title: Impaired enteroendocrine development in intestinal-specific Islet1 mouse mutants causes impaired glucose homeostasis.
abstract: Enteroendocrine cells secrete over a dozen different hormones responsible for coordinating digestion, absorption, metabolism, and gut motility. Loss of enteroendocrine cells is a known cause of severe congenital diarrhea. Furthermore, enteroendocrine cells regulate glucose metabolism, with the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) playing critical roles in stimulating insulin release by pancreatic β-cells. Islet1 (Isl1) is a LIM-homeodomain transcription factor expressed specifically in an array of intestinal endocrine cells, including incretin-expressing cells. To examine the impact of intestinal Isl1 on glycemic control, we set out to explore the role of intestinal Isl1 in hormone cell specification and organismal physiology. Mice with intestinal epithelial-specific ablation of Isl1 were obtained by crossing Villin-Cre transgenic animals with mice harboring a Isl1(loxP) allele (Isl1(int) model). Gene ablation of Isl1 in the intestine results in loss of GLP-1, GIP, cholecystokinin (CCK), and somatostatin-expressing cells and an increase in 5-HT (serotonin)-producing cells, while the chromogranin A population was unchanged. This dramatic change in hormonal milieu results in animals with lipid malabsorption and females smaller than their littermate controls. Interestingly, when challenged with oral, not intraperitoneal glucose, the Isl-1 intestinal-deficient animals (Isl1(int)) display impaired glucose tolerance, indicating loss of the incretin effect. Thus the Isl1(int) model confirms that intestinal biology is essential for organism physiology in glycemic control and susceptibility to diabetes.
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Division of Gastroenterology and Nutrition, Department of Pediatrics, Philadelphia, Pennsylvania; Department of Pathology and Laboratory Medicine, Philadelphia, Pennsylvania; and terryn@email.chop.edu.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Terry
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pathology and Laboratory Medicine, Philadelphia, Pennsylvania; and.
authors.forename: Erik R
authors.initials: ER
authors.lastname: Walp
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Division of Gastroenterology and Nutrition, Department of Pediatrics, Philadelphia, Pennsylvania;
authors.forename: Randall A
authors.initials: RA
authors.lastname: Lee
authors.affiliation: Perelman School of Medicine at the University of Pennsylvania, Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Philadelphia, Pennsylvania.
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Division of Gastroenterology and Nutrition, Department of Pediatrics, Philadelphia, Pennsylvania; Department of Pathology and Laboratory Medicine, Philadelphia, Pennsylvania; and.
authors.forename: Catherine Lee
authors.initials: CL
authors.lastname: May
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D002766:Cholecystokinin / Q000378:metabolism; D053379:Chromogranin A / Q000378:metabolism; D003967:Diarrhea / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism; D019858:Enteroendocrine Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D005755:Gastrins / Q000378:metabolism; D005838:Genotype; D054439:Ghrelin / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D044882:Glucose Metabolism Disorders / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005951:Glucose Tolerance Test; D019426:Integrases / Q000235:genetics; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism* / Q000473:pathology; D060850:LIM-Homeodomain Proteins / Q000172:deficiency* / Q000235:genetics; D008286:Malabsorption Syndromes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics; D010641:Phenotype; D012701:Serotonin / Q000378:metabolism; D013004:Somatostatin / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D015430:Weight Gain
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D053379:Chromogranin A; D004041:Dietary Fats; D005755:Gastrins; D054439:Ghrelin; D060850:LIM-Homeodomain Proteins; D008840:Microfilament Proteins; D014157:Transcription Factors; C506155:chromogranin A, mouse; C063843:insulin gene enhancer binding protein Isl-1; C026615:villin; D012701:Serotonin; D013004:Somatostatin; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D002766:Cholecystokinin; C045073:Cre recombinase; D019426:Integrases
keywords: Islet1; enteroendocrine; glucose regulation; incretins