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

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. C-13 magnetic resonance spectroscopy in vivo at 14.1T was used to detect C-13 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-C-13]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.