Blocking Glucagon Like Peptide-1 Receptors in the Exocrine Pancreas Improves Specificity for Beta 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 (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 only form ~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 higher than expected pancreatic uptake in subjects with long-term diabetes who lack β-cells. Exendin binds glucagon-like 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. Here we use 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 receptors. We then use lipophilic Cy-7 exendin to selectively pre-block exocrine GLP-1R in healthy and streptozotocin-induced diabetic (STZ) mice. Sufficient receptors remain on β-cells for subsequent labeling with a fluorescent- or ¹¹¹In-exendin, 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.