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

Khera, Eshita; Zhang, Liang; Roberts, Sheryl; Nessler, Ian; Sandoval, Darleen A.; Reiner, Thomas; Thurber, Greg M.

doi:10.2967/jnumed.118.224881

Cited by 13 publications

(11 citation statements)

References 37 publications

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“…Therefore, individuals with isolated IFG have lower serum FGF19 levels than those without isolated IFG, suggesting that FGF19 plays a role in the secretion of impaired basal insulin [5]. The effect of the incretin GLP-1, a hormone that releases insulin by a G-protein coupled receptor, is dependent upon glucose [30]. The present study showed that GLP-1 secretion is inhibited by FXR through decreased glycolysis [16].…”

Section: Discussionmentioning

confidence: 90%

Serum fibroblast growth factor 19 and endogenous islet beta cell function in type 2 diabetic patients

Tang

et al. 2019

Diabetol Metab Syndr

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Background Fibroblast growth factor 19 (FGF19) takes part in maintaining the balance of glycolipids and may be involved in regulating the secretory activity of islet beta cells in patients with type 2 diabetes. This study aimed to evaluate the relationship between the levels of serum FGF19 and endogenous islet beta cell function in type 2 diabetic patients. Methods Samples were obtained from 271 subjects: 85 drug-naïve type 2 diabetes participants exclusively on lifestyle intervention (N-DM group), 122 type 2 diabetes subjects previously used medications (DM group) and 64 normal controls (NC group). Serum FGF19 concentrations were measured by ELISA. The insulin sensitivity (MI), insulin secretion (AUCins/AUCglu) and insulin secretion-sensitivity index-2 (ISSI-2) were also measured in the N-DM and DM. Results Serum FGF19 levels decreased, in order, from the NC group [median (interquartile range), 245.03 (126.23–317.43) pg/mL] to the N-DM group [170.05 (89.01–244.70) pg/mL] and, finally, to the DM group [142.25 (55.55–187.58) pg/mL] (p for trend < 0.05). Among subjects in the DM group, there was a positive trend in the serum FGF19 concentration; plasma insulin levels at 60 min, 120 min (INS60, INS120, respectively); and area under the insulin curve (AUCins) at two points (r = 0.214, p = 0.025; r = 0.189, p = 0.048; r = 0.188, p = 0.049). However, the differences were no longer observed among the N-DM subjects. Simultaneously, the ISSI-2 was closely related to the serum FGF19 levels (r = 0.297, p = 0.002) among DM subjects. Furthermore, after adjusting for age, sex, duration, therapy and other clinical factors via multiple logistic regression analysis, ISSI-2 was a key independent factor in the levels of FGF19 (β = 0.281, t = 2.557, p = 0.013). Conclusions The serum FGF19 level has a close relation with endogenous beta cell function among DM subjects, as assessed by the ISSI-2. As ISSI-2 is higher in N-DM group, FGF19 may be a main protector in dysfunction of beta cell.

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Section: Discussionmentioning

confidence: 90%

Serum fibroblast growth factor 19 and endogenous islet beta cell function in type 2 diabetic patients

Tang

et al. 2019

Diabetol Metab Syndr

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“…A GLP-1R targeted peptide, exendin-4, was modified at the K12 position of the amino acid sequence with the unnatural alkyne-amino acid (S)-2-amino-4-pentynoic acid ( Figure 1A). As reported previously 4,24,26 , it can be used without significant reduction of peptide/GLP-1R target binding (~3 nM) 4 . Likewise, we have previously shown that cyanine dyes such as Cy7 exhibit the desired optical characteristics suitable for both optoacoustic and fluorescent imaging 36 .…”

Section: Synthesis and Analysis Of E4x12-cy7mentioning

confidence: 72%

“…In addition, the incorporation of 3D optoacoustic tomographic systems could work in favor with near infrared absorbers, known to provide more quantitative assessments as it has greater sensitivity than 2D systems 30 . Based on the previous success of specific ß-cell imaging agents for PET, fluorescence imaging or in combinations thereof 4,24,26 , we envision that a contrast agent such as E4x12-Cy7 could represent a potential platform for further development and optimization of ß-cell optoacoustic imaging.…”

Section: Discussionmentioning

confidence: 99%

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Optoacoustic imaging of GLP-1 Receptor with a near-infrared exendin-4 analog

Roberts

Khera

Choi

et al. 2020

Preprint

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Limitations in current imaging tools have long challenged the imaging of small pancreatic islets in animal models. Here, we report the first development and in vivo validation testing of a broad spectrum and high absorbance near infrared optoacoustic contrast agent, E4x12-Cy7. Our near infrared tracer (E4x12-Cy7) is based on the amino acid sequence of exendin-4 and targets the glucagon-like peptide-1 receptor (GLP-1R). Cell assays confirmed that E4x12-Cy7 has a high binding affinity (IC50 = 4.6 ± 0.8 nM). Using the multispectral optoacoustic tomography (MSOT), we imaged E4x12-Cy7 and optoacoustically visualized ß-cell insulinoma xenografts in vivo for the first time. In the future, similar optoacoustic tracers that are specific for ß-cells and combines optoacoustic and fluorescence imaging modalities could prove to be important tools for monitoring the pancreas for the progression of diabetes.

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“…With the equipment used in this work, the limit of detection For IRDye800CW was~20,000 antibodies/cell, while AlexaFluor 647 was~5000 antibodies/cell. With site-specific labeling of high affinity peptides, we have detected down to~1000 receptors per cell [41]. This level of sensitivity is needed for some targets given the > 100-fold differences in expression in ADC targets, for example [42].…”

Section: Discussionmentioning

confidence: 99%

Practical Guide for Quantification of In Vivo Degradation Rates for Therapeutic Proteins with Single-Cell Resolution Using Fluorescence Ratio Imaging

2020

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Many tools for studying the pharmacokinetics of biologics lack single-cell resolution to quantify the heterogeneous tissue distribution and subsequent therapeutic degradation in vivo. This protocol describes a dual-labeling technique using two near-infrared dyes with widely differing residualization rates to efficiently quantify in vivo therapeutic protein distribution and degradation rates at the single cell level (number of proteins/cell) via ex vivo flow cytometry and histology. Examples are shown for four biologics with varying rates of receptor internalization and degradation and a secondary dye pair for use in systems with lower receptor expression. Organ biodistribution, tissue-level confocal microscopy, and cellular-level flow cytometry were used to image the multi-scale distribution of these agents in tumor xenograft mouse models. The single-cell measurements reveal highly heterogeneous delivery, and degradation results show the delay between peak tumor uptake and maximum protein degradation. This approach has broad applicability in tracking the tissue and cellular distribution of protein therapeutics for drug development and dose determination.

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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

Cited by 13 publications

References 37 publications

Serum fibroblast growth factor 19 and endogenous islet beta cell function in type 2 diabetic patients

Serum fibroblast growth factor 19 and endogenous islet beta cell function in type 2 diabetic patients

Optoacoustic imaging of GLP-1 Receptor with a near-infrared exendin-4 analog

Practical Guide for Quantification of In Vivo Degradation Rates for Therapeutic Proteins with Single-Cell Resolution Using Fluorescence Ratio Imaging

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