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Cited by 41Pancreatic function and diabetesDiabetes Treatment and ManagementEndoplasmic Reticulum Stress and Disease

Endogenous GLP-1 as a key self-defense molecule against lipotoxicity in pancreatic islets

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HUANG, CHENGHU, YUAN, LI, CAO, SHUYI·2015·International Journal of Molecular Medicine
DOI 10.3892/ijmm.2015.2207PMC PMC4494597
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Abstract

The number of pro-α cells is known to increase in response to β cell injury and these cells then generate glucagon-like peptide-1 (GLP-1), thus attenuating the development of diabetes. The aim of the present study was to further examine the role and the mechanisms responsible for intra-islet GLP-1 production as a self-protective response against lipotoxicity. The levels of the key enzyme, prohormone convertase 1/3 (PC1/3), as well as the synthesis and release of GLP-1 in models of lipotoxicity were measured. Furthermore, islet viability, apoptosis, oxidative stress and inflammation, as well as islet structure were assessed after altering GLP-1 receptor signaling. Both prolonged exposure to palmitate and a high-fat diet facilitated PC1/3 expression, as well as the synthesis and release of GLP-1 induced by β cell injury and the generation of pro-α cells. Prolonged exposure to palmitate increased reactive oxygen species (ROS) production, and the antioxidant, N-acetylcysteine (NAC), partially prevented the detrimental effects induced by palmitate on β cells, resulting in decreased GLP-1 levels. Furthermore, the inhibition of GLP-1 receptor (GLP-1R) signaling by treatment with exendin‑(9-39) further decreased cell viability, increased cell apoptosis and caused a stronger inhibition of the β cell-specific transcription factor, pancreatic duodenal homeobox 1 (PDX1). Moreover, treatment with the GLP-1R agonist, liraglutide, normalized islet structure and function, resulting in a decrease in cell death and in the amelioration of β cell marker expression. Importantly, liraglutide maintained the oxidative balance and decreased inflammatory factor and p65 expression. Overall, our data demonstrate that an increase in the number of pro-α cells and the activation of the intra-islet GLP-1 system comprise a self-defense mechanism for enhancing β cell survival to combat lipid overload, which is in part mediated by oxidative stress and inflammation.

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  • Liraglutide (100 nM) inhibited the palmitate-induced expression of TNF-α, IL-1β, and IL-6 and p65 expression in isolated mouse islets.

    “Liraglutide (100 nM), a long-acting GLP-1 analogue, inhibited the palmitate-induced expression of these inflammatory factors and p65 expression [43].”

    From Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control (2016) · cites this paper as [43]

    The Results section, “Liraglutide helps to attenuate islet inflammation” (page unavailable), reports that liraglutide suppressed palmitate-induced TNF-α, IL-1β and IL-6 expression in isolated islets. The Methods specify 100 nmol/l liraglutide. The paper also says liraglutide decreased p65 expression, but the cited Results passage discusses p65 in islets from high-fat-diet mice, not palmitate-induced p65 expression in isolated islets. (LLM, conf=0.87)

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Authors
HUANG, C., YUAN, L., & CAO, S.
Affiliations
Wuhan Union Hospital (CN)
ORCID
HUANG, CHENGHU
Venue
International Journal of Molecular Medicine
Publisher
Spandidos Publications
Published
2015-05-12
Volume
36
Issue
1
Pages
173-185
ISSN
  • 1107-3756 (ISSN-L)
  • 1791-244X
DOI
10.3892/ijmm.2015.2207
PMC
PMC4494597
OpenAlex
W1885312652
Cited by
41
References
5
Citations by year
2026: 5 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 6 · 2021: 5 · 2020: 5 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 4
FWCI
3.36
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • International Journal of Molecular Medicine (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China (81370880)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
glucagon-like peptide-1, lipotoxicity, pancreatic islets, beta-cell injury, prohormone convertase 1/3, palmitate, high-fat diet, oxidative stress, inflammation, GLP-1 receptor signaling, liraglutide, exendin-9-39, PDX1, apoptosis, N-acetylcysteine, type 2 diabetes
MeSH terms
Glucagon-Like Peptide-1 Receptor, Liraglutide, Glucagon-Like Peptide-1 Receptor Agonists, Acetylcysteine, Animals, Cell Survival, Cells, Cultured, Inflammation, Male, Mice, Inbred C57BL, Palmitates, Peptide Fragments, Signal Transduction, Trans-Activators, Apoptosis, Reactive Oxygen Species, Oxidative Stress, Homeodomain Proteins, Proprotein Convertase 1, Glucagon-Secreting Cells, Insulin-Secreting Cells, Mice, Transcription Factor RelA, Glucagon-Like Peptide 1, Diet, High-Fat

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