title: Glucose metabolism is altered after loss of L cells and α-cells but not influenced by loss of K cells.
abstract: 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.
authors.affiliation: Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. jensp@sund.ku.dk
authors.forename: J
authors.initials: J
authors.lastname: Pedersen
authors.forename: R K
authors.initials: RK
authors.lastname: Ugleholdt
authors.forename: S M
authors.initials: SM
authors.lastname: Jørgensen
authors.forename: J A
authors.initials: JA
authors.lastname: Windeløv
authors.forename: K V
authors.initials: KV
authors.lastname: Grunddal
authors.forename: T W
authors.initials: TW
authors.lastname: Schwartz
authors.forename: E M
authors.initials: EM
authors.lastname: Füchtbauer
authors.forename: S S
authors.initials: SS
authors.lastname: Poulsen
authors.forename: P J
authors.initials: PJ
authors.lastname: Holst
authors.forename: J J
authors.initials: JJ
authors.lastname: Holst
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D004167:Diphtheria Toxin / Q000235:genetics; D019858:Enteroendocrine Cells / Q000145:classification / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D055785:Gene Knockdown Techniques; D041722:Genes, Transgenic, Suicide / Q000235:genetics; D050416:Glucagon-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000235:genetics
chemical_list: D004167:Diphtheria Toxin; D005749:Gastric Inhibitory Polypeptide; D005947:Glucose