Hippocampal Glucose Transport and Utilization: From Neurophysiology to Diabetes-related Dementia Development

Cerman Shehaby^*
*Correspondence: Cerman Shehaby, Department of Neurobiology, Poznan University of Medical Sciences, 60-355 Poznan, Poland, Email:

Introduction

The hippocampus, a key brain structure responsible for memory, learning and spatial navigation, is heavily dependent on glucose as its primary energy source. Glucose transport and utilization in the hippocampus are crucial for maintaining its neurophysiological functions. Any disruptions in these processes can have profound implications, contributing to the development of neurodegenerative disorders, including diabetes-related dementia. Understanding the interplay between hippocampal glucose metabolism and cognitive health is essential for elucidating the pathways leading to such conditions and for developing targeted interventions. At the cellular level, the hippocampus operates as a highly active metabolic hub, requiring a continuous and efficient supply of glucose to support neuronal signaling, synaptic plasticity and memory consolidation [1].

Description

Glucose is transported across the Blood-Brain Barrier (BBB) primarily by Glucose Transporter 1 (GLUT1), which facilitates its movement from the bloodstream into the brain’s extracellular fluid. Within the hippocampus, glucose is taken up by neurons and astrocytes through specific transporters such as GLUT3 and GLUT4, which are finely regulated to match the metabolic demands of the cells. Neurons rely on glucose to generate adenosine triphosphate (ATP) through glycolysis and oxidative phosphorylation, processes that fuel synaptic activity and neurotransmitter release. The utilization of glucose in the hippocampus is not merely a metabolic process but a tightly integrated component of neurophysiological function. During learning and memory tasks, the hippocampus experiences heightened metabolic demand, necessitating rapid glucose uptake and efficient energy production.

Astrocytes play a pivotal role in this process by supporting neurons through the astrocyte-neuron lactate shuttle. In this mechanism, astrocytes metabolize glucose into lactate, which is then transported to neurons as an energy substrate. This dynamic interplay ensures that neurons have a steady energy supply during periods of intense activity, maintaining cognitive performance. However, disruptions in hippocampal glucose transport and utilization can compromise its neurophysiological integrity, leading to cognitive decline. One major factor contributing to these disruptions is diabetes, a systemic condition characterized by chronic hyperglycemia and insulin resistance. Diabetes is associated with significant alterations in glucose metabolism, both peripherally and within the Central Nervous System (CNS). In the hippocampus, these changes manifest as impaired glucose uptake, mitochondrial dysfunction and oxidative stress, all of which detrimentally impact neuronal function and synaptic plasticity [2,3].

Chronic hyperglycemia, a hallmark of diabetes, exerts toxic effects on hippocampal neurons and astrocytes. Persistent high glucose levels lead to the production of Advanced Glycation End products (AGEs) and increased oxidative stress, which damage cellular components and disrupt glucose transporter expression and function. For instance, studies have shown reduced expression of GLUT1 and GLUT3 in the hippocampus under diabetic conditions, resulting in decreased glucose availability and energy production. This energy deficit impairs synaptic activity, weakens Long-Term Potentiation (LTP) and ultimately compromises memory and learning capabilities. Insulin resistance, another key feature of diabetes, further exacerbates the disruption of hippocampal glucose metabolism. Insulin is not only a peripheral hormone regulating blood glucose levels but also a neuromodulator in the brain, influencing synaptic plasticity and cognitive function.

In the hippocampus, insulin signaling enhances glucose uptake by upregulating GLUT4 translocation to neuronal membranes. However, in insulin-resistant states, this mechanism is impaired, leading to decreased glucose availability and synaptic dysfunction. The resulting energy imbalance in hippocampal neurons contributes to the cognitive deficits observed in diabetes-related dementia. Diabetes-related dementia represents a complex interplay between systemic metabolic dysfunction and neurodegenerative processes. The hippocampus, being highly susceptible to metabolic disturbances, serves as a critical link in this pathological cascade. Over time, chronic disruptions in glucose transport and utilization lead to neuroinflammation, neuronal loss and structural atrophy in the hippocampus, hallmarks of dementia. Moreover, diabetes amplifies the risk of vascular damage, further compromising cerebral glucose delivery and exacerbating hippocampal dysfunction [4,5].

Conclusion

Advanced imaging techniques, such as Positron Emission Tomography (PET) with glucose analog tracers, can provide insights into regional glucose uptake patterns in the hippocampus. Furthermore, elucidating the role of genetic and epigenetic factors in modulating glucose transporter expression and function may reveal new therapeutic targets. Studies focusing on the interplay between systemic and central glucose metabolism, as well as the impact of emerging antidiabetic therapies on brain health, will be instrumental in addressing the burden of diabetes-related dementia.

In conclusion, hippocampal glucose transport and utilization are fundamental to maintaining cognitive function, with disruptions in these processes playing a central role in the development of diabetes-related dementia. The intricate balance between glucose delivery, uptake and utilization in the hippocampus is essential for supporting neurophysiological functions such as memory and learning. However, diabetes-induced alterations in glucose metabolism compromise this balance, leading to energy deficits, synaptic dysfunction and neurodegeneration. Addressing these challenges requires a multifaceted approach, integrating lifestyle modifications, pharmacological interventions and advanced research methodologies. By unraveling the mechanisms underlying hippocampal glucose dysregulation, we can pave the way for effective strategies to prevent and treat diabetes-related cognitive decline, ultimately improving the quality of life for affected individuals.

Acknowledgement

None.

Conflict of Interest

None.

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