PMID- 34497830
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210910
IS  - 2296-889X (Print)
IS  - 2296-889X (Electronic)
IS  - 2296-889X (Linking)
VI  - 8
DP  - 2021
TI  - Glucotoxicity Activation of IL6 and IL11 and Subsequent Induction of Fibrosis May 
      Be Involved in the Pathogenesis of Islet Dysfunction.
PG  - 708127
LID - 10.3389/fmolb.2021.708127 [doi]
LID - 708127
AB  - Background: Islet dysfunction is the main pathological process of type 2 diabetes 
      mellitus (T2DM). Fibrosis causes islet dysfunction, but the current mechanism is 
      still unclear. Here, bioinformatics analysis identified gene clusters closely 
      related to T2DM and differentially expressed genes related to fibrosis, and 
      animal models verified the roles of these genes. Methods: Human islet 
      transcriptomic datasets were obtained from the Gene Expression Omnibus (GEO), and 
      weighted gene coexpression network analysis (WGCNA) was applied to screen the key 
      gene modules related to T2DM and analyze the correlations between the modules and 
      clinical characteristics. Enrichment analysis was performed to identify the 
      functions and pathways of the key module genes. WGCNA, protein-protein 
      interaction (PPI) analysis and receiver operating characteristic (ROC) curve 
      analysis were used to screen the hub genes. The hub genes were verified in 
      another GEO dataset, the islets of high-fat diet (HFD)-fed Sprague-Dawley rats 
      were observed by H&E and Masson's trichrome staining, the fibrotic proteins were 
      verified by immunofluorescence, and the hub genes were tested by 
      immunohistochemistry. Results: The top 5,000 genes were selected according to the 
      median absolute deviation, and 18 modules were analyzed. The yellow module was 
      highly associated with T2DM, and its positive correlation with glycated 
      hemoglobin (HbA1c) was significantly stronger than that with body mass index 
      (BMI). Enrichment analysis revealed that extracellular matrix organization, the 
      collagen-containing extracellular matrix and cytokine-cytokine receptor 
      interaction might influence T2DM progression. The top three hub genes, 
      interleukin 6 (IL6), IL11 and prostaglandin-endoperoxide synthase 2 (PTGS2), 
      showed upregulated expression in T2DM. In the validation dataset, IL6, IL11, and 
      PTGS2 levels were upregulated in T2DM, and IL6 and PTGS2 expression was 
      positively correlated with HbA1c and BMI; however, IL11 was positively correlated 
      only with HbA1c. In HFD-fed Sprague-Dawley rats, the positive of IL6 and IL11 in 
      islets was stronger, but PTGS2 expression was not significantly altered. The 
      extent of fibrosis, irregular cellular arrangement and positive actin alpha 2 
      (ACTA2) staining in islets was significantly greater in HFD-fed rats than in 
      normal diet-fed rats. Conclusion: Glucotoxicity is a major factor leading to 
      increased IL6 and IL11 expression, and IL6-and IL11-induced fibrosis might be 
      involved in islet dysfunction.
CI  - Copyright (c) 2021 Lu, Zhuang, Shen and Yang.
FAU - Lu, Liqin
AU  - Lu L
AD  - Endocrinology Department, The First Affifiliated Hospital of Fujian Medical 
      University, Fuzhou, China.
FAU - Zhuang, Lili
AU  - Zhuang L
AD  - Endocrinology Department, The First Affifiliated Hospital of Fujian Medical 
      University, Fuzhou, China.
FAU - Shen, Ximei
AU  - Shen X
AD  - Endocrinology Department, The First Affifiliated Hospital of Fujian Medical 
      University, Fuzhou, China.
AD  - Diabetes Research Institute of Fujian Province, Fuzhou, China.
FAU - Yang, Liyong
AU  - Yang L
AD  - Endocrinology Department, The First Affifiliated Hospital of Fujian Medical 
      University, Fuzhou, China.
AD  - Diabetes Research Institute of Fujian Province, Fuzhou, China.
LA  - eng
PT  - Journal Article
DEP - 20210823
PL  - Switzerland
TA  - Front Mol Biosci
JT  - Frontiers in molecular biosciences
JID - 101653173
PMC - PMC8419433
OTO - NOTNLM
OT  - IL11
OT  - IL6
OT  - T2DM
OT  - WGCNA
OT  - fibrosis
OT  - glycotoxicity
OT  - islet dysfunction
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/09/10 06:00
MHDA- 2021/09/10 06:01
PMCR- 2021/01/01
CRDT- 2021/09/09 06:53
PHST- 2021/05/11 00:00 [received]
PHST- 2021/08/02 00:00 [accepted]
PHST- 2021/09/09 06:53 [entrez]
PHST- 2021/09/10 06:00 [pubmed]
PHST- 2021/09/10 06:01 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 708127 [pii]
AID - 10.3389/fmolb.2021.708127 [doi]
PST - epublish
SO  - Front Mol Biosci. 2021 Aug 23;8:708127. doi: 10.3389/fmolb.2021.708127. 
      eCollection 2021.