Significance of Brain Glucose Hypometabolism, Altered Insulin Signal Transduction, and Insulin Resistance in Several Neurological Diseases

Abstract

Several neurological diseases share pathological alterations, even though they differ in their etiology. Neuroinflammation, altered brain glucose metabolism, oxidative stress, mitochondrial dysfunction and amyloidosis are biological events found in those neurological disorders. Altered insulin-mediated signaling and brain glucose hypometabolism are characteristic signs observed in the brains of patients with certain neurological diseases, but also others such as type 2 diabetes mellitus and vascular diseases. Thus, significant reductions in insulin receptor autophosphorylation and Akt kinase activity, and increased GSK-3 activity and insulin resistance, have been reported in these neurological diseases as contributing to the decline in cognitive function. Supporting this relationship is the fact that nasal and hippocampal insulin administration has been found to improve cognitive function. Additionally, brain glucose hypometabolism precedes the unmistakable clinical manifestations of some of these diseases by years, which may become a useful early biomarker. Deficiencies in the major pathways of oxidative energy metabolism have been reported in patients with several of these neurological diseases, which supports the hypothesis of their metabolic background. This review remarks on the significance of insulin and brain glucose metabolism alterations as keystone common pathogenic substrates for certain neurological diseases, highlighting new potential targets.

Type 2 Diabetes Mellitus and Alzheimer’s Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets

“…However, the female sex [ 28 ], and cardiovascular risk factors such as stroke, poorly controlled high blood pressure, hypercholesterolemia, obesity, and diabetes are suggested to be among the potential predisposing factors [ 25 , 28 , 35 ]. Indeed, AD could be considered a central metabolic disease due to glucose hypometabolism [ 38 , 39 ], associated with impaired insulin and insulin-like growth factor (IGF) signaling pathways in the brain, which are physiologically involved in energy production and neuronal survival and plasticity, and therefore play a key role in cognition and memory [ 40 , 41 ]. These metabolic disruptions occur years before the onset of AD [ 42 ] and worsen with AD progression [ 40 ].…”

Engineered Glucose Oxidase‐Carbon Nanotube Conjugates for Tissue‐Translatable Glucose Nanosensors

“…Glucose is the primary energy source for the brain and plays an essential role in neuronal activity. Disruptions to glucose metabolism homeostasis, such as hyperglycemia and hypoglycemia, have been linked to various pathologies, including cognitive impairment, dementia, Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, and epilepsy [31] . Therefore, quantifying spatiotemporal changes in local changes in glucose consumption in the brain may lead to a better understanding of the diseases and potentially contribute to the development of therapeutics.…”

The vasodilator naftidrofuryl attenuates short-term brain glucose hypometabolism in the lithium-pilocarpine rat model of status epilepticus without providing neuroprotection

“…Interictal [ 18 F]-FDG PET features glucose hypometabolism in the epileptogenic region. Furthermore, the severity of seizures seems to relate to the degree of hypometabolism and it has been suggested that reciprocal positive feedback exists between seizures and hypometabolism (Blázquez et al, 2022;Gaillard et al, 2002;Zilberter and Zilberter, 2017). Importantly, interictal brain glucose hypometabolism has been consistently reproduced in the silent latent period of the lithium-pilocarpine model of SE (Bascuñana et al, 2021;García-García et al, 2017, 2016Shiha et al, 2015).…”