Species differences in pancreatic binding of DO3A-VS-Cys40-Exendin4

Eriksson, Olof; Rosenström, Ulrika; Selvaraju, Ram Kumar; Eriksson, Barbro; Velikyan, Irina

doi:10.1007/s00592-017-1046-2

Cited by 28 publications

(27 citation statements)

References 9 publications

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“…To overcome these challenges, we used a lipophilic Cy7-exendin for blocking-first, to slow plasma clearance (16,22) and block both extracellular and intracellular stores of exocrine GLP-1R (30) and, second, to slow exendin diffusion compared with hydrophilic exendin (Supplemental Fig. 7) (16,21,31), which limits its diffusion into islets from the surrounding exocrine tissue (Supplemental Fig. 8).…”

Section: Discussionmentioning

confidence: 99%

“…Direct administration of labeled exendin leads to binding of GLP-1R on both b-cells and exocrine cells. Although the differential in vivo expression between endocrine and exocrine cells is significant (54,000 GLP-1R per b-cell in C57Bl6/J mice (16) vs. 1,400 GLP-1R per exocrine cell), the higher prevalence of exocrine cells can dramatically skew BCM quantification (16,21), since the limited spatial resolution of current imaging modalities cannot distinguish between b-cell signal and exocrine signal ( Fig. 2A).…”

Section: Single-cell Resolution Of Selective Exocrine Glp-1r Blockingmentioning

confidence: 99%

“…Although initially controversial because of cross-reactive antibodies combined with low absolute expression, several groups have verified measurable exocrine GLP-1R expression (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Species-dependent variability in exocrine-to-islet signal ratio (Table 1) (17,21) highlights additional challenges with evaluating exendin-based probes in animal models. We previously found an approximately 50-fold lower (accessible) GLP-1R expression on mouse exocrine cells than on b-cells (16), mediating significant non-b-cell uptake.…”

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confidence: 99%

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Blocking of Glucagonlike Peptide-1 Receptors in the Exocrine Pancreas Improves Specificity for β-Cells in a Mouse Model of Type 1 Diabetes

et al. 2019

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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 streptozotocininduced diabetic mice. Results: Sufficient receptors remain on βcells for subsequent labeling with a fluorescent-or 111 In-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.

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Section: Discussionmentioning

confidence: 99%

Section: Single-cell Resolution Of Selective Exocrine Glp-1r Blockingmentioning

confidence: 99%

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confidence: 99%

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Blocking of Glucagonlike Peptide-1 Receptors in the Exocrine Pancreas Improves Specificity for β-Cells in a Mouse Model of Type 1 Diabetes

et al. 2019

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“…However, uptake of these tracers in GLP-1R positive tumors leading to a possible application for fluorescent-guided surgery was not assessed (24,25). (27), the detected signal is most probably not only originating from the pancreatic islets. In mice, where fluorescence microscopy showed specific uptake of the tracer in the pancreatic islets, the endocrine-exocrine ratio of GLP-1R expression is known to be much higher (27).…”

Section: Pancreatic Uptake Of Exendin-4-irdye800cw Is Detected By In mentioning

confidence: 99%

Targeted Optical Imaging of the Glucagonlike Peptide 1 Receptor Using Exendin-4-IRDye 800CW

et al. 2020

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The treatment of choice for insulinomas and focal lesions in congenital hyperinsulinism (CHI) is surgery. However, intra-operative detection can be challenging. This could be overcome with intraoperative fluorescence imaging, which provides real-time lesion detection with a high spatial resolution. Here, a novel method for targeted near-infrared (NIR) fluorescence imaging of glucagon-like peptide 1 receptor (GLP-1R) positive lesions, using the GLP-1 agonist exendin-4, labeled with IRDye800CW, was examined in vitro and in vivo. Methods A competitive binding assay was performed using Chinese hamster lung (CHL) cells transfected with the GLP-1R. Tracer biodistribution was determined in BALB/c nude mice bearing subcutaneous CHL-GLP-1R xenografts. In vivo NIR fluorescence imaging of CHL-GLP-1R xenografts was performed. Localization of the tracer in the pancreatic islets of BALB/c nude mice was examined using fluorescence microscopy. Laparoscopic imaging was performed to detect the fluorescent signal of the tracer in the pancreas of mini pigs. Results Exendin-4-IRDye800CW binds the GLP-1R with an IC 50 value of 3.96 nM. The tracer accumulates in CHL-GLP-1R xenografts. Subcutaneous CHL-GLP-1R xenografts were visualized using in vivo NIR fluorescence imaging. The tracer accumulates specifically in the pancreatic islets of mice and a clear fluorescent signal was detected in the pancreas of mini pigs. Conclusion These date provide the first in vivo evidence of the feasibility of targeted fluorescence imaging of GLP-1R positive lesions. Intra-operative lesion delineation using exendin-4-IRDye800CW could benefit open as well as laparoscopic surgical procedures for removal of insulinomas and focal lesions in CHI.

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“… 17 Furthermore, extensive agonist displacement studies have been performed in this species to ascertain the specific binding of the radioactive probe. 18 Finally, the mini-pig is known to develop obesity and insulin resistance rapidly in response to a high-fat/high-sucrose diet, 19 and euglycemic clamp steady-state conditions can be maintained for extended periods. 20 …”

Section: Introductionmentioning

confidence: 99%

Pancreatic GLP-1r binding potential is reduced in insulin-resistant pigs

Malbert

Chauvin

Horowitz

2020

BMJ Open Diab Res Care

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IntroductionThe insulinotropic capacity of exogenous glucagon like peptide-1 (GLP-1) is reduced in type 2 diabetes and the insulin-resistant obese. We have tested the hypothesis that this response is the consequence of a reduced pancreatic GLP-1 receptor (GLP-1r) density in insulin-resistant obese animals.Research design and methodsGLP-1r density was measured in lean and insulin-resistant adult miniature pigs after the administration of a 68Ga-labeled GLP-1r agonist. The effect of hyperinsulinemia on GLP-1r was assessed using sequential positron emission tomography (PET), both in the fasted state and during a clamp. The impact of tissue perfusion, which could account for changes in GLP-1r agonist uptake, was also investigated using 68Ga-DOTA imaging.ResultsGLP-1r binding potential in the obese pancreas was reduced by 75% compared with lean animals. Similar reductions were evident for fat tissue, but not for the duodenum. In the lean group, induced hyperinsulinemia reduced pancreatic GLP-1r density to a level comparable with that of the obese group. The reduction in blood to tissue transfer of the GLP-1r ligand paralleled that of tissue perfusion estimated using 68Ga-DOTA.ConclusionsThese observations establish that a reduction in abdominal tissue perfusion and a lower GLP-1r density account for the diminished insulinotropic effect of GLP-1 agonists in type 2 diabetes.

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Species differences in pancreatic binding of DO3A-VS-Cys40-Exendin4

Cited by 28 publications

References 9 publications

Blocking of Glucagonlike Peptide-1 Receptors in the Exocrine Pancreas Improves Specificity for β-Cells in a Mouse Model of Type 1 Diabetes

Blocking of Glucagonlike Peptide-1 Receptors in the Exocrine Pancreas Improves Specificity for β-Cells in a Mouse Model of Type 1 Diabetes

Targeted Optical Imaging of the Glucagonlike Peptide 1 Receptor Using Exendin-4-IRDye 800CW

Pancreatic GLP-1r binding potential is reduced in insulin-resistant pigs

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