Noncanonical Activation of Akt/Protein Kinase B in β-Cells by the Incretin Hormone Glucose-dependent Insulinotropic Polypeptide
Therapeutics based on the actions of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), have recently been introduced for the treatment of type 2 diabetes mellitus. The serine/threonine kinase Akt is a major mediator of incretin action on t...
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| Published in | The Journal of biological chemistry Vol. 284; no. 16; pp. 10764 - 10773 |
|---|---|
| Main Authors | , , , |
| Format | Journal Article |
| Language | English |
| Published |
Elsevier Inc
17.04.2009
American Society for Biochemistry and Molecular Biology |
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| Abstract | Therapeutics based on the actions of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), have recently been introduced for the treatment of type 2 diabetes mellitus. The serine/threonine kinase Akt is a major mediator of incretin action on the pancreatic islet, increasing β-cell mass and function and promoting β-cell survival. The mechanisms underlying incretin activation of Akt are thought to involve an essential phosphoinositide 3-kinase-mediated phosphorylation of threonine 308, similar to the prototypical Akt activator, insulin-like growth factor-I (IGF-I). In this study, using activity assays on immunoprecipitated Akt, we discovered that GIP and GLP-1 were capable of stimulating Akt in the INS-1 β-cell line and isolated mouse islets via a mechanism that did not require phosphoinositide 3-kinase or phosphorylation of Thr308 and Ser473, and this pathway involved the production of cAMP. Furthermore, we found that GIP stimulated anti-apoptotic signaling via this alternate mode of Akt activation. We conclude that incretins can activate Akt via a novel noncanonical mechanism that may provide an alternative therapeutic target for the treatment of type 2 diabetes mellitus and have broader implications for Akt physiology in human health and disease. |
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| AbstractList | Therapeutics based on the actions of the incretin hormones, glucagon-like
peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), have
recently been introduced for the treatment of type 2 diabetes mellitus. The
serine/threonine kinase Akt is a major mediator of incretin action on the
pancreatic islet, increasing β-cell mass and function and promoting
β-cell survival. The mechanisms underlying incretin activation of Akt are
thought to involve an essential phosphoinositide 3-kinase-mediated
phosphorylation of threonine 308, similar to the prototypical Akt activator,
insulin-like growth factor-I (IGF-I). In this study, using activity assays on
immunoprecipitated Akt, we discovered that GIP and GLP-1 were capable of
stimulating Akt in the INS-1 β-cell line and isolated mouse islets via a
mechanism that did not require phosphoinositide 3-kinase or phosphorylation of
Thr
308
and Ser
473
, and this pathway involved the
production of cAMP. Furthermore, we found that GIP stimulated anti-apoptotic
signaling via this alternate mode of Akt activation. We conclude that
incretins can activate Akt via a novel noncanonical mechanism that may provide
an alternative therapeutic target for the treatment of type 2 diabetes
mellitus and have broader implications for Akt physiology in human health and
disease. Therapeutics based on the actions of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), have recently been introduced for the treatment of type 2 diabetes mellitus. The serine/threonine kinase Akt is a major mediator of incretin action on the pancreatic islet, increasing β-cell mass and function and promoting β-cell survival. The mechanisms underlying incretin activation of Akt are thought to involve an essential phosphoinositide 3-kinase-mediated phosphorylation of threonine 308, similar to the prototypical Akt activator, insulin-like growth factor-I (IGF-I). In this study, using activity assays on immunoprecipitated Akt, we discovered that GIP and GLP-1 were capable of stimulating Akt in the INS-1 β-cell line and isolated mouse islets via a mechanism that did not require phosphoinositide 3-kinase or phosphorylation of Thr³⁰⁸ and Ser⁴⁷³, and this pathway involved the production of cAMP. Furthermore, we found that GIP stimulated anti-apoptotic signaling via this alternate mode of Akt activation. We conclude that incretins can activate Akt via a novel noncanonical mechanism that may provide an alternative therapeutic target for the treatment of type 2 diabetes mellitus and have broader implications for Akt physiology in human health and disease. Therapeutics based on the actions of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), have recently been introduced for the treatment of type 2 diabetes mellitus. The serine/threonine kinase Akt is a major mediator of incretin action on the pancreatic islet, increasing β-cell mass and function and promoting β-cell survival. The mechanisms underlying incretin activation of Akt are thought to involve an essential phosphoinositide 3-kinase-mediated phosphorylation of threonine 308, similar to the prototypical Akt activator, insulin-like growth factor-I (IGF-I). In this study, using activity assays on immunoprecipitated Akt, we discovered that GIP and GLP-1 were capable of stimulating Akt in the INS-1 β-cell line and isolated mouse islets via a mechanism that did not require phosphoinositide 3-kinase or phosphorylation of Thr308 and Ser473, and this pathway involved the production of cAMP. Furthermore, we found that GIP stimulated anti-apoptotic signaling via this alternate mode of Akt activation. We conclude that incretins can activate Akt via a novel noncanonical mechanism that may provide an alternative therapeutic target for the treatment of type 2 diabetes mellitus and have broader implications for Akt physiology in human health and disease. |
| Author | Sampaio, Arthur V. Underhill, T. Michael Widenmaier, Scott B. McIntosh, Christopher H.S. |
| AuthorAffiliation | Department of Cellular and Physiological Sciences and the Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver V6T 1Z3, Canada |
| AuthorAffiliation_xml | – name: Department of Cellular and Physiological Sciences and the Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver V6T 1Z3, Canada |
| Author_xml | – sequence: 1 givenname: Scott B. surname: Widenmaier fullname: Widenmaier, Scott B. – sequence: 2 givenname: Arthur V. surname: Sampaio fullname: Sampaio, Arthur V. – sequence: 3 givenname: T. Michael surname: Underhill fullname: Underhill, T. Michael – sequence: 4 givenname: Christopher H.S. surname: McIntosh fullname: McIntosh, Christopher H.S. email: mcintoch@interchange.ubc.ca |
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| Copyright | 2009 © 2009 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. Copyright © 2009, The American Society for Biochemistry and Molecular Biology, Inc. |
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| Notes | To whom correspondence should be addressed: Dept. of Cellular and Physiological Sciences, Faculty of Medicine, Univ. of British Columbia, 2350 Health Sciences Mall, Vancouver, B. C. V6T 1Z3, Canada. Tel.: 604-822-3088; Fax: 604-822-2316; E-mail: mcintoch@interchange.ubc.ca. This work was supported by the Canadian Institutes of Health Research and the Canadian Foundation for Innovation (to C. H. S. M.) and scholarships from the Natural Sciences and Engineering Research Council of Canada and the Michael Smith Foundation for Health Research (to S. W.). |
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| SubjectTerms | Mechanisms of Signal Transduction |
| Title | Noncanonical Activation of Akt/Protein Kinase B in β-Cells by the Incretin Hormone Glucose-dependent Insulinotropic Polypeptide |
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