Measuring the Pancreatic β Cell Mass in Vivo with Exendin SPECT during Hyperglycemia and Severe Insulitis

Mol Pharm. 2019 Sep 3;16(9):4024-4030. doi: 10.1021/acs.molpharmaceut.9b00728. Epub 2019 Aug 8.

Abstract

Objective: Targeting the glucagon-like peptide-1 receptor with radiolabeled exendin is a very promising method to noninvasively determine the β cell mass in the pancreas, which is needed to unravel the pathophysiology of type 1 and type 2 diabetes. The present study aimed to explore the effects of both hyperglycemia and insulitis on the uptake of exendin in a spontaneous type 1 diabetes mouse model, nonobese diabetic (NOD) mice.

Methods: NOD mice (n = 75, 7-21 weeks old) were injected intravenously with [111In]In-DTPA-exendin-3, and single-photon emission computed tomography (SPECT) images were acquired 1 h pi. The pancreatic accumulation of [111In]In-DTPA-exendin-3 was quantified in vivo using SPECT and by ex vivo counting and correlated to the β cell mass (BCM). The influence of insulitis and hyperglycemia on the exendin uptake was assessed.

Results: The pancreas could be visualized longitudinally using SPECT. A linear correlation was found between the BCM (%) and pancreatic uptake (%ID/g) as measured by ex vivo counting (Pearson r = 0.64, p < 0.001), which was not affected by either insulitis (Pearson r = 0.66, p = 0.83) or hyperglycemia (Pearson r = 0.57, p = 0.51). Biodistribution and ex vivo autoradiography revealed remaining [111In]In-DTPA-exendin-3 uptake in the pancreas despite total ablation of BCM.

Conclusions: Despite hyperglycemia and severe insulitis, we have found a good correlation between BCM and pancreatic exendin uptake, even in a suboptimal model with relatively high background activity.

Keywords: GLP-1R; NOD mice; SPECT; exendin; receptor imaging; β cell mass.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoradiography
  • Diabetes Mellitus, Type 1 / diagnostic imaging
  • Diabetes Mellitus, Type 1 / metabolism*
  • Disease Models, Animal
  • Female
  • Hyperglycemia / metabolism*
  • Immunohistochemistry
  • Indium Radioisotopes / administration & dosage
  • Indium Radioisotopes / chemistry
  • Indium Radioisotopes / metabolism
  • Injections, Intravenous
  • Insulin-Secreting Cells / metabolism*
  • Mice
  • Mice, Inbred NOD
  • Pentetic Acid / administration & dosage
  • Pentetic Acid / chemistry
  • Pentetic Acid / metabolism
  • Peptides / administration & dosage
  • Peptides / chemistry
  • Peptides / metabolism*
  • Radiopharmaceuticals / metabolism
  • Tissue Distribution
  • Tomography, Emission-Computed, Single-Photon / methods*

Substances

  • Indium Radioisotopes
  • Peptides
  • Radiopharmaceuticals
  • exendin 3
  • Pentetic Acid
  • Indium-111