Accurate measurement of pancreatic islet β-cell mass using a second-generation fluorescent exendin-4 analog

Reiner, Thomas; Thurber, Greg M.; Gaglia, Jason L.; Vinegoni, Claudio; Liew, Chong Wee; Upadhyay, Rabi; Köhler, Rainer H.; Li, Li; Kulkarni, Rohit; Benoist, Christophe; Mathis, Diane; Weissleder, Ralph

doi:10.1073/pnas.1109859108

Cited by 113 publications

(139 citation statements)

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“…This is probably due to the fact that the antagonist exendin- is not suitable for in vivo targeting of the GLP-1R [31], indicating that agonistic activity is required for successful visualisation of beta cells in vivo. Importantly, Reiner et al have recently demonstrated the in vivo targeting of beta cells with a fluorescent labelled exendin-4 analogue [32].…”

Section: Discussionmentioning

confidence: 99%

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

et al. 2014

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Aims/hypothesis A reliable method for in vivo quantification of pancreatic beta cell mass (BCM) could lead to further insight into the pathophysiology of diabetes. The glucagonlike peptide 1 receptor, abundantly expressed on beta cells, may be a suitable target for imaging. We investigated the potential of radiotracer imaging with the GLP-1 analogue exendin labelled with indium-111 for determination of BCM in vivo in a rodent model of beta cell loss and in patients with type 1 diabetes and healthy individuals. MethodsThe targeting of 111 In-labelled exendin was examined in a rat model of alloxan-induced beta cell loss. Rats were injected with 15 MBq 111 In-labelled exendin and single photon emission computed tomography (SPECT) acquisition was performed 1 h post injection, followed by dissection, biodistribution and ex vivo autoradiography studies of pancreatic sections. BCM was determined by morphometric analysis after staining with an anti-insulin antibody. For clinical evaluation SPECT was acquired 4, 24 and 48 h after injection of 150 MBq 111 In-labelled exendin in five patients with type 1 Maarten Brom and Wietske Woliner-van der Weg contributed equally to this study. Diabetologia (2014) 57:950-959 DOI 10.1007 diabetes and five healthy individuals. The tracer uptake was determined by quantitative analysis of the SPECT images. Results In rats, 111 In-labelled exendin specifically targets the beta cells and pancreatic uptake is highly correlated with BCM. In humans, the pancreas was visible in SPECT images and the pancreatic uptake showed high interindividual variation with a substantially lower uptake in patients with type 1 diabetes. Conclusions/interpretation These studies indicate that 111 Inlabelled exendin may be suitable for non-invasive quantification of BCM.

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Section: Discussionmentioning

confidence: 99%

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

et al. 2014

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“…7,8,20 In the db/db time study a weightadjusted dose of 804 mg/kg (160 nmol/kg) was used. Vehicle controls were injected with 200 ml 1 X DPBS.…”

Section: Probing Of Mice and Preparation For Histologymentioning

confidence: 99%

“…Due to these properties, exendin-4-based imaging probes have been explored for in vivo imaging of b cells and insulinomas in several imaging modalities. [7][8][9][10][11][12][13] Although GLP-1R agonists are well studied for their pharmacological effects on b cells, less is known concerning the specificity and dynamics of GLP-1R expression in the pancreas. This is mainly due to a lack of specific antibodies against the GLP-1R, and species differences in GLP-1R expression.…”

Section: Introductionmentioning

confidence: 99%

Beta cell specific probing with fluorescent exendin-4 is progressively reduced in type 2 diabetic mouse models

Lehtonen

Schäffer

Rasch

et al. 2015

Islets

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Probes based on GLP-1R agonist exendin-4 have shown promise as in vivo b cell tracers. However, questions remain regarding the b cell specificity of exendin-4 probes, and it is unclear if the expression levels of the GLP-1R are affected in a type 2 diabetic state. Using in vivo probing followed by ex vivo imaging we found fluorescent exendin-4 probes to distinctly label the pancreatic islets in mice in a Glp-1r dependent manner. Furthermore, a co-localization study revealed a near 100 percent b cell specificity with less than one percent probing in other analyzed cell types. We then tested if probing was affected in models of type 2 diabetes using the Lepr db/db (db/db) and the Diet-Induced Obese (DIO) mouse. Although nearly all b cells continued to be probed, we observed a progressive decline in probing intensity in both models with the most dramatic reduction seen in db/db mice. This was paralleled by a progressive decrease in Glp-1r protein expression levels. These data confirm b cell specificity for exendin-4 based probes in mice. Furthermore, they also suggest that GLP-1R targeting probes may provide a tool to monitor b cell function rather than mass in type 2 diabetic mouse models.

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“…Preoperative imaging of insulinomas is critical, because it helps to precisely localize these often very small lesions in the pancreas. Therefore, imaging probes for optical (2), bimodal (3), SPECT (4-7), and PET (8-13) imaging as well as MRI (14) were developed to localize GLP-1 receptors preoperatively and in addition to determine b-cell mass in diabetic animal models and potentially in patients. In particular, SPECT (4,5,7) and PET (8,13,15) agents were successfully translated into the clinic, and several promising clinical studies were reported.…”

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confidence: 99%

Approaches to Improve the Pharmacokinetics of Radiolabeled Glucagon-Like Peptide-1 Receptor Ligands Using Antagonistic Tracers

Rylova

Waser

Pozzo³

et al. 2016

J Nucl Med

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The glucagon-like peptide-1 (GLP-1) receptors are important biomarkers for imaging pancreatic β-cell mass and detection of benign insulinomas. Using GLP-1 receptor antagonists, we aimed to eliminate the insulin-related side effects reported for all GLP-1 receptor agonists. Additionally, using a nonresidualizing tracer, 125 I-BoltonHunter-Exendin(9-39)NH 2 ( 125 I-BH-Ex(9-39)NH 2 ), we aimed to reduce the high kidney uptake, enabling a better detection of insulinomas in the tail and head of the pancreas. Methods: The affinity and biodistribution of Ex (9- ) uptake in Ins-1E tumor, 12.5 ± 2.2 %IA/g in the pancreas, and 235.8 ± 17.0 %IA/g in the kidney, with tumor-to-blood and tumor-to-kidney ratios of 100.52 and 0.17, respectively. Biodistribution of [Lys 40 (NODAGA-68 Ga)NH 2 ]Ex(9-39) showed only 2.2 ± 0.2 %IA/g uptake in Ins-1E tumor, 1.0 ± 0.1 %IA/g in the pancreas, and 78.4 ± 8.5 %IA/g in the kidney at 1 h after injection, with tumor-to-blood and tumor-to-kidney ratios of 7.33 and 0.03, respectively. In contrast, 125 I-BH-Ex(9-39)NH 2 showed tumor uptake (42.5 ± 8.1 %IA/g) comparable to the agonist and 28.8 ± 5.1 %IA/g in the pancreas at 1 h after injection. As we hypothesized, the kidney uptake of 125 I-BH-Ex(9-39)NH 2 was low, only 12.1 ± 1.4 %IA/g at 1 h after injection. The tumor-to-kidney ratio of 125 I-BH-Ex(9-39)NH 2 was improved 20-fold. Conclusion: Our results suggest that iodinated Ex(9-39)NH 2 may be a promising tracer for imaging GLP-1 receptor expression in vivo. Because of the 20-fold improved tumorto-kidney ratio 125 I-BH-Ex(9-39)NH 2 may offer higher sensitivity in the detection of insulinomas and imaging of β-cell mass in diabetic patients. Further studies with 124 I-BH-Ex(9-39)NH 2 are warranted.Key Words: GLP-1 receptor; insulinoma; β-cell mass; antagonist The glucagon-like peptide (GLP-1) receptors are important targets because they are overexpressed on more than 90% of benign insulinomas, some malignant insulinomas, most gastrinomas, and most phaeochromocytomas (1). Physiologically they are also expressed in the endocrine pancreas. Preoperative imaging of insulinomas is critical, because it helps to precisely localize these often very small lesions in the pancreas. Therefore, imaging probes for optical (2), bimodal (3), SPECT (4-7), and PET (8-13) imaging as well as MRI (14) were developed to localize GLP-1 receptors preoperatively and in addition to determine b-cell mass in diabetic animal models and potentially in patients. In particular, SPECT (4,5,7) and PET (8,13,15) agents were successfully translated into the clinic, and several promising clinical studies were reported. Still, there are a few shortcomings with the available tracers. The tracers accumulate highly in the kidneys when residualizing radiometals are used for labeling, possibly leading to not only unnecessary high radiation doses but also problems in localizing tumors in the tail and head of the pancreas (5,8,13). The usually low specific activity of the imaging tracers, exclusively agonists, and the concomitant relative...

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Accurate measurement of pancreatic islet β-cell mass using a second-generation fluorescent exendin-4 analog

Cited by 113 publications

References 38 publications

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

Beta cell specific probing with fluorescent exendin-4 is progressively reduced in type 2 diabetic mouse models

Approaches to Improve the Pharmacokinetics of Radiolabeled Glucagon-Like Peptide-1 Receptor Ligands Using Antagonistic Tracers

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