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Alterations of Brain Energy Metabolism in Type 2 Diabetic Goto-Kakizaki Rats Measured In Vivo by 13C Magnetic Resonance Spectroscopy

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Abstract

Type 2 diabetes (T2D) is associated with deterioration of brain structure and function. Here, we tested the hypothesis that T2D induces a reorganization of the brain metabolic networks that support brain function. For that, alterations of neuronal and glial energy metabolism were investigated in a T2D model, the Goto-Kakizaki (GK) rat. 13C magnetic resonance spectroscopy in vivo at 14.1 T was used to detect 13C labeling incorporation into carbons of glutamate, glutamine, and aspartate in the brain of GK (n = 7) and Wistar (n = 13) rats during intravenous [1,6-13C]glucose administration. Labeling of brain glucose and amino acids over time was analyzed with a two-compartment mathematical model of brain energy metabolism to determine the rates of metabolic pathways in neurons and glia. Compared to controls, GK rats displayed lower rates of brain glutamine synthesis (− 32%, P < 0.001) and glutamate-glutamine cycle (− 40%, P < 0.001), and mitochondrial tricarboxylic acid (TCA) cycle rate in neurons (− 7%, P = 0.036). In contrast, the TCA cycle rate of astrocytes was larger in GK rats than controls (+ 21%, P = 0.042). We conclude that T2D alters brain energy metabolism and impairs the glutamate-glutamine cycle between neurons and astrocytes, in line with diabetes-induced neurodegeneration and astrogliosis underlying brain dysfunction.

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Abbreviations

CMRglc(ox) :

Oxidative fraction of CMRglc

CMRglc :

Cerebral metabolic rate of glucose

FE:

Fractional enrichment

GTT:

Glucose tolerance test

K t :

Apparent Michaelis constant of glucose transport

MRS:

Magnetic resonance spectroscopy

T2D:

Type 2 diabetes

TCA cycle:

Tricarboxylic acid cycle

V dil :

Dilution of glial acetyl-CoA

V g :

Rate of glial TCA cycle resulting in full pyruvate oxidation

V GS :

Rate of glutamine synthetase

V in :

Dilution of pyruvate

V NT :

Rate of apparent glutamatergic neurotransmission

VOI:

Volume of interest

V out :

Pyruvate efflux

V PC :

Rate of pyruvate carboxylase

V TCA g :

Glial TCA cycle

V TCA n :

Neuronal TCA cycle

V X g :

Rate of oxoacid-amino acid exchange in glia

V X n :

Rate of oxoacid-amino acid exchange in neurons

ZDF:

Zucker diabetic fatty

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Acknowledgements

The authors are grateful to Dr. Ana F. Soares (LIFMET, EPFL) for fruitful discussions.

Funding

This research was supported by the Swiss National Science Foundation (grant 148250), National Competence Center in Biomedical Imaging (NCCBI), and by Centre d’Imagerie BioMédicale (CIBM) of the UNIL, UNIGE, HUG, CHUV, EPFL, and the Leenaards and Jeantet Foundations.

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Authors and Affiliations

  1. Laboratory for Functional and Metabolic Imaging (LIFMET), École Polytechnique Fédérale de Lausanne (EPFL), Station 6, 1015, Lausanne, CH, Switzerland

    Freya-Merret Girault, Sarah Sonnay, Rolf Gruetter & João M. N. Duarte

  2. Department of Radiology, University of Lausanne, Lausanne, Switzerland

    Rolf Gruetter

  3. Department of Radiology, University of Geneva, Geneva, Switzerland

    Rolf Gruetter

Authors
  1. Freya-Merret Girault
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  2. Sarah Sonnay
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  3. Rolf Gruetter
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  4. João M. N. Duarte
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Correspondence to João M. N. Duarte.

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All experiments were performed in accordance with the Swiss federal law on animal experimentation and approved by the local authority (EXPANIM-SCAV), and are reported according to the ARRIVE guidelines.

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Girault, FM., Sonnay, S., Gruetter, R. et al. Alterations of Brain Energy Metabolism in Type 2 Diabetic Goto-Kakizaki Rats Measured In Vivo by 13C Magnetic Resonance Spectroscopy. Neurotox Res 36, 268–278 (2019). https://doi.org/10.1007/s12640-017-9821-y

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