title: Insulin drives glucose-dependent insulinotropic peptide expression via glucose-dependent regulation of FoxO1 and LEF1/β-catenin.
abstract: Minutes after ingestion of fat or carbohydrates, vesicles stored in enteroendocrine cells release their content of incretin peptide hormones that, together with absorbed glucose, enhance insulin secretion by beta-pancreatic cells. Freshly-made incretins must therefore be packed into new vesicles in anticipation of the next meal with cells adjusting new incretin production to be proportional to the level of previous insulin release and absorbed blood glucose. Here we show that insulin stimulates the expression of the major human incretin, glucose-dependent insulinotropic peptide (GIP) in enteroendocrine cells but requires glucose to do it. Akt-dependent release of FoxO1 and glucose-dependent binding of LEF1/β-catenin mediate induction of Gip expression while insulin-induced phosphorylation of β-catenin does not alter its localization or transcriptional activity in enteroendocrine cells. Our results reveal a glucose-regulated feedback loop at the entero-insular axis, where glucose levels determine basal and insulin-induced Gip expression; GIP stimulation of insulin release, physiologically ensures a fine control of glucose homeostasis. How enteroendocrine cells adjust incretin production to replace incretin stores for future use is a key issue because GIP malfunction is linked to all forms of diabetes.
authors.affiliation: Department of Physiology, Biochemistry and Human Genetics, Faculty of Health Science, Rey Juan Carlos University, 28922 Alcorcon, Madrid, Spain.
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: García-Martínez
authors.affiliation: Department of Physiology, Biochemistry and Human Genetics, Faculty of Health Science, Rey Juan Carlos University, 28922 Alcorcon, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Chocarro-Calvo
authors.affiliation: Endocrine Tumor Unit (UFIEC), Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: De la Vieja
authors.affiliation: Department of Physiology, Biochemistry and Human Genetics, Faculty of Health Science, Rey Juan Carlos University, 28922 Alcorcon, Madrid, Spain. Electronic address: custodia.garcia@urjc.es.
authors.forename: Custodia
authors.initials: C
authors.lastname: García-Jiménez
mesh_terms: D002478:Cells, Cultured; D019858:Enteroendocrine Cells / Q000187:drug effects / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007328:Insulin; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D051176:beta Catenin; D005749:Gastric Inhibitory Polypeptide; D005947:Glucose
keywords: Diabetes; FoxO1; Glucose; Glucose-dependent insulinotropic peptide; Incretin; Insulin; β-Catenin