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Glucose metabolism is altered after loss of L cells and α-cells but not influenced by loss of K cells

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  • J Pedersen, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. jensp@sund.ku.dk, Danmark
  • Randi Kjærsgaard Ugleholdt, 1Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Danmark
  • Signe Marie Jørgensen, 1Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Danmark
  • Johanne Agerlin Windeløv, 1Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Danmark
  • Kaare Villum Grunddal, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Danmark
  • T W Schwartz, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
  • ,
  • Ernst-Martin Füchtbauer
  • S S Poulsen, Depatment of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Danmark
  • P J Holst, Department of International Health Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, Danmark
  • J J Holst, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Danmark
The enteroendocrine K and L cells are responsible for secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon like-peptide 1 (GLP-1), whereas pancreatic α-cells are responsible for secretion of glucagon. In rodents and humans, dysregulation of the secretion of GIP, GLP-1, and glucagon is associated with impaired regulation of metabolism. This study evaluates the consequences of acute removal of Gip- or Gcg-expressing cells on glucose metabolism. Generation of the two diphtheria toxin receptor cellular knockout mice, TgN(GIP.DTR) and TgN(GCG.DTR), allowed us to study effects of acute ablation of K and L cells and α-cells. Diphtheria toxin administration reduced the expression of Gip and content of GIP in the proximal jejunum in TgN(GIP.DTR) and expression of Gcg and content of proglucagon-derived peptides in both proximal jejunum and terminal ileum as well as content of glucagon in pancreas in TgN(GCG.DTR) compared with wild-type mice. GIP response to oral glucose was attenuated following K cell loss, but oral and intraperitoneal glucose tolerances were unaffected. Intraperitoneal glucose tolerance was impaired following combined L cell and α-cell loss and normal following α-cell loss. Oral glucose tolerance was improved following L cell and α-cell loss and supernormal following α-cell loss. We present two mouse models that allow studies of the effects of K cell or L cell and α-cell loss as well as isolated α-cell loss. Our findings show that intraperitoneal glucose tolerance is dependent on an intact L cell mass and underscore the diabetogenic effects of α-cell signaling. Furthermore, the results suggest that K cells are less involved in acute regulation of mouse glucose metabolism than L cells and α-cells.
OriginalsprogEngelsk
TidsskriftAmerican Journal of Physiology: Endocrinology and Metabolism
Vol/bind304
Nummer1
Sider (fra-til)E60-E73
Antal sider13
ISSN0193-1849
DOI
StatusUdgivet - 1 jan. 2013

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