A new deuterium-labeled compound [2,3,4,6,6'-2 H5 ]-D-glucose for deuterium magnetic resonance metabolic imaging.

Deuterium (2 H) magnetic resonance imaging is an emerging approach for noninvasively studying glucose metabolism in vivo, which is important for understanding pathogenesis and monitoring the progression of many diseases such as tumors, diabetes, and neurodegenerative diseases. However, the synthesis of 2 H-labeled glucose is costly because of the expensive raw substrates and the requirement for extreme reaction conditions, making the 2 H-labeled glucose rather expensive and unaffordable for clinic use. In this study, we present a new deuterated compound, [2,3,4,6,6'-2 H5 ]-D-glucose, with an approximate 10-fold reduction in production costs. The synthesis route uses cheaper raw substrate methyl-α-D-glucopyranoside, relies on mild reaction conditions (80°C), and has higher deuterium labeling efficiency. Magnetic resonance spectroscopy (MRS) and mass spectroscopy experiments confirmed the successful deuterium labeling in the compound. Animal studies demonstrated that the substrate could describe the glycolytic metabolism in a glioma rat model by quantifying the downstream metabolites through 2 H-MRS on an ultrahigh field system. Comparison of the glucose metabolism characteristics was carried out between [2,3,4,6,6'-2 H5 ]-D-glucose and commercial [6,6'-2 H2 ]-D-glucose in the animal studies. This cost-effective compound will help facilitate the clinical translation of deuterium magnetic resonance imaging, and enable this powerful metabolic imaging modality to be widely used in both preclinical and clinical research and applications.

GLP-1R Signaling and Functional Molecules in Incretin Therapy.

Glucagon-like peptide-1 receptor (GLP-1R) is a critical therapeutic target for type 2 diabetes mellitus (T2DM). The GLP-1R cellular signaling mechanism relevant to insulin secretion and blood glucose regulation has been extensively studied. Numerous drugs targeting GLP-1R have entered clinical treatment. However, novel functional molecules with reduced side effects and enhanced therapeutic efficacy are still in high demand. In this review, we summarize the basis of GLP-1R cellular signaling, and how it is involved in the treatment of T2DM. We review the functional molecules of incretin therapy in various stages of clinical trials. We also outline the current strategies and emerging techniques that are furthering the development of novel therapeutic drugs for T2DM and other metabolic diseases.

Aerobic glycolysis imaging of epileptic foci during the inter-ictal period.

BACKGROUND: In drug-resistant epilepsy, surgical resection of the epileptic focus can end seizures. However, success is dependent on the ability to identify foci locations and, unfortunately, current methods like electrophysiology and positron emission tomography can give contradictory results. During seizures, glucose is metabolized at epileptic foci through aerobic glycolysis, which can be imaged through the oxygen-glucose index (OGI) biomarker. However, inter-ictal (between seizures) OGI changes have not been studied, which has limited its application. METHODS: 18 healthy controls and 24 inter-ictal, temporal lobe epilepsy patients underwent simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) scans. We used [18F]fluorodeoxyglucose-PET (FDG-PET) to detect cerebral glucose metabolism, and calibrated functional MRI to acquire relative oxygen consumption. With these data, we calculated relative OGI maps. FINDINGS: While bilaterally symmetrical in healthy controls, we observed, in patients during the inter-ictal period, higher OGI ipsilateral to the epileptic focus than contralateral. While traditional FDG-PET results and temporal lobe OGI results usually both agreed with invasive electrophysiology, in cases where FDG-PET disagreed with electrophysiology, temporal lobe OGI agreed with electrophysiology, and vice-versa. INTERPRETATION: As either our novel epilepsy biomarker or traditional approaches located foci in every case, our work provides promising insights into metabolic changes in epilepsy. Our method allows single-session OGI measurement which can be useful in other diseases. FUNDING: This work was supported by ShanghaiTech University, the Shanghai Municipal Government, the National Natural Science Foundation of China Grant (No. 81950410637) and Shanghai Municipal Key Clinical Specialty (No. shslczdzk03403). F. H. and P. H. were supported by USA National Institute of Health grants (R01 NS-100106, R01 MH-067528).Z. W. was supported by the Key-Area Research and Development Program of Guangdong Province (2019B030335001), National Natural Science Foundation of China (No. 82151303), and National Key R&D Program of China (No. 2021ZD0204002).

High-resolution relaxometry-based calibrated fMRI in murine brain: Metabolic differences between awake and anesthetized states.

Functional magnetic resonance imaging (fMRI) techniques using the blood-oxygen level-dependent (BOLD) signal have shown great potential as clinical biomarkers of disease. Thus, using these techniques in preclinical rodent models is an urgent need. Calibrated fMRI is a promising technique that can provide high-resolution mapping of cerebral oxygen metabolism (CMRO2). However, calibrated fMRI is difficult to use in rodent models for several reasons: rodents are anesthetized, stimulation-induced changes are small, and gas challenges induce noisy CMRO2 predictions. We used, in mice, a relaxometry-based calibrated fMRI method which uses cerebral blood flow (CBF) and the BOLD-sensitive magnetic relaxation component, R2', the same parameter derived in the deoxyhemoglobin-dilution model of calibrated fMRI. This method does not use any gas challenges, which we tested on mice in both awake and anesthetized states. As anesthesia induces a whole-brain change, our protocol allowed us to overcome the former limitations of rodent studies using calibrated fMRI. We revealed 1.5-2 times higher CMRO2, dependent upon brain region, in the awake state versus the anesthetized state. Our results agree with alternative measurements of whole-brain CMRO2 in the same mice and previous human anesthesia studies. The use of calibrated fMRI in rodents has much potential for preclinical fMRI.