Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas.

Stoffers, Doris A.; Kieffer, Timothy J.; Hussain, Mehboob A.; Drucker, Daniel J.; Bonner-Weir, Susan; Habener, Joel F.; Egan, Josephine M.

doi:10.2337/diabetes.49.5.741

Cited by 528 publications

(370 citation statements)

References 51 publications

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“…GLP-1 mobilises intracellular Ca 2+ [35,36] via cyclic AMP guanine nucleotide exchange factor 2 (Epac) [37], an effect that may contribute to the insulinotropic action of the peptide. Moreover, this gluco-incretin hormone increases islet mass in mouse pancreas in vivo [31,38] and causes in vitro beta cell proliferation via transactivation of the epidermal growth factor receptor and subsequent activation of the phosphatidylinositol-3 kinase (PI-3K) and protein kinase C-ζ (PKC-ζ) signalling pathway in beta-(INS-1)-cells [30,39,40]. Finally, GLP-1 has recently been shown to delay beta cell apoptosis in Zucker diabetic rats, an animal model of diabetes [38], as well as in streptozotocin-treated mice and cytokinetreated rat islets in vitro [41].…”

Section: Introductionmentioning

confidence: 94%

“…c-fos, c-jun, junD and nur77 [28,29]. GLP-1 increases the DNA binding activity and expression level of the beta-cell-specific transcription factor pancreatic and duodenal homeobox gene-1 (PDX-1) [30,31], which is implicated in regulating expression of the insulin, GLUT2 and glucokinase genes, and in the regulation of beta cell differentiation [32,33,34]. GLP-1 mobilises intracellular Ca 2+ [35,36] via cyclic AMP guanine nucleotide exchange factor 2 (Epac) [37], an effect that may contribute to the insulinotropic action of the peptide.…”

Section: Introductionmentioning

confidence: 99%

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Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

et al. 2004

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Aims/hypothesis. We have provided evidence that glucagon-like peptide-1, a potential therapeutic agent in the treatment of diabetes, activates phosphatidylinositol-3 kinase/protein kinase B signalling in the pancreatic beta cell. Since this pathway promotes cell survival in a variety of systems, we tested whether glucagon-like peptide-1 protects beta cells against cell death induced by elevated glucose and/or non-esterified fatty acids. Methods. Human islets and INS832/13 cells were cultured at glucose concentrations of 5 or 25 mmol/l in the presence or absence of palmitate. Apoptosis was evaluated by monitoring DNA fragmentation and chromatin condensation. Wild-type and protein kinase B mutants were overexpressed in INS832/13 cells using adenoviruses. Nuclear factor-κB DNA binding was assayed by electrophoretic mobility shift assay. Results. In human pancreatic beta cells and INS832/13 cells, glucagon-like peptide-1 prevented beta cell apoptosis induced by elevated concentrations of (i) glucose (glucotoxicity), (ii) palmitate (lipotoxicity) and (iii) both glucose and palmitate (glucolipotoxicity). Overexpression of a dominant-negative protein kinase B suppressed the anti-apoptotic action of glucagonlike peptide-1 in INS832/13 cells, whereas a constitutively active protein kinase B prevented beta cell apoptosis induced by elevated glucose and palmitate. Glucagon-like peptide-1 enhanced nuclear factor-κB DNA binding activity and stimulated the expression of inhibitor of apoptosis protein-2 and Bcl-2, two antiapoptotic genes under the control of nuclear factor-κB. Inhibition of nuclear factor-κB by BAY 11-7082 abolished the prevention of glucolipotoxicity by glucagon-like peptide-1. Conclusions/interpretation. The results demonstrate a potent protective effect of glucagon-like peptide-1 on beta cell gluco-, lipo-and glucolipotoxicity. This effect is mediated via protein kinase B activation and possibly its downstream target nuclear factor-κB.

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Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

et al. 2004

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“…But in this respect, the GLP-1-based therapies possess a unique potential: GLP-1 has trophic effects on beta cells [91]. Not only does it stimulate beta cell proliferation [92,93], it also enhances the differentiation of new beta cells from progenitor cells in the pancreatic duct epithelium [94] and, perhaps most importantly, GLP-1 is capable of inhibiting apoptosis of beta cells including human beta cells [95]. Since the normal number of beta cells is maintained in a balance between apoptosis and proliferation, this observation is of considerable interest, and raises the possibility that GLP-1 could be useful in conditions in which beta cell apoptosis is increased.…”

Section: Protective Effects Of Glp-1mentioning

confidence: 99%

Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005

2006

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The incretin hormones are intestinal polypeptides that enhance postprandial insulin secretion. Gastric inhibitory polypeptide (GIP) was initially thought to regulate gastric acid secretion, whereas glucagon-like peptide-1 (GLP-1) was discovered as a result of a systematic search for intestinal insulinotropic products of proglucagon gene expression. The incretin effect is markedly impaired or absent in patients with type 2 diabetes because of decreased secretion of GLP-1 and a loss of the insulinotropic effects of GIP. Metabolic control can be restored or greatly improved by administration of exogenous GLP-1, but this peptide is almost immediately degraded by dipeptidyl peptidase IV (DPP-IV), and therefore has little clinical value. DPP-IV-resistant analogues (incretin mimetics) have been identified or developed, and inhibitors of DPP-IV have also proved effective in protecting endogenous GLP-1 (and GIP) from degradation. Both principles have been tested in clinical studies. The incretin mimetics, administered by sc injection, have demonstrated lasting improvement in HbA 1 c in patients insufficiently treated with conventional oral therapy, and their use has been associated with steady weight loss for up to 2 years. The DPP-IV inhibitors, given once or twice daily by mouth, also appear to provide lasting improvement in HbA 1 c, but are weight-neutral. The first incretin mimetic has reached the market in the US, and applications for approval of the first inhibitors are expected to be filed early in 2006.

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“…These include stimulation of glucose-dependent insulin secretion [10,11], and inhibition of glucagon release [11,12], gastric emptying [12,13] and food intake [14,15]. Recent data show that the actions of GLP-1 that protect against diabetes also include the enhancement of beta cell mass in rodents, through inhibition of beta cell apoptosis, and stimulation of beta cell proliferation and islet neogenesis [16][17][18][19]. Furthermore, GLP-1 and its agonists increase the survival of immortalised rodent beta cell lines when challenged with various apoptotic stimulators, including hydrogen peroxide, fatty acids, streptozotocin and staurosporine [17,[20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B

et al. 2005

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Aims/hypothesis: The gut hormone glucagonlike peptide-1 (GLP-1) decreases beta cell apoptosis in a protein kinase B (PKB)-dependent fashion, and increases islet cell mass and function in vivo. In contrast, cytokines induce beta cell apoptosis, leading to decreased islet mass and type 1 diabetes. In the present study we used rat INS-1E beta cells and primary rat islet cells to examine the potential role of PKB as a mediator of the effect of GLP-1 on cytokine-induced apoptosis. Methods: Cell viability was determined by MTTassay, and apoptosis and necrosis by Hoechst 33342-propidium iodide staining. Immunoblot analysis was used to detect changes in protein expression, including active (phosphorylated) and total PKB, phosphorylated and total glycogen synthase kinase-3β, activated caspase-3 and inducible nitric oxide synthase. Reactive oxygen species were determined by 1,7-dichlorofluorescein (DCF) analysis, and mutant forms of PKB were introduced into cells using adenoviral vectors. Results: Incubation of INS-1E cells with cytokines (IL-1β, TNF-α and interferon-γ; 10-50 ng/ml) for 18 h significantly decreased cell viability (by 44%, p<0.001), cell proliferation (by 80%, p<0.001), and activation of PKB (by 67%, p<0.001). Pre-treatment with exendin-4 (10 −7 mol/l), a long-acting GLP-1 receptor agonist, partially protected the cells against cytokine-induced toxicity (p<0.01) in association with a reduction in cytokine-induced inhibition of PKB phosphorylation (p<0.05). Exendin-4 pre-treatment did not change cell proliferation. Cytokine treatment increased apoptosis (by 156%, p<0.05) and necrosis (from undetectable to 2.6% of cells). These increases were both reduced by pre-treatment with exendin-4 (p<0.05-0.01). Furthermore, cytokine-induced apoptosis and necrosis were significantly increased in cells infected with kinase-dead PKB (p<0.05), and the protective effect of exendin-4 on both parameters was fully abolished in these cells. Similar changes were observed in primary islet cells. In parallel with these changes, exendin-4 decreased the cytokine-induced activation of caspase-3 (by 46%, p<0.05), and decreased levels of inducible nitric oxide synthase (by 71%, p<0.05) and reactive oxygen species (by 27%, p< 0.05). Conclusions/interpretation: The results of our study indicate that GLP-1 plays a protective role against cytokineinduced apoptosis and necrosis in beta cells through a PKB-dependent signalling pathway.

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Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas.

Cited by 528 publications

References 51 publications

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005

Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B

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