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

Pedersen J, Ugleholdt RK, Jorgensen SM, Windelov JA, Grunddal KV, Schwartz TW, Fuchtbauer EM, Poulsen SS, Holst PJ, Holst JJ. Glucose metabolism is altered after loss of L cells and alpha-cells but not influenced by loss of K cells. Am J Physiol Endocrinol Metab 304: E60-E73, 2013. First published October 31, 2012; doi:10.1152/ajpendo.00547.2011.-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 alpha-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 alpha-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 alpha-cell loss and normal following alpha-cell loss. Oral glucose tolerance was improved following L cell and alpha-cell loss and supernormal following alpha-cell loss. We present two mouse models that allow studies of the effects of K cell or L cell and alpha-cell loss as well as isolated alpha-cell loss. Our findings show that intraperitoneal glucose tolerance is dependent on an intact L cell mass and underscore the diabetogenic effects of alpha-cell signaling. Furthermore, the results suggest that K cells are less involved in acute regulation of mouse glucose metabolism than L cells and alpha-cells.