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Diabetes Obes Metab. 2017 May;19(5):705-712. doi: 10.1111/dom.12879. Epub 2017 Mar 10.

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

Author information

1
Histology and Imaging Department, Global Research, Novo Nordisk A/S, Måløv, Denmark.
2
Type 1 Diabetes Research Center, Global Research, Novo Nordisk Inc., Seattle, Washington.
3
Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
4
Visiopharm, Hørsholm, Denmark.
5
Metabolic Disease Research, Global Research, Novo Nordisk A/S, Måløv, Denmark.

Abstract

AIMS:

Glucagon-like peptide-1 (GLP-1) is an incretin hormone which stimulates insulin release and inhibits glucagon secretion from the pancreas in a glucose-dependent manner. Incretin-based therapies, consisting of GLP-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, are used for the treatment of type 2 diabetes (T2D). Immunohistochemical studies for GLP-1R expression have been hampered previously by the use of unspecific polyclonal antibodies. This study aimed to assess the expression levels of GLP-1R in a set of T2D donor samples obtained via nPOD.

METHODS:

This study used a new monoclonal antibody to assess GLP-1R expression in pancreatic tissue from 23 patients with T2D, including 7 with a DPP-4 inhibitor and 1 with a history of GLP-1R agonist treatment. A software-based automated image analysis algorithm was used for quantitating intensities and area fractions of GLP-1R positive compartments.

RESULTS:

The highest intensity GLP-1R immunostaining was seen in beta-cells in islets (average signal intensity, 76.1 [±8.1]). GLP-1R/insulin double-labelled single cells or small clusters of cells were also frequently located within or in close vicinity of ductal epithelium in all samples and with the same GLP-1R immunostaining intensity as found in beta-cells in islets. In the exocrine pancreas a large proportion of acinar cells expressed GLP-1R with a 3-fold lower intensity of immunoreactivity as compared to beta-cells (average signal intensity 25.5 [±3,3]). Our studies did not unequivocally demonstrate GLP-1R immunoreactivity on normal-appearing ductal epithelium. Pancreatic intraepithelial neoplasia (PanINs; a form of non-invasive pancreatic ductular neoplasia) was seen in most samples, and a minority of these expressed low levels of GLP-1R.

CONCLUSION:

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.

KEYWORDS:

GLP-1; incretin; liraglutide; type 2 diabetes

PMID:
28094469
DOI:
10.1111/dom.12879
[Indexed for MEDLINE]

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