Dataset Information

The impact of the glucagon-like peptide 1 receptor agonist liraglutide on the streptozotocin-induced diabetic mouse kidney proteome.

ABSTRACT: In diabetes mellitus (DM), the kidneys are exposed to increased levels of hyperglycemia-induced oxidative stress. Elevated amounts of reactive oxygen species (ROS) are believed to provoke ultrastructural changes in kidney tissue and can eventually result in DM late complications such as diabetic nephropathy. While it is reported that glucagon-like peptide 1 receptors (GLP-1R) are present in the kidney vasculature, the effects of GLP-1 on the kidney proteome in DM is not well described. Thus, we set out to investigate potential effects on the proteomic level. Here the effects of GLP-1R agonism using the GLP-1 analogue liraglutide are studied in the kidneys of streptozotocin (STZ)-treated mice (n = 6/group) by label-free shotgun mass spectrometry (MS) and targeted MS. Unsupervised and supervised multivariate analyses are followed by one-way ANOVA. Shotgun MS data of vehicle and liraglutide-treated mouse groups are separated in the supervised multivariate analysis and separation is also achieved in the subsequent unsupervised multivariate analysis using targeted MS data. The mouse group receiving the GLP-1R agonist liraglutide has increased protein abundances of glutathione peroxidase-3 (GPX3) and catalase (CATA) while the abundances of neuroplastin (NPTN) and bifunctional glutamate/proline-tRNA ligase (SYEP) are decreased compared to the STZ vehicle mice. The data suggest that GLP-1R agonism mainly influences abundances of structurally involved proteins and proteins involved in oxidative stress responses in the STZ mouse kidney. The changes could be direct effects of GLP-1R agonism in the kidneys or indirectly caused by a systemic response to GLP-1R activation.

SUBMITTER: Liljedahl L

PROVIDER: S-EPMC6389751 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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The impact of the glucagon-like peptide 1 receptor agonist liraglutide on the streptozotocin-induced diabetic mouse kidney proteome.

Liljedahl Leena L Pedersen Maiken H MH McGuire James N JN James Peter P

Physiological reports 20190201 4

In diabetes mellitus (DM), the kidneys are exposed to increased levels of hyperglycemia-induced oxidative stress. Elevated amounts of reactive oxygen species (ROS) are believed to provoke ultrastructural changes in kidney tissue and can eventually result in DM late complications such as diabetic nephropathy. While it is reported that glucagon-like peptide 1 receptors (GLP-1R) are present in the kidney vasculature, the effects of GLP-1 on the kidney proteome in DM is not well described. Thus, we ...[more]

PMID: 30806030

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Project description:BackgroundThe glucagon-like peptide-1 receptor (GLP1R) agonist liraglutide improves glycemic control and reduces body weight of adult type 2 diabetic patients. However, efficacy and safety of liraglutide in adolescents has not been systematically investigated. Furthermore, possible pro-proliferative effects of GLP1R agonists on the endocrine and exocrine pancreas need to be further evaluated. We studied effects of liraglutide in adolescent pigs expressing a dominant-negative glucose-dependent insulinotropic polypeptide receptor (GIPR(dn)) in the beta-cells, leading to a pre-diabetic condition including disturbed glucose tolerance, reduced insulin secretion and progressive reduction of functional beta-cell mass.MethodsTwo-month-old GIPR(dn) transgenic pigs were treated daily with liraglutide (0.6-1.2 mg per day) or placebo for 90 days. Glucose homeostasis was evaluated prior to and at the end of the treatment period by performing mixed meal and intravenous glucose tolerance tests (MMGTT and IVGTT). Finally animals were subjected to necropsy and quantitative-stereological analyses were performed for evaluation of alpha- and beta-cell mass, beta-cell proliferation as well as acinus-cell proliferation.ResultsMMGTT at the end of the study revealed 23% smaller area under the curve (AUC) for glucose, a 36% smaller AUC insulin, and improved insulin sensitivity, while IVGTT showed a 15% smaller AUC glucose but unchanged AUC insulin in liraglutide- vs. placebo-treated animals. Liraglutide led to marked reductions in body weight gain (-31%) and food intake (-30%) compared to placebo treatment, associated with reduced phosphorylation of insulin receptor beta (INSRB)/insulin-like growth factor-1 receptor beta (IGF1RB) and protein kinase B (AKT) in skeletal muscle. Absolute alpha- and beta-cell mass was reduced in liraglutide-treated animals, but alpha- and beta-cell mass-to-body weight ratios were unchanged. Liraglutide neither stimulated beta-cell proliferation in the endocrine pancreas nor acinus-cell proliferation in the exocrine pancreas, excluding both beneficial and detrimental effects on the pig pancreas.ConclusionsAlthough plasma liraglutide levels of adolescent transgenic pigs treated in our study were higher compared to human trials, pro-proliferative effects on the endocrine or exocrine pancreas or other liraglutide-related side-effects were not observed.

Dataset Information

The impact of the glucagon-like peptide 1 receptor agonist liraglutide on the streptozotocin-induced diabetic mouse kidney proteome.

Publications

The impact of the glucagon-like peptide 1 receptor agonist liraglutide on the streptozotocin-induced diabetic mouse kidney proteome.

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