Immunohistochemical assessment of glucagon‐like peptide 1 receptor (<scp>GLP‐1R</scp>) expression in the pancreas of patients with type 2 diabetes

Kirk, Rikke Kaae; Pyke, Charles; Herrath, Matthias G. von; Hasselby, Jane Preuss; Pedersen, Lars; Mortensen, Pia Gottrup; Knudsen, Lotte Bjerre; Coppieters, Ken

doi:10.1111/dom.12879

Cited by 20 publications

(18 citation statements)

References 32 publications

(63 reference statements)

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“…Meanwhile, the expression of another lncRNA, MALAT1, was significantly higher in pancreatic the duct of adenocarcinoma than in paracancerous tissues [16]. In addition, GLP1, as an incretin hormone, stimulates the release of insulin and represses glucagon secretion from the pancreas in a glucose-dependent manner [19]. The activation of GLP1 and GIP1R has been found to result in non-glycemic effects on various tissues by expressing incretin receptors [20].…”

Section: Discussionmentioning

confidence: 99%

LINC01121 Inhibits Cell Apoptosis While Facilitating Proliferation, Migration, and Invasion Though Negative Regulation of the Camp/PKA Signaling Pathway via GLP1R

Qian¹,

Zhou²,

Chen³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Pancreatic cancer is an aggressive malignancy as a result of highly metastatic potential. The current study was carried out to alter the expression of LINC01121 in pancreatic cancer, with the aim of elucidating its effects on the biological processes of cell proliferation, migration, invasion, and apoptosis. We hypothesized that both the GLP1R gene and cAMP/PKA signaling pathway participate in the aforementioned process. Methods: Microarray data (GSE14245, GSE27890 and GSE16515) and annotating probe files linked to pancreatic cancer were downloaded through the GEO database. The Multi Experiment Matrix (MEM) site was used to predict the target gene of lncRNA. Both pancreatic cancer tissues (n = 56) and paracancerous tissues (n = 45) were collected from patients diagnosed with pancreatic cancer. Immunohistochemistry was applied to identify the positive expression rate of GLP1R protein. Isolated pancreatic cancer cells and PANC-1 cells were independently classified into the blank, negative control (NC), LINC01121 vector, siRNA-LINC01121, siRNA-GLP1R and siRNA-LINC01121 + siRNA-GLP1R groups. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were applied to detect the expressions of LINC01121, GLP1R, cAMP, PKA, CREB, Bcl-2, Bad and PCNA. Cell proliferation, migration, invasion, cycle progression, and apoptosis were examined by MTT assay, scratch test, Transwell assay and flow cytometry analyses of Annexin V-FITC/PI staining. Results: Observations were made indicating that LINC01121 was highly expressed, while low expressions of GLP1R in pancreatic cancer were detected based on microarray data, which was largely in consistent with the data collected of LINC01121 and GLP1R within the tissues. The target prediction program and luciferase activity analysis was testament to the notion suggesting that GLP1R was indeed a target of LINC01121. In contrast to the blank and NC groups, the LINC01121 vector group exhibited increased expressions of LINC01121; decreased mRNA and protein levels of GLP1R, Bad, cAMP, and PKA; increased protein levels of CREB, Bcl-2, PCNA, p-PKA and p-CREB; increased cell proliferation, migration and invasion; and decreased cell apoptosis. There was no significant difference detected among the blank, NC, and siRNA-LINC01121 + siRNA-GLP1R groups, except that decreased LINC01121 expression was determined in the siRNA-LINC01121 + siRNA-GLP1R group. Parallel data were observed in the pancreatic cancer cells and PANC-1 cells. Conclusion: The current study presents evidence indicating that LINC01121 might inhibit apoptosis while acting to promote proliferation, migration, and invasion of pancreatic cancer cells, supplementing the stance held that LINC01121 functions as a tumor promoter by means of its involvement in the process of translational repression of the GLP1R and inhibition of the cAMP/PKA signaling pathway.

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Section: Discussionmentioning

confidence: 99%

LINC01121 Inhibits Cell Apoptosis While Facilitating Proliferation, Migration, and Invasion Though Negative Regulation of the Camp/PKA Signaling Pathway via GLP1R

Qian¹,

Zhou²,

Chen³

et al. 2018

Cell Physiol Biochem

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“…The core effect of GLP-1 RAs in T2D is good glycaemic control, which is achieved through effects on GLP-1 receptors in the pancreas, essentially stimulating insulin release from pancreatic islet β-cells in a glucose-dependent manner and suppressing glucagon secretion from pancreatic islet alpha (α)-cells, which contributes to the reduction in blood glucose levels in people with hyperglycaemia. 8,9,14,24,33,34 This glycaemic control has been shown consistently across clinical trials with the three QW and other GLP-1 RAs. [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51] The differing half-lives and MoA appear to influence the degree of the glycaemic control.…”

Section: Mechanism Of Action Related To Glycaemic Controlsupporting

confidence: 56%

A review of GLP‐1 receptor agonists in type 2 diabetes: A focus on the mechanism of action of once‐weekly agents

Cornell

2020

J Clin Pharm Ther

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“…An explanation was postulated to elucidate the possible underlying mechanisms of such drug-induced pancreatic changes: the glucagon-like peptide 1(GLP-1) receptor is normally expressed in the pancreatic duct and islet's cells and is indirectly stimulated by DPP-4 inhibitors as they lead to a further increase of the circulating level of GLP-1 [60]. Prolonged GLP-1 stimulation resulted in the expansion of pancreatic acinar and ductal cells and their growth into the small pancreatic ducts; this could lead to ductal occlusion, thereby triggering pancreatitis [61].…”

Section: Discussionmentioning

confidence: 99%

The Biological Impacts of Sitagliptin on the Pancreas of a Rat Model of Type 2 Diabetes Mellitus: Drug Interactions with Metformin

Shawky

Morsi

Bana

et al. 2019

Biology

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Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is a beneficial class of antidiabetic drugs. However, a major debate about the risk of developing pancreatitis is still existing. The aim of the work was to study the histological and immunohistochemical effects of sitagliptin on both endocrine and exocrine pancreases in a rat model of type 2 diabetes mellitus and to correlate these effects with the biochemical findings. Moreover, a possible synergistic effect of sitagliptin, in combination with metformin, was also evaluated. Fifty adult male rats were used and assigned into five equal groups. Group 1 served as control. Group 2 comprised of untreated diabetic rats. Group 3 diabetic rats received sitagliptin. Group 4 diabetic rats received metformin. Group 5 diabetic rats received both combined. Treatments were given for 4 weeks after the induction of diabetes. Blood samples were collected for biochemical assay before the sacrification of rats. Pancreases were removed, weighed, and were processed for histological and immunohistochemical examination. In the untreated diabetic group, the islets appeared shrunken with disturbed architecture and abnormal immunohistochemical reactions for insulin, caspase-3, and inducible nitric oxide synthase (iNOS). The biochemical findings were also disturbed. Morphometrically, there was a significant decrease in the islet size and islet number. Treatment with sitagliptin, metformin, and their combination showed an improvement, with the best response in the combined approach. No evidence of pancreatic injury was identified in the sitagliptin-treated groups. In conclusion, sitagliptin had a cytoprotective effect on beta-cell damage. Furthermore, the data didn’t indicate any detrimental effects of sitagliptin on the exocrine pancreas.

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Immunohistochemical assessment of glucagon‐like peptide 1 receptor (GLP‐1R) expression in the pancreas of patients with type 2 diabetes

Abstract: These data confirm the ubiquity of early stage PanIN lesions in patients with T2D and do not support the hypothesis that incretin-based therapies are associated with progression towards the more advanced stage PanIN lesions.

Cited by 20 publications

References 32 publications

LINC01121 Inhibits Cell Apoptosis While Facilitating Proliferation, Migration, and Invasion Though Negative Regulation of the Camp/PKA Signaling Pathway via GLP1R

LINC01121 Inhibits Cell Apoptosis While Facilitating Proliferation, Migration, and Invasion Though Negative Regulation of the Camp/PKA Signaling Pathway via GLP1R

A review of GLP‐1 receptor agonists in type 2 diabetes: A focus on the mechanism of action of once‐weekly agents

The Biological Impacts of Sitagliptin on the Pancreas of a Rat Model of Type 2 Diabetes Mellitus: Drug Interactions with Metformin

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