Abstract
Purpose: In diabetes, pancreatic beta cell mass declines significantly prior to onset of fasting hyperglycemia. This decline may be due to endoplasmic reticulum (ER) stress, and the system L amino acid transporter LAT1 may be a biomarker of this process. In this study, we used 5-(2- 18F-fluoroethoxy)-L-tryptophan ( 18F-L-FEHTP) to target LAT1 as a potential biomarker of beta cell function in diabetes. Procedures: Uptake of 18F-L-FEHTP was determined in wild-type C57BL/6 mice by ex vivo biodistribution. Both dynamic and static positron emission tomography (PET) images were acquired in wild-type and Akita mice, a model of ER stress-induced diabetes, as well as in mice treated with streptozotocin (STZ). LAT1 expression in both groups of mice was evaluated by immunofluorescence microscopy. Results: Uptake of 18F-L-FEHTP was highest in the pancreas, and static PET images showed highly specific pancreatic signal. Time-activity curves showed significantly reduced 18F-L-FEHTP uptake in Akita mice, and LAT1 expression was also reduced. However, mice treated with STZ, in which beta cell mass was reduced by 62%, showed no differences in 18F-L-FEHTP uptake in the pancreas, and there was no significant correlation of 18F-L-FEHTP uptake with beta cell mass. Conclusions:18F-L-FEHTP is highly specific for the pancreas with little background uptake in kidney or liver. We were able to detect changes in LAT1 in a mouse model of diabetes, but these changes did not correlate with beta cell function or mass. Therefore, 18F-L-FEHTP PET is not a suitable method for the noninvasive imaging of changes in beta cell function during the progression of diabetes.
Highlights
In both Type 1 and Type 2 diabetes, the ability of the beta cells in the pancreatic islets of Langerhans to produce insulin is disrupted
There is an extensive preclinical period of time during which beta cell mass is significantly reduced prior to the onset of fasting hyperglycemia1, and there have been several efforts to detect these changes non-invasively, with the hypothesis that disease onset may be delayed and/or halted. Such efforts have focused on engineering transgenic mice in which uptake of an imaging contrast agent is genetically enhanced in beta cells using the mouse insulin promoter2 or on identifying biomarkers on the beta cell membrane that can be targeted by specific ligands that carry image contrast3,4
While using bioluminescence to image these same changes in beta cell mass is a more sensitive and cost-effective approach8, positron emission tomography (PET) has the advantage of being a clinical imaging modality, and our study showed that PET had the sensitivity to track changes in beta cell mass before the onset of fasting hyperglycemia
Summary
In both Type 1 and Type 2 diabetes, the ability of the beta cells in the pancreatic islets of Langerhans to produce insulin is disrupted. There is an extensive preclinical period of time during which beta cell mass is significantly reduced prior to the onset of fasting hyperglycemia, and there have been several efforts to detect these changes non-invasively, with the hypothesis that disease onset may be delayed and/or halted Such efforts have focused on engineering transgenic mice in which uptake of an imaging contrast agent is genetically enhanced in beta cells using the mouse insulin promoter or on identifying biomarkers on the beta cell membrane that can be targeted by specific ligands that carry image contrast. Targeting the GLP-1R using peptide analogs of GLP-1 and exendin-4 have been shown to be useful in imaging benign insulinomas and transplanted islets, but have very limited capacity to image beta cells in the native rodent pancreas15,16 This is due largely to unfavourable pharmacokinetics that result in accumulation of PET signal in the kidneys and liver, obscuring any signal that might have been emitted from pancreatic beta cells
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