Glucose metabolism is altered after loss of L cells and α-cells but not influenced by loss of K cells
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Glucose metabolism is altered after loss of L cells and α-cells but not influenced by loss of K cells. / Pedersen, J; Ugleholdt, R K; Jørgensen, S M; Windeløv, J A; Grunddal, K V; Schwartz, T W; Füchtbauer, Ernst-Martin; Poulsen, S S; Holst, P J; Holst, Jens Juul.
In: American Journal of Physiology: Endocrinology and Metabolism, Vol. 304, No. 1, 01.01.2013, p. E60-73.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Glucose metabolism is altered after loss of L cells and α-cells but not influenced by loss of K cells
AU - Pedersen, J
AU - Ugleholdt, R K
AU - Jørgensen, S M
AU - Windeløv, J A
AU - Grunddal, K V
AU - Schwartz, T W
AU - Füchtbauer, Ernst-Martin
AU - Poulsen, S S
AU - Holst, P J
AU - Holst, Jens Juul
PY - 2013/1/1
Y1 - 2013/1/1
N2 - 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.
AB - 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.
KW - Animals
KW - Apoptosis
KW - Diphtheria Toxin
KW - Enteroendocrine Cells
KW - Female
KW - Gastric Inhibitory Polypeptide
KW - Gene Knockdown Techniques
KW - Genes, Transgenic, Suicide
KW - Glucagon-Secreting Cells
KW - Glucose
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Inbred DBA
KW - Mice, Transgenic
KW - Organ Specificity
U2 - 10.1152/ajpendo.00547.2011
DO - 10.1152/ajpendo.00547.2011
M3 - Journal article
C2 - 23115082
VL - 304
SP - E60-73
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
SN - 0193-1849
IS - 1
ER -
ID: 45840781