Pedersen, J2; Ugleholdt, Randi Kjærsgaard3; Jørgensen, Signe Marie3; Windeløv, Johanne Agerlin3; Grunddal, Kaare Villum4; Schwartz, T W4; Füchtbauer, Ernst-Martin8; Poulsen, S S5; Holst, P J6; Holst, J J7
1 Department of Molecular Biology and Genetics - Molecular Cell and Developmental Biology, Department of Molecular Biology and Genetics, Science and Technology, Aarhus University2 Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. email@example.com 1Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen4 Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen5 Depatment of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen6 Department of International Health Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen7 Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen8 Department of Molecular Biology and Genetics - Molecular Cell and Developmental Biology, Department of Molecular Biology and Genetics, Science and Technology, Aarhus University
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.
American Journal of Physiology: Endocrinology and Metabolism, 2013, Vol 304, Issue 1