The Role of Iron Overload in Diabetic Cognitive Impairment: A Review

Abstract

It is well documented that diabetes mellitus (DM) is strongly associated with cognitive decline and structural damage to the brain. Cognitive deficits appear early in DM and continue to worsen as the disease progresses, possibly due to different underlying mechanisms. Normal iron metabolism is necessary to maintain normal physiological functions of the brain, but iron deposition is one of the causes of some neurodegenerative diseases. Increasing evidence shows that iron overload not only increases the risk of DM, but also contributes to the development of cognitive impairment. The current review highlights the role of iron overload in diabetic cognitive impairment (DCI), including the specific location and regulation mechanism of iron deposition in the diabetic brain, the factors that trigger iron deposition, and the consequences of iron deposition. Finally, we also discuss possible therapies to improve DCI and brain iron deposition.

Quantitative susceptibility mapping for iron monitoring of multiple subcortical nuclei in type 2 diabetes mellitus: a systematic review and meta-analysis

“…This is true even when iron levels are within the normal range or in cases of excessive accumulation. Although previous evidence has shown that iron overload increases the risk of T2DM and cognitive impairment ( 16 , 42 ), our meta-analysis revealed that T2DM patients have more iron deposition in the DGM. This may be due to the reciprocal effects of T2DM and iron overload/accumulation ( 13 , 43 , 44 ).…”

“…Iron plays a crucial role in metabolic processes and regulation, determining metabolic rates, glucose production, oxygen transport, protein synthesis, fuel utilization, muscle oxygenation, insulin effectiveness, deoxyribonucleic acid (DNA) synthesis, and the characteristics of fat cells ( 16 , 42 , 45 ). Although iron is necessary for neurotransmitter synthesis and mitochondrial function, its excessive accumulation can lead to various diseases, including oxidative stress, diabetic retinopathy, neuronal damage, chronic inflammation, and abnormal glucose and lipid metabolism ( 10 , 16 , 46 – 49 ).…”

“…Previous studies have established a significant link between excessive iron accumulation in the body and the risk of developing T2DM ( 50 ). High iron levels can be a risk factor for T2DM and its complications ( 16 , 51 – 56 ). Notably, diabetes has also been associated with increased iron accumulation in the brain through multiple mechanisms ( 16 ).…”

“…Type 2 diabetes mellitus (T2DM) is a multifaceted metabolic disorder characterized by pancreatic β-cell damage, hyperglycemia, insulin resistance, and insufficient insulin production ( 8 , 13 ). This condition is intricately associated with cognitive decline, affecting various aspects such as executive function, memory, attention, and visuospatial abilities ( 8 , 14 – 16 ), and manifests as structural brain alterations, such as atrophy and iron accumulation ( 16 , 17 ). The perturbation of insulin signaling exacerbates the distribution of iron in neuronal tissues, resulting in neuronal iron overload and potential complications including neuropathy ( 18 ).…”

The association between the oxidative balance score and cognitive function in individuals with diabetes: NHANES 2011- 2014

“…The combination therapy involving vitamins C and E has the potential to enhance passive avoidance learning and memory in rats with diabetes [25]. There is increasing evidence suggesting that elevated iron levels not only increase the likelihood of diabetes but also play a role in the development of cognitive decline [26]. Elevated copper levels in the hippocampus may lead to cognitive decline in individuals with type 2 diabetes [27].…”