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The incretin effect in female mice with double deletion of GLP-1 and GIP receptors

Ahrén, Bo LU ; Yamada, Yuichiro and Seino, Yutaka (2020) In Journal of the Endocrine Society 4(2).
Abstract

To establish the contribution of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) for the incretin effect after oral glucose, studies were undertaken in female mice with genetic deletion of receptors for GIP and GLP-1 (double incretin receptor knockout [DIRKO] mice) and their wild-type (WT) counterparts. Insulin secretion was explored after oral glucose (doses ranging from 0 to 100 mg), after intravenous glucose (doses ranging from 0 to 0.75 g/kg), and after oral and intravenous glucose at matching circulating glucose. DIRKO mice had glucose intolerance after oral glucose challenges in association with impaired beta-cell function. Suprabasal area under the curve for C-peptide... (More)

To establish the contribution of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) for the incretin effect after oral glucose, studies were undertaken in female mice with genetic deletion of receptors for GIP and GLP-1 (double incretin receptor knockout [DIRKO] mice) and their wild-type (WT) counterparts. Insulin secretion was explored after oral glucose (doses ranging from 0 to 100 mg), after intravenous glucose (doses ranging from 0 to 0.75 g/kg), and after oral and intravenous glucose at matching circulating glucose. DIRKO mice had glucose intolerance after oral glucose challenges in association with impaired beta-cell function. Suprabasal area under the curve for C-peptide (AUCC-peptide) correlated linearly with suprabasal AUCglucose both in WT (r = 0.942, P = .017) and DIRKO mice (r = 0.972, P = .006). The slope of this regression was lower in DIRKO than in WT mice (0.012 ± 0.006 vs 0.031 ± 0.006 nmol C-peptide/mmol glucose, P = .042). In contrast, there was no difference in the insulin response to intravenous glucose between WT and DIRKO mice. Furthermore, oral and intravenous glucose administration at matching glucose levels showed that the augmentation of insulin secretion after oral glucose (the incretin effect) in WT mice (11.8 ± 2.3 nmol/L min) was entirely absent in DIRKO mice (3.3 ± 1.2 nmol/L min). We conclude that GIP and GLP-1 are required for normal glucose tolerance and beta-cell function after oral glucose in mice, that they are the sole incretin hormones after oral glucose at higher dose levels, and that they contribute by 65% to insulin secretion after oral glucose.

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author
; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animal models, Glucose tolerance, Incretin effect, Incretin hormones, Insulin secretion
in
Journal of the Endocrine Society
volume
4
issue
2
article number
bvz036
publisher
Oxford University Press
external identifiers
  • scopus:85083052331
  • pmid:32010875
ISSN
2472-1972
DOI
10.1210/jendso/bvz036
language
English
LU publication?
yes
id
256a8c84-f6a5-47b0-a7d1-5f5c82d70d70
date added to LUP
2020-05-07 15:30:59
date last changed
2022-09-09 19:41:16
@article{256a8c84-f6a5-47b0-a7d1-5f5c82d70d70,
  abstract     = {{<p>To establish the contribution of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) for the incretin effect after oral glucose, studies were undertaken in female mice with genetic deletion of receptors for GIP and GLP-1 (double incretin receptor knockout [DIRKO] mice) and their wild-type (WT) counterparts. Insulin secretion was explored after oral glucose (doses ranging from 0 to 100 mg), after intravenous glucose (doses ranging from 0 to 0.75 g/kg), and after oral and intravenous glucose at matching circulating glucose. DIRKO mice had glucose intolerance after oral glucose challenges in association with impaired beta-cell function. Suprabasal area under the curve for C-peptide (AUC<sub>C-peptide</sub>) correlated linearly with suprabasal AUC<sub>glucose</sub> both in WT (r = 0.942, P = .017) and DIRKO mice (r = 0.972, P = .006). The slope of this regression was lower in DIRKO than in WT mice (0.012 ± 0.006 vs 0.031 ± 0.006 nmol C-peptide/mmol glucose, P = .042). In contrast, there was no difference in the insulin response to intravenous glucose between WT and DIRKO mice. Furthermore, oral and intravenous glucose administration at matching glucose levels showed that the augmentation of insulin secretion after oral glucose (the incretin effect) in WT mice (11.8 ± 2.3 nmol/L min) was entirely absent in DIRKO mice (3.3 ± 1.2 nmol/L min). We conclude that GIP and GLP-1 are required for normal glucose tolerance and beta-cell function after oral glucose in mice, that they are the sole incretin hormones after oral glucose at higher dose levels, and that they contribute by 65% to insulin secretion after oral glucose.</p>}},
  author       = {{Ahrén, Bo and Yamada, Yuichiro and Seino, Yutaka}},
  issn         = {{2472-1972}},
  keywords     = {{Animal models; Glucose tolerance; Incretin effect; Incretin hormones; Insulin secretion}},
  language     = {{eng}},
  number       = {{2}},
  publisher    = {{Oxford University Press}},
  series       = {{Journal of the Endocrine Society}},
  title        = {{The incretin effect in female mice with double deletion of GLP-1 and GIP receptors}},
  url          = {{http://dx.doi.org/10.1210/jendso/bvz036}},
  doi          = {{10.1210/jendso/bvz036}},
  volume       = {{4}},
  year         = {{2020}},
}