Thus, insulin, a highly active hormone and a crucial polypeptide in the body, plays an important role in the brain (
Figure 1). Like glucose, insulin also crosses the BBB, and when in the brain, insulin binds to insulin receptors on neurons and glial cells; there, its main function is to modulate glucose transfer into different brain cells for maintaining the normal functioning of the brain
[21]. Additionally, insulin in the brain contributes to the control of nutrient homeostasis, reproduction, cognition, and memory, as well as to neurotrophic, neuromodulatory
[22], and neuroprotective effects.
3. Involvement of Diabetes in the Development of Alzheimer’s Disease
3.1. Abnormal Protein Processing
The main feature of AD is abnormal protein processing in the brain, through which amyloid-β plaques and neurofibrillary tangles are formed, causing morphological pathologies in the brain tissue due to disintegrated microtubules, synaptic impairment, and neuronal apoptosis, thus, resulting in cognitive impairments and several psychopathologies (Figure 2).
Figure 2. Abnormal protein processing occurs in the brain of patients with Alzheimer’s disease, which leads to the disintegration of microtubules and formation of tau aggregates and amyloid-β plaques, causing morphological pathologies, several cognitive impairments, and behavioral changes (Created by
BioRender.com, accessed on 23 August 2021).
Diabetes has been shown to be involved in the development of AD by affecting abnormal protein processing. Disturbed insulin signaling, associated with type 2 diabetes, affects the expression and metabolism of amyloid-β
[26]. Moreover, abnormally phosphorylated tau protein, which induces the instability of neuronal microtubules and apoptosis of neurons in AD
[27][28], has been observed in animal models of diabetes. Increased tau phosphorylation has been observed in type 1 and type 2 diabetes of mouse and rat models
[29][30][31][32][33], as well as in humans with type 2 diabetes
[34].
3.2. Deficient Insulin Signaling
Dysfunctional insulin receptor signaling is known to affect the expression and metabolism of amyloid-β and tau protein
[26] and their clearance
[35]. Insulin receptors are proposed to regulate synaptic activity as well; therefore, the malfunctioning of the receptors could cause neurodegeneration
[36]. Moreover, insulin resistance in connection with hyperinsulinemia induces the accumulation of amyloid-β due to the lack of available insulin-degrading enzymes (IDEs). Normally, insulin and amyloid-β are both degraded by IDE. When insulin levels are increased, such as in type 2 diabetes, insulin uses the majority of IDE, and undegraded amyloid-β starts to accumulate in neurons
[37]. As a possible treatment, insulin sensitizers have been tested in rodents
[38] and early AD patients
[39], with positive results in improving cognitive performances. Further studies are still needed to confirm the exact potential of insulin sensitizers for AD treatment. Apart from increased amyloid-β accumulation in neurons, hyperinsulinemia causes tau hyperphosphorylation in primary cortical neurons and hippocampal neurons
[40][41][42], provoking their degeneration.
Alterations in insulin receptor signaling in type 2 diabetes and AD develop due to changes in both major signaling pathways. The mitogen-activated protein kinase (MAPK) pathway, required for cell proliferation, differentiation, and apoptosis
[43], is accelerated in the brain of patients with AD
[44]. The expression of MAPK co-localizes with aggregated tau in the hippocampus and cortical regions in AD brains, indicating that MAPK signaling is also involved in tau phosphorylation, synaptic plasticity, and neuroinflammation
[45][46]. With respect to diabetes, Dusp8, which codes for a dual-specificity phosphatase involved in MAPK signaling and is predominantly expressed in the brain, was implicated by genome-wide association studies as a type 2 diabetes risk gene. There is evidence that Dusp8 can have sex-specific effects in mice and men on hypothalamic insulin resistance, hippocampal size, and cognitive, emotional, and hedonic behaviors
[47][48][49]. The second insulin receptor signaling pathway, the Akt pathway—which is responsible for cell growth and survival, protein synthesis, and inhibition of the glycogen synthase kinase-3β (GSK-3β) enzyme
[50][51][52][53][54]—is also affected by both AD and type 2 diabetes
[55]. GSK-3β in the hippocampus and cortex is important for glycogenesis and glucose clearance. In normal conditions, its activity is inhibited by phosphorylation by insulin signaling via an insulin receptor. However, in type 2 diabetes, elevated activity of GSK-3β is proposed to trigger the reduction in glucose clearance by developing insulin resistance
[54]. Moreover, increased GSK-3β activity is thought to result in increased amyloid-β production and tau phosphorylation
[53][56]. Experiments in AD animal models and cell cultures have shown that GSK-3β is a good target for treatment development, as inhibiting GSK-3β successfully slowed down neurodegeneration
[56][57].
3.3. The Cholinergic Hypothesis
Acetylcholine is a neurotransmitter that is involved in cholinergic neurotransmission. It is used by cholinergic neurons and has an important role in the peripheral and central nervous system, as cholinergic neurons are critical for cognition and memory. AD patients present with a continuous decline of cholinergic neurotransmission in their brain
[58]. This occurs due to a decrease in the production of acetylcholine as well as the hydrolysis of acetylcholine. A mechanism of action has been proposed with a cholinergic hypothesis, which suggests that insulin plays an important role in acetylcholine production
[59]. In case of hypoinsulinemia, less acetylcholine is produced due to a reduced expression of choline acetyltransferase (
Figure 3). This direct effect of insulin on acetylcholine production has additionally strengthened the link between AD development, insulin malfunction, and diabetes; thus, AD has recently been considered a neuroendocrine disease and has been referred to as type 3 diabetes, possessing characteristics of type I and type II diabetes
[59][60][61][62].
Figure 3. A schematic overview of the major intersection points of diabetes and Alzheimer’s disease pathophysiology.
3.4. Glucose Metabolism Disorders
Apart from the impairments in brain insulin production and signaling, additional conditions are found at the intersection of diabetes and AD, such as oxidative stress and the formation of advanced glycation end products. Abnormal glucose metabolism and oxidative stress trigger the formation of advanced glycation end products which cause brain damage
[14]. Advanced glycation end products are formed by the glycation of proteins or lipids in case of chronic hyperglycemia, and present a useful biomarker for degenerative diseases such as diabetes and AD. In normal aging, the formation of these molecules occurs in low levels, while it is greatly accelerated in patients with diabetes and AD
[63][64]. Moreover, advanced glycation end products were found to induce the glycation of amyloid-β and tau, resulting in their formation and aggregation
[65] (
Figure 3). An increased expression of receptors for advanced glycation end products in neurons was determined in diabetic mice with impaired cognition
[66], as well as at a clinical level in patients with AD and diabetes compared to non-diabetic AD patients
[67].
3.5. Oxidative Stress
Impaired glucose metabolism has other effects in the body as well. It causes an accelerated production of free radicals, which results in oxidative stress in cells. Oxidative stress is well known to contribute to the development of diabetes and its neuropathies
[68][69]. It has been indicated that oxidative cell damage occurs early in the development of AD
[15], as increased concentrations of oxidized proteins in the hippocampus and in the frontal and parietal lobes were determined in patients with only a mild cognitive impairment. Oxidative stress is strongly linked to amyloid-β accumulation. Preclinical research in mice showed that antioxidant capacity decreases first, followed by an increase in lipid peroxidation, and finally, results in AD development
[70][71].
Moreover, oxidative stress triggers local inflammations in the brain
[72]. Some studies report that the use of anti-inflammatory drugs can decrease the risk of AD development, while others report no beneficial effects of taking these agents for treating AD
[73][74][75].
3.6. Deficits in Mitochondrial Activity
Another factor correlating diabetes to AD is mitochondrial malfunctioning
[6][16][55]. Mitochondrial activity is essential for normal neuronal functioning regarding ATP synthesis and for controlling calcium homeostasis
[76]. While the efficiency of calcium homeostasis regulation decreases in the brain with normal aging, an increased calcium uptake by mitochondria has been observed among AD pathologies
[77][78], as well as a decrease in mitochondrial mass and an increase in mitochondrial DNA in the cytoplasm
[79]. Excessive calcium uptake triggers an increase in the level of reactive oxygen species and inhibition of ATP synthesis, resulting in neuronal degeneration and apoptosis. The exact mechanism of action regarding how mitochondrial malfunctioning is correlated to AD is not yet fully understood. However, it is proposed that mitochondrial electron transport is negatively affected by amyloid-β
[80], which further on leads to mitochondrial malfunction and dysregulation of calcium homeostasis. Increased levels of intracellular calcium have been found to co-localize with neurofibrillary tangles and amyloid-β aggregates
[78][81][82].
Interestingly, as excessive calcium uptake by mitochondria causes damage in neurons in AD, it initiates similar damage also in pancreatic cells, causing insulin malfunctions that lead to diabetes pathologies
[83]. High levels of calcium in pancreatic β-cells are thought to trigger the malfunctioning of insulin secretion
[84]. Insulin deficiency and oxidative stress due to a lower antioxidant capacity of neuronal mitochondria have been observed in type 1 diabetic rats
[85], and these defects in mitochondrial DNA are determined to be inheritable. Moreover, in type 2 diabetes, a similar low antioxidant activity of mitochondria has been observed. However, in this type of diabetes, obesity is usually present, which is also known to be associated with smaller mitochondria and reduced energetic capacity
[86].
3.7. Cholesterol-Associated Pathologies
The malfunctioning of cholesterol transportation within the circulatory system has been observed in diabetes and AD, yet the details of the underlying processes are unclear. In the case of diabetes, cholesterol has been found to be accumulated within pancreatic β-cells, causing a decrease in insulin secretion
[87]. In AD mouse models, cholesterol has been determined at the same locations as amyloid-β plaques and tau proteins
[88]. Therefore, it has been proposed that cholesterol is directly involved in the formation of protein abnormalities in AD (
Figure 3).
Normal blood lipid levels are maintained by apolipoprotein E, which is expressed mainly in the brain and liver. Some alleles (
APOE ε4) of the gene for apolipoprotein E result in the development of hypercholesterolemia and have been found in 40% of AD patients
[55]. Additionally, the risk for AD development associated with
APOE ε4 is doubled by diabetes
[89]. Apolipoprotein E, synthesized from
APOE ε4, is linked to abnormal protein processing, which is present in AD patients; in addition, apolipoprotein E is able to cooperate with amyloid-β aggregates and it promotes the phosphorylation of tau in neurons, inducing neurodegeneration
[17][90].
4. Insulin Effects on Cognition and Mental Health
4.1. Cognitive Changes
Cognitive changes in people with dementia are well documented and studied. Recently, diabetes has received significant attention in psychiatry due to its high mutual frequency with mood disorders and cognitive impairment. Several symptoms of AD, such as cognitive dysfunctions regarding attention, memory, vocabulary, information processing, motor strength and speed, visual-motor and spatial skills as well as impaired general intelligence, were observed in patients with type 1 and type 2 diabetes
[55][91]. Deficits in spatial learning and long-term potentiation in the hippocampus, which are important for memory formation, have been observed in patients with type 1 diabetes. Moreover, the most prevalent form of diabetes, type 2 diabetes, has been determined to trigger early cognitive and mental changes in a similar way as type 1 diabetes. While in type 1 diabetes the major problem causing physiological and cognitive deficits is insulin deficiency, in type 2 diabetes it is the malfunctioning of insulin receptor activity that has enormous consequences on the brain. Hence, insulin resistance, hyperinsulinemia, and impaired insulin signaling have been determined to cause many cognitive pathologies (
Figure 4)
[50][55].
Figure 4. Diabetes causes several cognitive impairments, typical for Alzheimer’s disease.
The age of onset of diabetes, its duration, and degree of glycemic control are the main factors affecting how severe cognitive dysfunction will occur
[92][93]. The degree of cognitive impairment progresses with long-lasting diabetes and poorly maintained glycemic control, and with the presence of diabetic complications such as depression and hypertension
[21].
4.2. Mental Changes
Alzheimer’s disease is accompanied by depression and anxiety, which are the most prevalent mood disorders
[94]. Diabetes often co-occurs with depression and anxiety, suggesting that insulin malfunctioning can play a role in mental changes. In association with the various effects on different brain cells, insulin has been shown to affect not only cognition, but also mood and psychiatric functioning
[21]. The importance of brain insulin resistance is clearly seen in neuronal insulin receptor knock-out mice, which display spontaneous and life-long depressive-like and anxiety-like phenotypes
[95].
The idea of influencing emotional behaviors with insulin dates back a century, when psychiatrists used insulin to cure mental illnesses by inducing a coma or as a shock treatment
[96]. Now, researchers know that insulin receptors are highly present in the limbic region of the brain, where reward-based functioning, motivation, and emotions derive from. Many studies have proposed that diabetes and the development of mood disorders and their increased severity are causally linked
[97]. One of the possibilities for the mechanism of action is the insulin modulation of brain serotonergic neurons and their neurotransmission, resulting in the development of anxiety and depressive symptoms
[98]. Therefore, it is largely accepted that the risk of developing mood disorders is significantly increased in diabetic patients. Interestingly, there is a bidirectional correlation, as a 60% increase in risk for developing type 2 diabetes has been observed in depressed patients
[99], yet a detailed mechanism of this correlation is not fully understood. Anhedonia is one of the domains of depression, defined as an incapacity to feel pleasure. It is suggested that anhedonia is associated with poor glycemic control in patients with type 2 diabetes. However, in patients with type 1 diabetes, a negative correlation between anhedonia symptoms and glycemic control was reported
[100][101]. Further research is needed to clarify the mechanism of action which connects anhedonia with diabetes and AD.