Blocking of glucagonlike peptide-1 receptors in the exocrine pancreas improves specificity for β-cells in a mouse model of type 1 diabetes Journal Article
| Authors: | Khera, E.; Zhang, L.; Roberts, S.; Nessler, I.; Sandoval, D.; Reiner, T.; Thurber, G. M. |
| Article Title: | Blocking of glucagonlike peptide-1 receptors in the exocrine pancreas improves specificity for β-cells in a mouse model of type 1 diabetes |
| Abstract: | The diabetes community has long desired an imaging agent to quantify the number of insulin-secreting beta-cells, beyond just functional equivalents (insulin secretion), to help diagnose and monitor early stages of both type 1 and type 2 diabetes mellitus. Loss in the number of beta-cells can be masked by a compensatory increase in function of the remaining cells. Since beta-cells form only about 1% of the pancreas and decrease as the disease progresses, only a few imaging agents, such as exendin, have demonstrated clinical potential to detect a drop in the already scarce signal. However, clinical translation of imaging with exendin has been hampered by pancreatic uptake that is higher than expected in subjects with long-term diabetes who lack beta-cells. Exendin binds glucagonlike peptide-1 receptor (GLP-1R), previously thought to be expressed only on beta-cells, but recent studies report low levels of GLP-1R on exocrine cells, complicating beta-cell mass quantification. Methods: Here, we used a GLP-1R knockout mouse model to demonstrate that exocrine binding of exendin is exclusively via GLP-1R (similar to 1,000/cell) and not any other receptor. We then used lipophilic Cy-7 exendin to selectively preblock exocrine GLP-1R in healthy and streptozotocin-induced diabetic mice. Results: Sufficient receptors remain on beta-cells for subsequent labeling with a fluorescent- or In-111-exendin. Conclusion: Selective GLP-1R blocking, which improves contrast between healthy and diabetic pancreata and provides a potential avenue for achieving the long-standing goal of imaging beta-cell mass in the clinic. |
| Keywords: | tissue; expression; mouse model; disease; type 1 diabetes; mass; acinar-cells; islets; streptozotocin; exendin; beta cell mass; exocrine glp-1r; liraglutide overdose |
| Journal Title: | Journal of Nuclear Medicine |
| Volume: | 60 |
| Issue: | 11 |
| ISSN: | 0161-5505 |
| Publisher: | Society of Nuclear Medicine |
| Date Published: | 2019-11-01 |
| Start Page: | 1635 |
| End Page: | 1641 |
| Language: | English |
| ACCESSION: | WOS:000493975400026 |
| DOI: | 10.2967/jnumed.118.224881 |
| PROVIDER: | wos |
| PMCID: | PMC6836864 |
| PUBMED: | 31076502 |
| Notes: | Source: Wos |
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