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

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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.
Original languageEnglish
JournalAmerican Journal of Physiology: Endocrinology and Metabolism
Issue number1
Pages (from-to)E60-73
Number of pages14
Publication statusPublished - 1 Jan 2013

    Research areas

  • Animals, Apoptosis, Diphtheria Toxin, Enteroendocrine Cells, Female, Gastric Inhibitory Polypeptide, Gene Knockdown Techniques, Genes, Transgenic, Suicide, Glucagon-Secreting Cells, Glucose, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Organ Specificity

ID: 45840781