Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), GIP(3–42) and GLP-1(9–36)amide, on insulin secretion and glucose homeostasis in ob/ob mice

Parker, Jeremy; Lavery, K.S.; Irwin, Nigel; Green, Brian; Greer, Brett; Harriott, Patrick; O’Harte, Finbarr; Gault, Victor; Flatt, Peter R.

doi:10.1677/joe.1.06904

Cited by 17 publications

(5 citation statements)

References 36 publications

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“…Moreover, the GLP-1(9-36) concentrations employed in our study correspond to the concentrations used in previous experiments [7], [19] and the effects observed are not caused by alterations in cell viability or the chemokine receptor expression. Furthermore, the phenomenon demonstrated is not due to unspecific effects of the peptide nor caused by endotoxins as shown by experiments with scrambled GLP-1(9-36) and heat-inactivated GLP-1(9-36).…”

Section: Discussionsupporting

confidence: 54%

Glucagon-Like Peptide-1(9-36) Inhibits Chemokine-Induced Migration of Human CD4-Positive Lymphocytes

2013

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IntroductionInhibitors of dipeptidyl peptidase-IV (DPP-IV), which decrease the degradation of glucose-lowering GLP-1(7-36) to the metabolically inactive GLP-1(9-36), are current new treatment options for patients with type 2 diabetes mellitus, a high-risk population for cardiovascular disease. However, the effects of the metabolite GLP-1(9-36) on atherosclerosis are unknown. Thus, the present study examined the effect of GLP-1(9-36) on chemokine-induced CD4-positive lymphocyte migration as one of the early and critical steps in atherogenesis.Methods and ResultsStimulation of isolated human CD4-positive lymphocytes with SDF-1 led to a 3.4 fold (p<0.001; n = 7) increase in cell migration. Pretreatment of cells with GLP-1(9-36) reduced this effect in a concentration-dependent manner by 41% to a 2.0 fold induction at 10 nmol/L GLP-1(9-36) (p<0.001 compared to SDF-1-treated cells, n = 7). Similar effects were obtained when RANTES was used as a chemokine to induce cell migration. The action of GLP-1(9-36) on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity. Downstream in the PI-3 kinase signaling pathway, GLP-1(9-36) inhibited SDF-1-induced phosphorylation of MLC and cofilin and decreased f-actin formation as well as ICAM3 translocation as shown by Western blotting, flow cytometry and immunohistochemistry, respectively. However, the effect of GLP-1(9-36) on PI-3 kinase signaling was not associated with increased intracellular levels of cAMP. Furthermore, experiments with siRNA demonstrated that the inhibitory effect of GLP-1(9-36) on SDF-1-induced ICAM3-translocation was preserved in human CD4-positive lymphocytes lacking the GLP-1 receptor, suggesting signaling independent of the known GLP-1 receptor.ConclusionThus, GLP-1(9-36) inhibits chemokine-induced CD4-positive lymphocyte migration by inhibition of the PI3-kinase pathway independent of cAMP and GLP-1 receptor signaling. Further studies are needed to assess whether such effects may be clinically relevant for patients with type 2 diabetes treated with DPP-IV inhibitors.

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Section: Discussionsupporting

confidence: 54%

Glucagon-Like Peptide-1(9-36) Inhibits Chemokine-Induced Migration of Human CD4-Positive Lymphocytes

2013

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“…GLP-1 (9-36amide) also improves cardiac output in the post-ischemic mouse heart when administered during reperfusion, and it affects vasodilation in mesenteric arteries in mice [201]. This scenario contrasts with the apparent lack of effect of high doses of GLP-1 (9-36amide) on glucoregulation in ob/ob mice or on cognitive function in high-fat fed mice [202,203]. Indeed, there is evidence that truncated GLP-1 (9-36amide) has no effect on glucose clearance or insulin secretion in healthy humans [196].…”

Section: Glp-1 Degradationmentioning

confidence: 99%

Glucagon-like peptide 1 (GLP-1)

Müller¹,

Finan²,

Bloom³

et al. 2019

Molecular Metabolism

1,147

861

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BackgroundThe glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity.Scope of reviewIn this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases.Major conclusionsSince its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders

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“…Moreover, the GLP-1(9-36) concentrations employed in our study correspond to the concentrations used in previous experiments [7,19] and the effects observed are not caused by alterations in cell viability or the chemokine receptor expression. Furthermore, the phenomenon demonstrated is not due to unspecific effects of the peptide nor caused by endotoxins as shown by experiments with scrambled GLP-1(9-36) and heat-inactivated GLP-1 .…”

Section: Discussionmentioning

confidence: 55%

Correction: Glucagon-Like Peptide-1(9-36) Inhibits Chemokine-Induced Migration of Human CD4-Positive Lymphocytes

Liberman¹,

Esser²,

Burgmaier³

2013

PLoS ONE

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Introduction: Inhibitors of dipeptidyl peptidase-IV (DPP-IV), which decrease the degradation of glucose-lowering to the metabolically inactive , are current new treatment options for patients with type 2 diabetes mellitus, a high-risk population for cardiovascular disease. However, the effects of the metabolite GLP-1(9-36) on atherosclerosis are unknown. Thus, the present study examined the effect of GLP-1(9-36) on chemokine-induced CD4-positive lymphocyte migration as one of the early and critical steps in atherogenesis.Methods and Results: Stimulation of isolated human CD4-positive lymphocytes with SDF-1 led to a 3.4 fold (p,0.001; n = 7) increase in cell migration. Pretreatment of cells with GLP-1(9-36) reduced this effect in a concentration-dependent manner by 41% to a 2.0 fold induction at 10 nmol/L GLP-1(9-36) (p,0.001 compared to SDF-1-treated cells, n = 7). Similar effects were obtained when RANTES was used as a chemokine to induce cell migration. The action of GLP-1(9-36) on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity. Downstream in the PI-3 kinase signaling pathway, GLP-1(9-36) inhibited SDF-1-induced phosphorylation of MLC and cofilin and decreased factin formation as well as ICAM3 translocation as shown by Western blotting, flow cytometry and immunohistochemistry, respectively. However, the effect of GLP-1(9-36) on PI-3 kinase signaling was not associated with increased intracellular levels of cAMP. Furthermore, experiments with siRNA demonstrated that the inhibitory effect of GLP-1(9-36) on SDF-1induced ICAM3-translocation was preserved in human CD4-positive lymphocytes lacking the GLP-1 receptor, suggesting signaling independent of the known GLP-1 receptor.Conclusion: Thus, GLP-1(9-36) inhibits chemokine-induced CD4-positive lymphocyte migration by inhibition of the PI3kinase pathway independent of cAMP and GLP-1 receptor signaling. Further studies are needed to assess whether such effects may be clinically relevant for patients with type 2 diabetes treated with DPP-IV inhibitors.

show abstract

Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), GIP(3–42) and GLP-1(9–36)amide, on insulin secretion and glucose homeostasis in ob/ob mice

Cited by 17 publications

References 36 publications

Glucagon-Like Peptide-1(9-36) Inhibits Chemokine-Induced Migration of Human CD4-Positive Lymphocytes

Glucagon-Like Peptide-1(9-36) Inhibits Chemokine-Induced Migration of Human CD4-Positive Lymphocytes

Glucagon-like peptide 1 (GLP-1)

Correction: Glucagon-Like Peptide-1(9-36) Inhibits Chemokine-Induced Migration of Human CD4-Positive Lymphocytes

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