Abstract
Increasing evidence suggests there is a relationship between cognitive impairment and metabolic dysfunction. Diabetes is a chronic disease, and metabolic factors affecting brain metabolisms, such as serum glucose, insulin, and glucagon, are altered according to disease progression. In our previous study, we applied hyperpolarized [1-13C] pyruvate magnetic resonance spectroscopy in prediabetic mice after feeding them a 60% high-fat diet (HFD) for 6 months. Ultimately, we detected significantly increased [1-13C]lactate conversion in the whole brain and an almost five-fold increased [1-13C]lactate/pyruvate ratio in the hippocampal region. In the present study, we induced diabetes in mice by injecting streptozotocin and feeding them an HFD for 6 months. Unlike in prediabetic mice, [1-13C]lactate conversion in the diabetic mice did not differ from that in the control group, but [1-13C]lactate/total 13C ratio showed an almost 1.4-fold increase in the hippocampal region. We measured the amount of the lactate and mRNA levels of glucose transporters from isolated hippocampus and cortex samples. In the hippocampus, significantly decreased GLUT1 mRNA levels and increased lactate were detected, suggesting an inconsistency between glucose and pyruvate metabolism. Pyruvate can be produced from oxaloacetate as well as glucose. We investigated ATP citrate lyase (ACLY) because it cleaves citrate into oxaloacetate and acetyl CoA. Phosphorylated ACLY (Ser455), the active form, was increased in both hippocampus and cortex samples of mice injected with streptozotocin and fed an HFD. Also, phosphorylated ACLY/total ACLY showed a positive correlation with lactate amount in the hippocampus. Our results suggest that the brain has different responses to diabetic progression, but, in the hippocampus, maintains metabolic alteration toward increasing lactate production from the prediabetic to the diabetic stage. We suggest that ACLY-mediated pyruvate be used to support lactate levels in the hippocampus in cases of limited glucose availability.
Highlights
Diabetes has been recognized as a risk factor for Alzheimer’s disease
Higher hyperpolarized [1-13C]lactate/total 13C ratio is visualized in the region containing the hippocampus in mice injected with streptozotocin and fed an high-fat diet (HFD) To investigate the brain response to the metabolic change provoked by diabetes, we performed hyperpolarized 13C MR chemical shift imaging in the brain
[1-13C]lactate production was still maintained and a higher [1-13C] lactate/total 13C ratio was visualized in the brains of mice injected with streptozotocin and fed an HFD (Fig. 2a)
Summary
Diabetes has been recognized as a risk factor for Alzheimer’s disease. According to epidemiological research, patients with diabetes demonstrate dementia at a rate that is two to three times higher than that of those without diabetes [1, 2]. Elevated serum glucose levels in people without diabetes were associated with the development of dementia [13], while acute hyperglycemia increased amyloid beta levels in the hippocampal interstitial fluid in an Alzheimer’s disease model [14], leading to the implication that hyperglycemia could induce cognitive impairment as well. Given the fact that diabetes is a chronic disease and metabolic factors such as serum glucose, insulin, and glucagon are altered by disease progression [15, 16], new information about how the brain responds to disease progression could provide insight into the development of Alzheimer’s disease in patients with diabetes
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