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Glucagon-like peptide-1 protects beta-cells against apoptosis by increasing the activity of an IGF-2/IGF-1 receptor autocrine loop.

Cornu M, Yang JY, Jaccard E, Poussin C, Widmann C, Thorens B - Diabetes (2009)

Bottom Line: We found that IGF-1 receptor expression was markedly reduced in the mutant islets.We found that GLP-1 robustly stimulated IGF-1 receptor expression and Akt phosphorylation and that increased Akt phosphorylation was dependent on IGF-1 but not insulin receptor expression.We demonstrated, both in MIN6 cell line and primary beta-cells, that reducing IGF-1 receptor or IGF-2 expression or neutralizing secreted IGF-2 suppressed GLP-1-induced protection against apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

ABSTRACT

Objective: The gluco-incretin hormones glucagon-like peptide (GLP)-1 and gastric inhibitory peptide (GIP) protect beta-cells against cytokine-induced apoptosis. Their action is initiated by binding to specific receptors that activate the cAMP signaling pathway, but the downstream events are not fully elucidated. Here we searched for mechanisms that may underlie this protective effect.

Research design and methods: We performed comparative transcriptomic analysis of islets from control and GipR(-/-);Glp-1-R(-/-) mice, which have increased sensitivity to cytokine-induced apoptosis. We found that IGF-1 receptor expression was markedly reduced in the mutant islets. Because the IGF-1 receptor signaling pathway is known for its antiapoptotic effect, we explored the relationship between gluco-incretin action, IGF-1 receptor expression and signaling, and apoptosis.

Results: We found that GLP-1 robustly stimulated IGF-1 receptor expression and Akt phosphorylation and that increased Akt phosphorylation was dependent on IGF-1 but not insulin receptor expression. We demonstrated that GLP-1-induced Akt phosphorylation required active secretion, indicating the presence of an autocrine activation mechanism; we showed that activation of IGF-1 receptor signaling was dependent on the secretion of IGF-2. We demonstrated, both in MIN6 cell line and primary beta-cells, that reducing IGF-1 receptor or IGF-2 expression or neutralizing secreted IGF-2 suppressed GLP-1-induced protection against apoptosis.

Conclusions: An IGF-2/IGF-1 receptor autocrine loop operates in beta-cells. GLP-1 increases its activity by augmenting IGF-1 receptor expression and by stimulating secretion; this mechanism is required for GLP-1-induced protection against apoptosis. These findings may lead to novel ways of preventing beta-cell loss in the pathogenesis of diabetes.

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Related in: MedlinePlus

GLP-1 increased IGF-1R expression and signaling in MIN6 cells. A: MIN6 cells were treated with GLP-1 for the indicated periods of time, and IGF-1R expression and Akt phosphorylation were analyzed by Western blot analysis. B: MIN6 cells were transfected with a control (Un) or an IGF-1R siRNA and treated for 18 h with GLP-1. GLP-1 induced IGF-1 receptor expression, Akt phosphorylation on both T308 and S473, and Bad phosphorylation. Preventing IGF-1R expression suppressed GLP-1–induced Akt and Bad phosphorylation. For all panels, data are means ± SD, n = 3 independent experiments. ***P < 0.001.
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Figure 2: GLP-1 increased IGF-1R expression and signaling in MIN6 cells. A: MIN6 cells were treated with GLP-1 for the indicated periods of time, and IGF-1R expression and Akt phosphorylation were analyzed by Western blot analysis. B: MIN6 cells were transfected with a control (Un) or an IGF-1R siRNA and treated for 18 h with GLP-1. GLP-1 induced IGF-1 receptor expression, Akt phosphorylation on both T308 and S473, and Bad phosphorylation. Preventing IGF-1R expression suppressed GLP-1–induced Akt and Bad phosphorylation. For all panels, data are means ± SD, n = 3 independent experiments. ***P < 0.001.

Mentions: To investigate in more detail the regulation by gluco-incretins of IGF-1R expression and signaling, we used MIN6 cells as a model system and concentrated our study on the effect of GLP-1, since GLP-1 and GIP use the same signaling pathway. We first demonstrated that, as in primary islets, GLP-1 increased IGF-1R expression with maximal induction reached after ∼18 h of treatment (Fig. 2A). In addition, we found that induction of IGF-1R expression was associated with a corresponding increase in Akt phosphorylation on Thr308 (Fig. 2A). We then showed that GLP-1 treatment also induced Akt phosphorylation on Ser473 and the phosphorylation of Bad, a proapoptotic protein inactivated by phosphorylation by IGF-1R signaling (25,26) (Fig. 2B). We also determined that preventing IGF-1R expression by transfecting the cells with an IGF-1R–specific siRNA suppressed GLP-1–induced Akt phosphorylation on both sites and the phosphorylation of Bad (Fig. 2B). GLP-1 treatment of the cells induced an approximately threefold increase in IRS-2 expression (see Fig. S1 in an online-only appendix, available at http://diabetes.diabetesjournals.org/cgi/content/full/db09-0063/DC1).


Glucagon-like peptide-1 protects beta-cells against apoptosis by increasing the activity of an IGF-2/IGF-1 receptor autocrine loop.

Cornu M, Yang JY, Jaccard E, Poussin C, Widmann C, Thorens B - Diabetes (2009)

GLP-1 increased IGF-1R expression and signaling in MIN6 cells. A: MIN6 cells were treated with GLP-1 for the indicated periods of time, and IGF-1R expression and Akt phosphorylation were analyzed by Western blot analysis. B: MIN6 cells were transfected with a control (Un) or an IGF-1R siRNA and treated for 18 h with GLP-1. GLP-1 induced IGF-1 receptor expression, Akt phosphorylation on both T308 and S473, and Bad phosphorylation. Preventing IGF-1R expression suppressed GLP-1–induced Akt and Bad phosphorylation. For all panels, data are means ± SD, n = 3 independent experiments. ***P < 0.001.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2712796&req=5

Figure 2: GLP-1 increased IGF-1R expression and signaling in MIN6 cells. A: MIN6 cells were treated with GLP-1 for the indicated periods of time, and IGF-1R expression and Akt phosphorylation were analyzed by Western blot analysis. B: MIN6 cells were transfected with a control (Un) or an IGF-1R siRNA and treated for 18 h with GLP-1. GLP-1 induced IGF-1 receptor expression, Akt phosphorylation on both T308 and S473, and Bad phosphorylation. Preventing IGF-1R expression suppressed GLP-1–induced Akt and Bad phosphorylation. For all panels, data are means ± SD, n = 3 independent experiments. ***P < 0.001.
Mentions: To investigate in more detail the regulation by gluco-incretins of IGF-1R expression and signaling, we used MIN6 cells as a model system and concentrated our study on the effect of GLP-1, since GLP-1 and GIP use the same signaling pathway. We first demonstrated that, as in primary islets, GLP-1 increased IGF-1R expression with maximal induction reached after ∼18 h of treatment (Fig. 2A). In addition, we found that induction of IGF-1R expression was associated with a corresponding increase in Akt phosphorylation on Thr308 (Fig. 2A). We then showed that GLP-1 treatment also induced Akt phosphorylation on Ser473 and the phosphorylation of Bad, a proapoptotic protein inactivated by phosphorylation by IGF-1R signaling (25,26) (Fig. 2B). We also determined that preventing IGF-1R expression by transfecting the cells with an IGF-1R–specific siRNA suppressed GLP-1–induced Akt phosphorylation on both sites and the phosphorylation of Bad (Fig. 2B). GLP-1 treatment of the cells induced an approximately threefold increase in IRS-2 expression (see Fig. S1 in an online-only appendix, available at http://diabetes.diabetesjournals.org/cgi/content/full/db09-0063/DC1).

Bottom Line: We found that IGF-1 receptor expression was markedly reduced in the mutant islets.We found that GLP-1 robustly stimulated IGF-1 receptor expression and Akt phosphorylation and that increased Akt phosphorylation was dependent on IGF-1 but not insulin receptor expression.We demonstrated, both in MIN6 cell line and primary beta-cells, that reducing IGF-1 receptor or IGF-2 expression or neutralizing secreted IGF-2 suppressed GLP-1-induced protection against apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

ABSTRACT

Objective: The gluco-incretin hormones glucagon-like peptide (GLP)-1 and gastric inhibitory peptide (GIP) protect beta-cells against cytokine-induced apoptosis. Their action is initiated by binding to specific receptors that activate the cAMP signaling pathway, but the downstream events are not fully elucidated. Here we searched for mechanisms that may underlie this protective effect.

Research design and methods: We performed comparative transcriptomic analysis of islets from control and GipR(-/-);Glp-1-R(-/-) mice, which have increased sensitivity to cytokine-induced apoptosis. We found that IGF-1 receptor expression was markedly reduced in the mutant islets. Because the IGF-1 receptor signaling pathway is known for its antiapoptotic effect, we explored the relationship between gluco-incretin action, IGF-1 receptor expression and signaling, and apoptosis.

Results: We found that GLP-1 robustly stimulated IGF-1 receptor expression and Akt phosphorylation and that increased Akt phosphorylation was dependent on IGF-1 but not insulin receptor expression. We demonstrated that GLP-1-induced Akt phosphorylation required active secretion, indicating the presence of an autocrine activation mechanism; we showed that activation of IGF-1 receptor signaling was dependent on the secretion of IGF-2. We demonstrated, both in MIN6 cell line and primary beta-cells, that reducing IGF-1 receptor or IGF-2 expression or neutralizing secreted IGF-2 suppressed GLP-1-induced protection against apoptosis.

Conclusions: An IGF-2/IGF-1 receptor autocrine loop operates in beta-cells. GLP-1 increases its activity by augmenting IGF-1 receptor expression and by stimulating secretion; this mechanism is required for GLP-1-induced protection against apoptosis. These findings may lead to novel ways of preventing beta-cell loss in the pathogenesis of diabetes.

Show MeSH
Related in: MedlinePlus