schuit, Franciscus

doi:10.1016/j.bcp.2004.02.035

Cited by 22 publications

(18 citation statements)

References 27 publications

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“…Although most studies including the knockout of one or both receptors for GLP-1 and GIP suggest a similar mode of action of the two hormones in -cells (Preitner et al 2004) however, subtle differences have been reported. Thus GLP-1 receptors seem to be more prone to desensitization than GIP receptors (Delmeire et al 2004) and in type 2 diabetes the -cell response to GIP is reduced, whereas the response to GLP-1 is retained (Holst & Gromada 2004).…”

Section: Discussionmentioning

confidence: 99%

Stimulation of pancreatic β-cell replication by incretins involves transcriptional induction of cyclin D1 via multiple signalling pathways

Friedrichsen¹,

Neubauer²,

Lee³

et al. 2006

Journal of Endocrinology

143

110

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The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), have been suggested to act as -cell growth factors and may therefore be of critical importance for the maintenance of a proper -cell mass. We have investigated the molecular mechanism of incretin-induced -cell replication in primary monolayer cultures of newborn rat islet cells. GLP-1, GIP and the long-acting GLP-1 derivative, liraglutide, increased -cell replication 50-80% at 10-100 nM upon a 24 h stimulus, whereas glucagon at a similar concentration had no significant effect. The stimulatory effect of GLP-1 and GIP was efficiently mimicked by the adenylate cyclase activator, forskolin, at 10 nM (90% increase) and was additive (170-250% increase) with the growth response to human growth hormone (hGH), indicating the use of distinct intracellular signalling pathways leading to mitosis by incretins and cytokines, respectively. The response to both GLP-1 and GIP was completely blocked by the protein kinase A (PKA) inhibitor, H89. In addition, the phosphoinositol 3-kinase (PI3K) inhibitor wortmannin and the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059, both inhibited GLP-1-and GIP-stimulated proliferation. The p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, had no inhibitory effect on either GLP-1 or GIP stimulated proliferation. Cyclin Ds act as molecular switches for the G0/G1-S phase transition in many cell types and we have previously demonstrated hGH-induced cyclin D2 expression in the insulinoma cell line, INS-1. GLP-1 time-dependently induced the cyclin D1 mRNA and protein levels in INS-1E, whereas the cyclin D2 levels were unaffected. However, minor effect of GLP-1 stimulation was observed on the cyclin D3 mRNA levels. Transient transfection of a cyclin D1 promoter-luciferase reporter construct into islet monolayer cells or INS-1 cells revealed approximately a 2-3 fold increase of transcriptional activity in response to GLP-1 and GIP, and a 4-7 fold increase in response to forskolin. However, treatment of either cell type with hGH had no effect on cyclin D1 promoter activity. The stimulation of the cyclin D1 promoter by GLP-1 was inhibited by H89, wortmannin, and PD98059. We conclude that incretin-induced -cell replication is dependent on cAMP/PKA, p42 MAPK and PI3K activities, which may involve transcriptional induction of cyclin D1. GLP-1, GIP and liraglutide may have the potential to increase -cell replication in humans which would have significant impact on long-term diabetes treatment.

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Section: Discussionmentioning

confidence: 99%

Stimulation of pancreatic β-cell replication by incretins involves transcriptional induction of cyclin D1 via multiple signalling pathways

Friedrichsen¹,

Neubauer²,

Lee³

et al. 2006

Journal of Endocrinology

143

110

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“…Irrespective of knowledge of the full range of actions contributing to the antihyperglycemic effect of N-AcGIP-(LysPAL 37 ), a currently envisaged problem of long-term treatment with stable analogs of GIP or GLP-1 concerns desensitization of hormone receptor action (Delmeire et al, 2004). Although this has been observed during prolonged exposure of pancreatic ␤ cells to GIP during culture in vitro (Tseng et al, 1996), there was no evidence that treatment with N-AcGIP(LysPAL 37 ) for 14 days compromised the glucose-lowering or insulin-releasing actions of N-AcGIP-(LysPAL 37 ) in any way.…”

Section: Discussionmentioning

confidence: 99%

A Novel, Long-Acting Agonist of Glucose-Dependent Insulinotropic Polypeptide Suitable for Once-Daily Administration in Type 2 Diabetes

Irwin¹,

Green²,

Mooney³

et al. 2005

J Pharmacol Exp Ther

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Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone with a potentially therapeutic role in type 2 diabetes. Rapid degradation by dipeptidylpeptidase IV has prompted the development of enzyme-resistant N-terminally modified analogs, but renal clearance still limits in vivo bioactivity. In this study, we report long-term antidiabetic effects of a novel, N-terminally protected, fatty acid-derivatized analog of GIP, N-AcGIP(LysPAL 37 ), in obese diabetic (ob/ob) mice. Oncedaily injections of N-AcGIP(LysPAL 37 ) over a 14-day period significantly decreased plasma glucose, glycated hemoglobin, and improved glucose tolerance compared with ob/ob mice treated with saline or native GIP. Plasma insulin and pancreatic insulin content were significantly increased by N-AcGIP ). This was accompanied by a significant enhancement in the insulin response to glucose together with a notable improvement of insulin sensitivity. No evidence was found for GIP receptor desensitization and the metabolic effects of NAcGIP(LysPAL 37 ) were independent of any change in feeding or body weight. Similar daily injections of native GIP did not affect any of the parameters measured. These data demonstrate the ability of once-daily injections of N-terminally modified, fatty acid-derivatized analogs of GIP, such as N-AcGIP(LysPAL 37 ), to improve diabetes control and to offer a new class of agents for the treatment of type 2 diabetes.

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“…It seems unlikely to us that the dose is an issue, because other studies with exenatide in animal models have employed doses of 1 nmol/kg (27), 24 nmol/kg (25), or 50 nmol/kg (24). The alter- native that GLP-1 receptor desensitization occurs is perhaps plausible from in vitro studies (28), although this phenomenon has not been observed to any appreciable extent in vivo (29,30). Thus, the observation of lack of effect of exenatide on energy intake and body weight regulation would appear to be speciesand animal model-specific.…”

Section: Discussionmentioning

confidence: 85%

A Novel Glucagon-like Peptide-1 (GLP-1)/Glucagon Hybrid Peptide with Triple-acting Agonist Activity at Glucose-dependent Insulinotropic Polypeptide, GLP-1, and Glucagon Receptors and Therapeutic Potential in High Fat-fed Mice

Gault

Bhat

Irwin³

et al. 2013

Journal of Biological Chemistry

111

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Background: Glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon have important gluco-regulatory actions. Results: Fusion of amino acid sequences of GLP-1, GIP, and glucagon produces hybrid peptides with triple-acting agonist activity. Conclusion: Hybrid peptides possess beneficial biological actions equivalent, or superior to, activation of single receptors. Significance: Multitargeting peptides offer a new class of therapeutics for obesity and diabetes.

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Prior in vitro exposure to GLP-1 with or without GIP can influence the subsequent beta cell responsiveness

Cited by 22 publications

References 27 publications

Stimulation of pancreatic β-cell replication by incretins involves transcriptional induction of cyclin D1 via multiple signalling pathways

Stimulation of pancreatic β-cell replication by incretins involves transcriptional induction of cyclin D1 via multiple signalling pathways

A Novel, Long-Acting Agonist of Glucose-Dependent Insulinotropic Polypeptide Suitable for Once-Daily Administration in Type 2 Diabetes

A Novel Glucagon-like Peptide-1 (GLP-1)/Glucagon Hybrid Peptide with Triple-acting Agonist Activity at Glucose-dependent Insulinotropic Polypeptide, GLP-1, and Glucagon Receptors and Therapeutic Potential in High Fat-fed Mice

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