title: Islet amyloid polypeptide exerts a novel autocrine action in β-cell signaling and proliferation.
abstract: The toxic effects of human islet amyloid polypeptide (IAPP) on pancreatic islets have been widely studied. However, much less attention has been paid to the physiologic actions of IAPP on pancreatic β cells, which secrete this peptide together with insulin upon glucose stimulation. Here, we aimed to explore the signaling pathways and mitogenic actions of IAPP on β cells. We show that IAPP activated Erk1/2 and v-akt murine thymoma viral oncogene homolog 1 (Akt) at the picomolar range (10-100 pM) in mouse pancreatic islets and MIN6 β cells cultured at low glucose concentrations. In contrast, IAPP decreased the induction of these pathways by high glucose levels. Consistently, IAPP induced a 1.7-fold increase of β-cell proliferation at low-glucose conditions, whereas it reduced β-cell proliferation at high glucose levels. Strikingly, the specific antagonist of the IAPP receptor AC187 (100 nM) decreased the activation of Erk1/2 and Akt and reduced β-cell proliferation by 24% in glucose-stimulated β cells, uncovering a key role of endogenously released IAPP in β-cell responses to glucose. We conclude that exogenously added IAPP exerts a dual effect on β-cell mitogenic signaling and proliferation, depending on the glucose concentration. Importantly, secreted IAPP contributes to the signaling and mitogenic response of β cells to glucose through an autocrine mechanism.
authors: *Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain; and Department of Metabolism, Nutrition and Hormones, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain.
authors: Montse
authors: M
authors: Visa
authors: *Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain; and Department of Metabolism, Nutrition and Hormones, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain.
authors: Gema
authors: G
authors: Alcarraz-Vizán
authors: *Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain; and Department of Metabolism, Nutrition and Hormones, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain.
authors: Joel
authors: J
authors: Montane
authors: *Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain; and Department of Metabolism, Nutrition and Hormones, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain.
authors: Lisa
authors: L
authors: Cadavez
authors: *Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain; and Department of Metabolism, Nutrition and Hormones, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain.
authors: Carlos
authors: C
authors: Castaño
authors: *Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain; and Department of Metabolism, Nutrition and Hormones, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain.
authors: María Luisa
authors: ML
authors: Villanueva-Peñacarrillo
authors: *Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain; and Department of Metabolism, Nutrition and Hormones, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain servitja@clinic.ub.es anovials@clinic.ub.es.
authors: Joan-Marc
authors: JM
authors: Servitja
authors: *Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain; and Department of Metabolism, Nutrition and Hormones, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain servitja@clinic.ub.es anovials@clinic.ub.es.
authors: Anna
authors: A
authors: Novials
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058287:Receptors, Islet Amyloid Polypeptide / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D007328:Insulin; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; D058287:Receptors, Islet Amyloid Polypeptide; C087166:AC 187; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
keywords: Akt; Erk1/2; amylin; pancreatic islets; type 2 diabetes