Liraglutide regulates the viability of pancreatic α-cells and pancreatic β-cells through cAMP-PKA signal pathway

Xu, Xuejuan; Chen, Jinsong; Li-dong, HU; Ming, Liang; Wang, Xiaozhou; Feng, Suying; Shen, Jie; L, Xin

doi:10.1016/j.lfs.2017.12.012

Cited by 11 publications

(8 citation statements)

References 38 publications

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“…These results suggest that the role of this drug in ameliorating hyperglycemia follows a mechanism that is non-exclusive to β-cells and has other players involved, such as islet insulin + glucagon + cells and ductal insulin-expressing cells. The herein reported findings go beyond the previously reported beneficial effect of liraglutide in β-cell function, both in vivo (39) and in vitro in terms of insulin secretion (51). However, neogenesis from ducts was not reported in a previous study due to differences in dosage, disease induction, and especially lineage tracing issues (39).…”

Section: Discussionsupporting

confidence: 42%

Repurposed Analog of GLP-1 Ameliorates Hyperglycemia in Type 1 Diabetic Mice Through Pancreatic Cell Reprogramming

et al. 2020

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Type 1 diabetes is an autoimmune disease caused by the destruction of the insulin-producing β-cells. An ideal immunotherapy should combine the blockade of the autoimmune response with the recovery of functional target cell mass. With the aim to develop new therapies for type 1 diabetes that could contribute to β-cell mass restoration, a drug repositioning analysis based on systems biology was performed to identify the β-cell regenerative potential of commercially available compounds. Drug repositioning is a strategy used for identifying new uses for approved drugs that are outside the scope of the medical indication. A list of 28 non-synonymous repurposed drug candidates was obtained, and 16 were selected as diabetes mellitus type 1 treatment candidates regarding pancreatic β-cell regeneration. Drugs with poor safety profile were further filtered out. Lastly, we selected liraglutide for its predictive efficacy values for neogenesis, transdifferentiation of α-cells, and/or replication of pre-existing β-cells. Liraglutide is an analog of glucagon-like peptide-1, a drug used in patients with type 2 diabetes. Liraglutide was tested in immunodeficient NOD-Scid IL2rg −/− (NSG) mice with type 1 diabetes. Liraglutide significantly improved the blood glucose levels in diabetic NSG mice. During the treatment, a significant increase in β-cell mass was observed due to a boost in β-cell number. Both parameters were reduced after withdrawal. Interestingly, islet bihormonal glucagon + insulin + cells and insulin + ductal cells arose during treatment. In vitro experiments showed an increase of insulin and glucagon gene expression in islets cultured with liraglutide in normoglycemia conditions. These results point to β-cell replacement, including transdifferentiation and neogenesis, as aiding factors and support the role of liraglutide in β-cell mass restoration in type 1 diabetes. Understanding the mechanism of action of this drug could have potential clinical relevance in this autoimmune disease.

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Section: Discussionsupporting

confidence: 42%

Repurposed Analog of GLP-1 Ameliorates Hyperglycemia in Type 1 Diabetic Mice Through Pancreatic Cell Reprogramming

et al. 2020

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“…Activation of cAMP signaling pathway by liraglutide improved islet β cell viability, which could contribute to T2D therapy. 42 Purple module was related to PPAR signaling pathway ( Figure 7D ). Our previous study has demonstrated that PPAR pathway promoted β-cell generation from embryonic stem cells coupled with mitochondrial biogenesis.…”

Section: Discussionmentioning

confidence: 99%

Identification of key gene pathways and coexpression networks of islets in human type 2 diabetes

Pan

Yang

et al. 2018

DMSO

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PurposeThe number of people with type 2 diabetes (T2D) is growing rapidly worldwide. Islet β-cell dysfunction and failure are the main causes of T2D pathological processes. The aim of this study was to elucidate the underlying pathways and coexpression networks in T2D islets.Materials and methodsWe analyzed the differentially expressed genes (DEGs) in the data set GSE41762, which contained 57 nondiabetic and 20 diabetic samples, and developed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Protein–protein interaction (PPI) network, the modules from the PPI network, and the gene annotation enrichment of modules were analyzed as well. Moreover, a weighted correlation network analysis (WGCNA) was applied to screen critical gene modules and coexpression networks and explore the biological significance.ResultsWe filtered 957 DEGs in T2D islets. Then GO and KEGG analyses identified that key pathways like inflammatory response, type B pancreatic cell differentiation, and calcium ion-dependent exocytosis were involved in human T2D. Three significant modules were filtered from the PPI network. Ribosome biogenesis, extrinsic apoptotic signaling pathway, and membrane depolarization during action potential were associated with the modules, respectively. Furthermore, coexpression network analysis by WGCNA identified 13 distinct gene modules of T2D islets and revealed four modules, which were strongly correlated with T2D and T2D biomarker hemoglobin A1c (HbA1c). Functional annotation showed that these modules mainly enriched KEGG pathways such as NF-kappa B signaling pathway, tumor necrosis factor signaling pathway, cyclic adenosine monophosphate signaling pathway, and peroxisome proliferators-activated receptor signaling pathway.ConclusionThe results provide potential gene pathways and underlying molecular mechanisms for the prevention, diagnosis, and treatment of T2D.

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“…Regarding monitoring of the administered antidiabetic treatment, there is also limited evidence to support the role of miRNA-375. Xu et al recently published the results of their study in a mouse model, demonstrating that liraglutide treatment increased miRNA-375 and cell apoptosis in pancreatic α-cells via inhibition of the cAMP-PKA signaling pathway, while it activated the same pathway in β-cells, resulting in downregulation of miRNA-375 [30]. In an experimental mouse model of high fat diet induced obesity, Lee et al demonstrated that exenatide, another GLP-1 receptor agonist, ameliorates serum levels of miRNA-375, reflecting the improvement in insulin sensitivity.…”

Section: Mirna-375: Diagnostic and Prognostic Implicationsmentioning

confidence: 99%

Is miRNA-375 a promising biomarker for early detection and monitoring of patients with type 2 diabetes?

Patoulias¹

2018

Arch Med Sci Atheroscler Dis

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miRNAs are small, non-coding RNAs, functioning as negative suppressors of target gene expression. A significant proportion of the transcriptome is subject to miRNA modulation. A single miRNA determines the expression of hundreds of genes, while miRNAs are relatively stable in biological fluids. Thus, they have attracted scientific interest regarding their use as biomarkers for several diseases. miRNA-375 mainly influences β-cell function and insulin secretion. Several studies, primarily experimental, have assessed its role as a biomarker in type 2 diabetes, while recently obtained human evidence supports this potential role. Besides its diagnostic potential, miRNA-375 may also have therapeutic implications. In view of the growing epidemic of type 2 diabetes, there is an unmet need for identification of biomarkers for early recognition and monitoring of these patients. Long-term, prospective human studies are required to elucidate whether miRNA-375 can evolve as a key player in diagnosis and prognosis of type 2 diabetes.

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Liraglutide regulates the viability of pancreatic α-cells and pancreatic β-cells through cAMP-PKA signal pathway

Cited by 11 publications

References 38 publications

Repurposed Analog of GLP-1 Ameliorates Hyperglycemia in Type 1 Diabetic Mice Through Pancreatic Cell Reprogramming

Repurposed Analog of GLP-1 Ameliorates Hyperglycemia in Type 1 Diabetic Mice Through Pancreatic Cell Reprogramming

Identification of key gene pathways and coexpression networks of islets in human type 2 diabetes

Is miRNA-375 a promising biomarker for early detection and monitoring of patients with type 2 diabetes?

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