title: Regulation of Glucose Uptake and Enteroendocrine Function by the Intestinal Epithelial Insulin Receptor.
abstract: Insulin receptors (IRs) and IGF-I receptors (IGF-IR) are major regulators of metabolism and cell growth throughout the body; however, their roles in the intestine remain controversial. Here we show that genetic ablation of the IR or IGF-IR in intestinal epithelial cells of mice does not impair intestinal growth or development or the composition of the gut microbiome. However, the loss of IRs alters intestinal epithelial gene expression, especially in pathways related to glucose uptake and metabolism. More importantly, the loss of IRs reduces intestinal glucose uptake. As a result, mice lacking the IR in intestinal epithelium retain normal glucose tolerance during aging compared with controls, which show an age-dependent decline in glucose tolerance. Loss of the IR also results in a reduction of glucose-dependent insulinotropic polypeptide (GIP) expression from enteroendocrine K-cells and decreased GIP release in vivo after glucose ingestion but has no effect on glucagon-like peptide 1 expression or secretion. Thus, the IR in the intestinal epithelium plays important roles in intestinal gene expression, glucose uptake, and GIP production, which may contribute to pathophysiological changes in individuals with diabetes, metabolic syndrome, and other insulin-resistant states.
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA.|JRG Adipocytes and Metabolism, Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Center Munich, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Siegfried
authors.identifier: 0000-0001-7575-0920
authors.initials: S
authors.lastname: Ussar
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA.|Division of Clinical Chemistry and Pathobiochemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Max-Felix
authors.initials: MF
authors.lastname: Haering
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA.|First Department of Internal Medicine, University of Toyama, Toyama, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Fujisaka
authors.affiliation: German Center for Diabetes Research (DZD), Neuherberg, Germany.|Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Center Munich, Neuherberg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Lutter
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA.|Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH.|The Diabetes Institute, Ohio University, Athens, OH.
authors.forename: Kevin Y
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Center for Clinical and Translational Metagenomics, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Center for Clinical and Translational Metagenomics, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Georg K
authors.initials: GK
authors.lastname: Gerber
authors.affiliation: Center for Clinical and Translational Metagenomics, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Bry
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA c.ronald.kahn@joslin.harvard.edu.
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004275:DNA, Ribosomal / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics / Q000378:metabolism; D000069196:Gastrointestinal Microbiome / Q000235:genetics / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000254:growth & development; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D011972:Receptor, Insulin / Q000235:genetics*; D051269:Sodium-Glucose Transporter 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D004275:DNA, Ribosomal; D051273:Glucose Transporter Type 2; D012333:RNA, Messenger; C495682:Slc2a2 protein, mouse; C495675:Slc5a1 protein, mouse; D051269:Sodium-Glucose Transporter 1; D005749:Gastric Inhibitory Polypeptide; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D005947:Glucose