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In vivo imaging of cerebral glucose metabolism of GLP-1R knockout mice with deuterium magnetic resonance spectroscopy
Hui Li1, Yujiao Fang1, Da Wang1, Bowen Shi1, and Garth John Thompson1
1Shanghaitech, Shanghai, China

Synopsis

Keywords: Deuterium, Deuterium, FDG-PET

Motivation: The regulation of brain glucose metabolism by GLP1-1R has not been fully verified.

Goal(s): To explore feasibility of dynamic DMRS in mice brain, and the physiological role of GLP-1R in mouse brain glucose metabolism.

Approach: we apply DMRS and FDG-PET to quantify dynamic cerebral glucose change, and combine with rs-fMRI to investigate changes in whole-brain functional connectivity.

Results: GLP-1R KO mice exhibit impaired brain glucose metabolism and central nervous system intolerance to high doses of exogenous glucose. And the functional brain connectivity in GLP-1R KO mice was significantly lower than that in WT group.

Impact: The decline in functional connectivity may hinder the coordination of work and information transmission between brain regions, thus inhibit normal metabolic regulatory processes. These findings provide a theoretical basis for the treatment strategies of disorders related to brain glucose metabolism

Background

Glucagon-like peptide-1 (GLP-1) and its receptors (GLP-1R) play an important role in regulating blood sugar and maintaining energy homeostasis. Recently, GLP-1R have been considered potential targets for the treatment of disorders related to glucose metabolism in the brain1,2. Deuterium magnetic resonance spectroscopy (DMRS) is a non-invasive, radiation-free technique based on magnetic resonance which can provide quantitative information about neural metabolism and map brain metabolic flux3,4. To explore the physiological role of GLP-1R in mouse brain glucose metabolism, we applied two complementary imaging techniques, DMRS and fluorodeoxyglucose (FDG) positron emission tomography (PET) in GLP-1R knockout mice (GLP-1R KO) and wild-type C57BL/6N (WT) mice.

Methods

Based on a 9.4-tesla ultra-high-field magnetic resonance imaging (MRI) system with a PET insert, the metabolic dynamics of GLP-1R KO and WT mice were continuously collected before and after [6,6]-2H2 glucose injection while using DMRS, and, in a separate cohort, glucose uptake measured with FDG PET. In addition, rest state-functional MRI was performed on both groups to compare brain functional connectivity against the result of DMRS.

Results

The metabolic rate[GT1] of GLP-1R KO mice was significantly slower than that of WT mice (p=0.035, WT mice 0.02335±0.057 mM/min, GLP-1R KO mice 0.01998±0.07 mM/min)(Figure 1 and 2). Quantification of the mean [18F]FDG signal in the whole brain also showed significantly reduced glucose uptake in GLP-1R KO mice versus control mice (p=0.025) (Figure 3). Observing rs-fMRI, the functional brain connectivity in GLP-1R KO mice was significantly lower than that in WT group[GT2] (p= 0.0094 for gFCD, p=0.0002 for whole-brain correlation, p<0.0001 for ALFF) (Figure 4). [GT1]Please look up the name for this specific metabolic rate, which step is it we are measuring in the metabolic cycle? [GT2]List p value if you also list it for the previous two methods

Conclusion

We found that GLP-1R KO mice exhibit impaired brain glucose metabolism and central nervous system intolerance to high doses of exogenous glucose. GLP-1R KO mice have reduced glucose metabolism combined with reduced functional connectivity, a correlation also observed in human studies. This suggests that the GLP-1R KO mouse model may serve as a model for correlated metabolic and functional connectivity loss. In addition, our results validate DMRS as a preclinical in-vivo method with good correspondence to existing PET and fMRI-based methods.

Acknowledgements

This work was supported by the National Natural Science Foundation of China Grant.

References

1. Gejl M, Rungby J, Brock B, et al., 2014. At the Centennial of Michaelis and Menten, Competing Michaelis–Menten Steps Explain Effect of GLP-1 on Blood–Brain Transfer and Metabolism of Glucose[J]. Basic & Clinical Pharmacology & Toxicology, 115 (2): 162-171.

2. Burmeister M A, Ayala J, Drucker D J, et al., 2013. Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose[J]. American Journal of Physiology. Endocrinology and Metabolism, 304 (7): E677-685.

3. De Feyter H M, Behar K L, Corbin Z A, et al., 2018. Deuterium metabolic imaging (DMI) for MRI-based 3D mapping of metabolism in vivo[J]. Science Advances, 4 (8): eaat7314.

4. De Feyter H M, de Graaf R A, 2021. Deuterium metabolic imaging – Back to the future[J]. Journal of Magnetic Resonance, 326: 106932.

Figures

Figure 1. Metabolic dynamics measured with DMRS. Representative DMRS spectra from a WT mouse, before and after injection of [6,6]- 2H2 glucose. (A) Water phantom containing 2.5 mM/L deuterated glucose. (B) Natural abundance of water in the brain prior to glucose injection. (C) First scan after glucose injection, set as 0 minutes. (D-G) Signal at 20, 40, 60, and 70 minutes. Each spectrum was acquired over ~5 minutes. (H) The region of interest in brain is highlighted in the green box. 2H resonance signals shown in (C): (1) HDO, 4.7 ppm; (2) Glucose, 3.8 ppm.

Figure 2. The metabolic rate of [6,6]-2H2 glucose in the WT and GLP-1R KO mouse brains (A) Dynamics of deuterium labelled glucose concentration. Each data point represents the mean ± SEM. (B) The rate constant (k) for [6,6]- 2H2 glucose metabolism. Unpaired t-test; The data represents as mean ± SD, p=0.0345. N=6 for GLP-1R KO mice, N= 5 for WT mice.

Figure 3. Glucose metabolism in the WT and GLP-1R KO mouse brains. (A) Representative PET images from coronal, sagittal, and axial views of WT and GLP-1R KO mice taken 45~60 min after 18 F-FDG injections. (B) Quantitative analysis of 18F-FDG uptake in the whole brain. GPL-1R mice showed a significantly lower SUV in the whole brain compared to WT mice. Unpaired t-test; Data presented as mean ± SEM, p=0.025, N=6 for GLP-1R KO mice, N=7 for WT mice.

Figure 4. Comparison of functional connectivity averages across the whole brain in rs-fMRI between WT and GLP-1R KO mice. (A) Functional connectivity density maps in the brain. (B) Whole-brain correlation maps in the brain. (C) The Amplitude of low-frequency fluctuations maps in the brain. The functional brain connectivity in GLP-1R KO mice was significantly lower than that in WT group. Unpaired t-test; p= 0.0094 for gFCD, p=0.0002 for whole-brain correlation, p<0.0001 for ALFF. Data presented as mean ± SD, N=5 for GLP-1R KO mice, N= 11 for WT mice.

Proc. Intl. Soc. Mag. Reson. Med. 32 (2024)
3044
DOI: https://doi.org/10.58530/2024/3044