Association of glucagon‐like peptide‐1 receptor‐targeted imaging probe with in vivo glucagon‐like peptide‐1 receptor agonist glucose‐lowering effects

Abstract

Aims/Introduction Glucagon‐like peptide‐1 receptor agonists (GLP‐1RA) are used for treatment of type 2 diabetes mellitus worldwide. However, some patients do not respond well to the therapy, and caution must be taken for certain patients, including those with reduced insulin secretory capacity. Thus, it is clinically important to predict the efficacy of GLP‐1RA therapy. GLP‐1R‐targeted imaging has recently emerged to visualize and quantify β‐cells. We investigated whether GLP‐1R‐targeted imaging can predict the efficacy of GLP‐1RA treatment. Materials and Methods We developed 111 Indium‐labeled exendin‐4 derivative ( 111 In‐Ex4) as a GLP‐1R‐targeting probe. Diabetic mice were selected from NONcNZO10/LtJ male mice that were fed for different durations with 11% fat chow. After 3‐week administration of dulaglutide as GLP‐1RA therapy, mice with non‐fasting blood glucose levels <300 mg/dL and >300 mg/dL were defined as responders and non‐responders, respectively. In addition, ex vivo 111 In‐Ex4 pancreatic accumulations ( 111 In‐Ex4 pancreatic values) were examined. Results The non‐fasting blood glucose levels after treatment were 172.5 ± 42.4 mg/dL in responders ( n = 4) and 330.8 ± 20.7 mg/dL in non‐responders ( n = 5), respectively. Ex vivo 111 In‐Ex4 pancreatic values showed significant correlations with post‐treatment glycohemoglobin and glucose area under curve during an oral glucose tolerance test ( R 2 = 0.76 and 0.80; P < 0.01 and <0.01, respectively). The receiver operating characteristic area under curve for identifying responders by ex vivo 111 In‐Ex4 pancreatic values was 1.00 ( P < 0.01). Conclusion Ex vivo 111 In‐Ex4 pancreatic values reflected dulaglutide efficacy, suggesting clinical possibilities for expanding GLP‐1R‐targeted imaging applications.

Non-invasive Beta-cell Imaging: Visualization, Quantification, and Beyond

“…Although chronic hyperglycemia might affect probe uptake via changes in GLP-1R expression levels on the b-cell membrane surface (110), the pancreatic uptake of [Lys 12 ( 111 In-BnDTPA-Ahx)]exendin-4 in SPECT images could replicate the BCM relationship among these model mice with different glycemic states (35,102,103). Moreover, the pancreatic uptake of [Lys 12 ( 111 In-BnDTPA-Ahx)]exendin-4 maintained a linear correlation with histological BCM, even among diabetic and non-diabetic RCS-10 mice (11). The pancreatic uptake of the probe consists of combined probe intensities of cell-surface bindings to GLP-1R and intracellular accumulations.…”

“…Moreover, severe insulitis and hyperglycemia did not affect the linear correlation between the pancreatic probe uptake and histological BCM in nonobese diabetic (NOD) mice (106). Although mice were reported to show relatively higher exendin uptake in the exocrine pancreas compared with rats (66, 107), [Lys 12 ( 111 In-BnDTPA-Ahx)] exendin-4 demonstrated good linear correlations between ex vivo pancreatic uptake and histological BCM in several diabetic model mouse strains such as NOD (r = 0.90) (102), db/db (35), and RCS-10 mice (r 2 = 0.75) (11). These 111 In-labeled exendin-3 and exendin-4 derivatives can therefore be promising probes for BCM quantification using ex vivo SPECT imaging.…”

“…Lastly, GLP-1R-targeted imaging can be employed to better select antidiabetic drugs including GLP-1R agonists. The pancreatic uptake of [Lys 12 ( 111 In-BnDTPA-Ahx)]exendin-4 is reflected in the in vivo glucose-lowering effects of dulaglutide in diabetic RCS-10 mice, which suggests that the pancreatic uptake value could predict responders and non-responders to dulaglutide therapy (11). Given that the probe's pancreatic uptake was significantly correlated with BCM and GLP-1R mRNA expression, GLP-1R-targeted imaging can be a predictive indicator of the efficacy of not only GLP-1R agonists but also other antidiabetic drugs.…”

“…Residual BCM is therefore an important factor in managing type 1 diabetes mellitus, whereas viable graft islet volume largely affects the outcomes in islet cell transplantation (8). In type 2 diabetes mellitus, substantially reduced BCM is observed, even at diagnosis, and can affect the responsiveness of antidiabetic therapy (3,(9)(10)(11). Therefore, a BCM evaluation leads to not only a deeper and more concise understanding of the individual's diabetic state but also the development and evaluation of antidiabetic therapy aimed at BCM restoration and protection.…”

First-in-Human Evaluation of Positron Emission Tomography/Computed Tomography With [18F]FB(ePEG12)12-Exendin-4: A Phase 1 Clinical Study Targeting GLP-1 Receptor Expression Cells in Pancreas

“…Although evaluation of the pancreatic b cell function is mandatory to understand the failure of insulin secretion, the systemic b-cell function consists on not only the ability of insulin secretion of individual b cells but also pancreatic b-cell mass (BCM). Actually, BCM has central importance in the progression of diabetes and responsiveness of anti-diabetic treatment (2). Some autopsy and histological studies reported reduced BCM in patients with impaired fasting blood glucose (FBG) levels and/or with type 2 diabetes mellitus (3)(4)(5).…”