RT Journal Article
SR Electronic
T1 Blocking of Glucagonlike Peptide-1 Receptors in the Exocrine Pancreas Improves Specificity for β-Cells in a Mouse Model of Type 1 Diabetes
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1635
OP 1641
DO 10.2967/jnumed.118.224881
VO 60
IS 11
A1 Eshita Khera
A1 Liang Zhang
A1 Sheryl Roberts
A1 Ian Nessler
A1 Darleen Sandoval
A1 Thomas Reiner
A1 Greg M. Thurber
YR 2019
UL http://jnm.snmjournals.org/content/60/11/1635.abstract
AB The diabetes community has long desired an imaging agent to quantify the number of insulin-secreting β-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 β-cells can be masked by a compensatory increase in function of the remaining cells. Since β-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 β-cells. Exendin binds glucagonlike peptide-1 receptor (GLP-1R), previously thought to be expressed only on β-cells, but recent studies report low levels of GLP-1R on exocrine cells, complicating β-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 (∼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 β-cells for subsequent labeling with a fluorescent- or 111In-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 β-cell mass in the clinic.