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The issue

Diabetes is one of the most prevalent diseases in the global population today. In the last decade, its prevalence has increased globally, and it is estimated that 463 million adults are diabetics. If this trend continues, by 2045 it is estimated that 700 million adults will suffer from this condition. [1] The increase in the number of cases can be attributed to a higher incidence of risk factors such as a sedentary lifestyle, a diet high in energy density from simple carbohydrates, obesity, and increased life expectancy. [2] Diabetes Mellitus (DM) is defined as a heterogeneous group of endocrine pathologies whose main feature is hyperglycemia secondary to an alteration in insulin production or to the resistance of peripheral tissues to its action. It is further divided into different types: Type 1 Diabetes Mellitus (DM1) and Type 2 Diabetes Mellitus (DM2). [3] DM has a negative impact on the quality of life of those who suffer from it, as it is associated with acute complications that may have permanent neurological consequences or pose a risk to life; it also has chronic micro and macrovascular complications secondary to the deposition of glucose metabolites and inflammatory damage, with the most common being diabetic retinopathy, nephropathy, diabetic polyneuropathy, and generalized vascular injury. Recently, cognitive impairment secondary to diabetes has been studied and recognized as a chronic complication resulting from metabolic dysregulation. [1]

In DM2, micro and macrovascular complications develop secondary to chronic tissue exposure to hyperglycemia. [1] The main factor promoting these complications is widespread vascular damage caused by the accumulation of glucose metabolites and endothelial damage resulting from chronic inflammatory state due to glucotoxicity. These endothelial alterations are related to problems in learning, memory, attention, and eventually the development of dementia in DM2 patients. [4] 

What is memory?

To understand exactly what problems DM2 is causing in memory and learning, we must first understand what memory is from a physiological point of view. Memory can be defined as the process involved in the acquisition, storage, encoding, and retrieval of information. It is thus an essential cognitive function for the survival of an organism and the maintenance of a good quality of life. While several neurotransmitters are involved in memory function, the catecholaminergic system has been significantly associated with pathological conditions related to memory deficits. The main catecholaminergic neuronal pathways originate from the cell bodies of dopaminergic neurons located in the mesencephalon. These are divided into three groups: nigrostriatal, mesocorticolimbic, and tuberoinfundibular. Most of the brain's dopamine is found in the striatum, originating from the substantia nigra, which is involved in the control of motivated behavior and procedural aspects of movement. The main limbic and cortical sources of dopamine are cell bodies located in the ventral tegmental area (VTA), which have essential roles in cognitive functions such as emotional regulation, motivation, and reward. The cell bodies of noradrenergic neurons are located in the locus coeruleus (LC), located in the lateral floor of the fourth ventricle. The LC innervates all brain regions including the forebrain, brainstem, cerebellum, and limbic structures (such as the hippocampus, amygdala, and septum). Catecholaminergic inputs from the LC and VTA regulate various aspects of memory, from acquisition to consolidation (long-term relative stabilization), memory persistence, and reconsolidation. [5]

Image 1. Image of a brain generated with Meta IA

In simple terms, memory is mainly divided into short-term and long-term. Short-term memory, also known as working or operational memory, is limited and breaks down into four main parts: the visuospatial sketchpad, the episodic buffer, the phonological loop, and the central executive. This mainly refers to the active maintenance of information in a specialized system aimed at integrating, controlling, and regulating the working memory system. On the other hand, long-term memory or consolidation retains information for a much longer time. It is involved in the conscious recognition of places or things. Additionally, it encompasses all knowledge collected throughout life, used in things like language. Finally, it is characterized by the unconscious storage of information, such as riding a bicycle. [5]

Causes of deficits

Diabetic patients perform worse in applying six cognitive domains, which are complex attention, executive functions, learning and memory, language, visuoperceptual skills, and social cognition. [6] The greatest deficit is in the areas of information processing, psychomotor efficiency, executive functions, and verbal learning. [7] It has been reported that, throughout their lives, 44% of diabetic patients will present attention problems and 50% memory problems; [6] these deficits decrease the quality of life of patients and have an economic impact on health institutions responsible for providing them care, as they tend to be chronic and progressive in nature. [8] 

The association of DM2 with obesity and metabolic alterations such as hypertriglyceridemia and hypercholesterolemia also plays an important role in the development of cognitive impairment. [9] The increase in adipocytes alters the regulation systems responding to hormones inducing tissue resistance to their action, especially in the case of leptin and insulin. Leptin resistance prevents the feeling of satiety and insulin resistance prevents proper utilization of glucose creating hyperglycemia. This hormonal disruption has a systemic effect making obesity a predisposing factor for alterations across all systems, especially in the CNS. [10] Hypertriglyceridemia and high consumption of saturated fatty acids play a vital role in the early activation of inflammatory pathways as these lipid molecules interact with toll-like receptor 4 (TLR4) and activate the primary response gene for myeloid differentiation (My88) [11] which leads to the activation of Nuclear Factor Kappa B (NF-κB) in astrocytes, this in turn promotes the formation of pro-inflammatory cytokines such as Interleukin-1β (IL-1β), Tumor Necrosis Factor-α (TNF-α), and Interleukin-6 (IL-6), causing an alteration in protein expression and compromising the integrity of the blood-brain barrier (BBB). [12] Neuronal inflammation is associated with cognitive impairment, especially learning and memory. TNF-α is an important cytokine generated during neuroinflammation. Previous studies indicated that TNF-α alters hippocampus-dependent memory, including contextual fear and spatial memories. TNF-α negatively regulates the retrieval and reconsolidation of hippocampus-dependent memory. [13] This pro-inflammatory state is associated with an increase in the formation of reactive oxygen species (ROS) as a result of an increase in mitochondrial respiration and the increase in expression of the enzyme NADPH oxidase. [14] It has been shown that these alterations have a significant impact on the hippocampus, which is a key brain area for memory and learning. [15] It is possible that part of the deficit specifically present in this area is also associated with an increase in Aβ levels secondary to excess circulating lipids and the consequent alterations in the BBB. [16] 

Image 2: Representative diagram of cognitive impairment

High levels of LDL cholesterol and low levels of HDL cholesterol are risk factors for the presence of endothelial dysfunction and alterations in tissue perfusion, resulting in structural changes at the brain level and inducing the development of cognitive impairment. [17] HDL cholesterol is involved in the removal of endothelial deposits of low-density lipoproteins in the brain via apolipoprotein E (APOE) and heparan sulfate proteoglycans in the subendothelial space of the cerebral microvasculature. Additionally, HDL particles have an inhibitory capacity over oxidized LDL particles concerning endothelium-dependent vasodilation, moreover, they prevent the expression of adhesion molecules induced by cytokines. [18]

In addition to molecular imbalances, various degrees of cerebral atrophy and extensive changes in communicating white matter fibers have also been identified in DM2 patients, these are independent of age and are related to the years of disease progression and metabolic control. When compared to healthy subjects, those with DM2 presented a reduction in total brain volume, from 0.5% to 2.0%, evidencing a phenomenon of premature brain aging. [19]

Furthermore, DM2 has been found to be associated with decreased cortical thickness in the frontal and temporal lobes, the caudate nucleus, and the putamen. This impacts visuospatial performance, motor planning, and executive functions. The degree of involvement will be directly related to the degree of atrophy in each structure and may correlate with the degree of metabolic dysregulation of the patient. [20] 

Changes consistent with alterations in myelination have also been found, independent of age. These changes induce an increase in the mean diffusivity level in the uncinate fasciculus, inferior longitudinal fasciculus, and splenium of the corpus callosum, implying a decrease in inter-structural connectivity capacity, resulting in slower information processing speed and an increase in cerebrovascular injury load, leading to cognitive impairment associated with diabetes. [20, 21] These injuries evolve more rapidly in patients with poor metabolic control, those with other complications related to microvascular injury, and patients aged 40-64 years. [17] On the other hand, alterations in insulin signaling pathways contribute to synaptogenesis and synaptic remodeling, so their affection impacts the learning and memory abilities of individuals. [22] 

The complete picture

The discovery of these alterations is relatively recent, generating increasing concern and a reconsideration of the issues that this disease represents. The general public has a very limited understanding of the true danger this disease represents, as it does not consist solely of blood sugar control, but involves systemic complications affecting the vast majority of the body and has a much more aggressive evolution in patients with poor metabolic control, who tend to be vulnerable individuals, thus it is important to inform people of the full spectrum of these types of chronic diseases with such high prevalence. The first step is prevention, but once this point has passed, a broad treatment approach should be adopted, addressing both causes (glycemic control) and consequences, which is why pharmacological proposals have been sought aimed at reducing the effects of DM2 on cognitive impairment.

References

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