There is an increasing awareness of the importance of insulin in the development of Alzheimer's disease (AD) suggesting that AD may represent a brain-specific form of diabetes and could thus be classified as type 3 diabetes.
Impaired insulin signalling
Effect of impaired insulin signalling
Similarities in AD and T2D pathologies
Diabetes and obesity as a risk factor for AD
Type 3 diabetes
Alzheimer’s Disease (AD) is a debilitating neurodegenerative disorder that contributes to 60-70% of dementia cases. It is rapidly rising in prevalence but still has no preventative treatment.1
The characteristic pathology of Amyloid b (Ab) aggregation and hyperphosphorylation of tau, found upon AD’s discovery in 1907, are still its most identifiable features.2 However, they have yet to be linked to one precipitating factor, with the aetiology of this disease still not fully understood.
There are several hypotheses that propose a potential trigger. The foremost of which are currently the ‘Amyloid Cascade Hypothesis’ (Figure 1)3 and the ‘Tau Hypothesis’ (Figure 2)4,5 However, recently research has been considering impaired insulin signalling as the trigger, due to its association with accelerated cognitive decline and neurodegeneration in AD.6,7,8
Figure 1. Amyloid Cascade Hypothesis
The amyloid cascade hypothesis presents the argument that the first pathological event to occur in AD is the deposition of Ab. This then triggers a cascade of events, which leads to the consequent development of senile plaques (SPs), due to Ab aggregation, and neurofibrillary tangles (NFTs), due to hyperphosphorylation of tau. Further proteins are obtained throughout the process such as APOE, complement proteins, ubiquitin (Ub) and glial fibrillary acidic protein (GFAP). These contribute to the development of SPs and NFTs, which ultimately result in cell death and dementia.9
Figure 2. The Tau Hypothesis
Specific mutations lead to increased phosphorylation of tau. This prevents tau from binding to microtubules and stabilising them, leading to their degeneration and a consequent loss of function. This inability to bind to microtubules leads to increased levels of free tau which aggregates to form NFTs, leading to neuronal death. This loss of microtubule function and neuronal death contributes to the development of dementia.10
Insulin and insulin-like growth factors type 1 and 2 (IGF-I and IGF-II) are normally produced by neurons in both the central and peripheral nervous systems.11 D’Ercole et al found extensive involvement of insulin and IGF-I in the regulation of neuronal development.12 A summary of this work states they influence ‘neuronal growth, survival, differentiation, migration, energy metabolism, gene expression, protein synthesis, cytoskeletal assembly, synapse formation and plasticity’.6 Modulation of these elements is crucial to insulin’s role in facilitating long term potentiation (LTP), which enables memory formation and learning.13
In the brains of AD patients however, levels of these growth factors are significantly reduced in the hippocampus, hypothalamus and frontal cortex.11 These areas of the brain form part of the corticolimbic system and are vital to the formation and consolidation of memories.14
One study found that in the hippocampus of AD brains, a 4-fold reduction in the expression of insulin mRNA and a 5- to 6-fold reduction in IGF-I mRNA has been indicated. Furthermore, it found an 8 to 10-fold decrease in receptor expression in the hippocampus and hypothalamus in AD brains.11 It is primarily this reduced sensitivity in growth factor receptors that has thus been found to contribute to the insulin/IGF-I resistance found in the brain in AD.
Early on in AD, the utilisation of glucose is shown to decrease by nearly 45%.6 Glucose metabolism is primarily regulated by insulin, its receptors and the downstream signalling cascade.15 In addition to affecting glucose utilisation in the brain, disruption of the insulin/insulin receptor signal transduction cascade has been shown to affect acetylcholine, cholesterol and ATP levels, alongside increased aggregation of Ab and hyperphosphorylation of tau.8
Insulin and IGF-1 regulate the phosphorylation of tau by inhibiting glycogen-synthase kinase-3 (GSK-3b), through the activation of the phosphatidylinositol 3-kinase (PI3K/Akt) pathway. Insulin and IGF-1 reduce the phosphorylation of tau by downregulating GSK-3b activity.16 Consequently, when insulin and IGF-1 signalling is disrupted, their neuroprotective function ceases. This leads to increased activation of GSK-3b and the subsequent hyperphosphorylation of tau, which aggregates and contributes to the formation of neurofibrillary tangles (NFTs).17
Insulin also influences the processing of Ab, resulting in its extracellular accumulation as senile plaques (SPs). Insulin regulates Ab metabolism by accelerating its intracellular trafficking, which increases its secretion and decreasing its breakdown by insulin degrading enzyme.18
Furthermore, Ab has been found to interrupt insulin signalling by competitively binding to, and reducing insulin’s affinity for, the insulin receptors.19 This further disrupts insulin signalling, thus increasing the activation of GSK-3b and causing the consequent hyperphosphorylation of tau, which intensifies AD pathology and neurodegeneration.6
Whilst impaired insulin signalling has been found to be the main defect AD and type 2 diabetes have in common, several reviews have suggested additional similarities in their physiological processes. Both conditions are classed as degenerative diseases, with AD featuring a loss of neurons and type 2 diabetes undergoing pancreatic b cell degeneration.20
Furthermore, type 2 diabetes displays the characteristic SPs and NFTs found in AD, due to a similar overactivity of GSK-3b, Ab aggregation and hyperphosphorylation of tau. Additionally, both disorders are related to cardiovascular disease, irregular blood vessels, abnormally high levels of oxidative stress and an augmented inflammatory response.21
Significant research has gone into exploring whether type 2 diabetes causes AD or is merely a risk factor that considerably increases the likelihood of its development.22 Both conditions are highly prevalent, especially after the age of 65 years.
The increasing prevalence of diabetes and the continuously ageing population suggests that if a direct causal relationship was found between the two, reports that the prevalence of AD will continue to dramatically increase in the coming years will be validated.23 A relationship between the two conditions is intimated by numerous pieces of evidence, one of which is the insulin resistance and deficiency found in AD, as previously discussed. It has been consistently found that those with type 2 diabetes are at an increased risk of developing MCI, dementia and AD.11,24,25
One study showed there was an increased risk of 65%, amongst those with diabetes mellitus, of developing AD.26 Streptozotocin-induced diabetes in animal experiments modelled insulin resistance and deficiency, and were found to develop characteristic AD pathology and showed cognitive decline.27,28,29
Animal experiments modelling type 2 diabetes in obese rodents found significantly impaired cognitive function.30,31 However, whilst these models did demonstrate cognitive decline, they failed to demonstrate some of the key pathological findings in AD, such as SPs, NFTs and abnormal IGF-1 levels.32 Therefore, although type 2 diabetes might contribute to the development of AD, alone it is not enough to cause it.22
Although a causal link has not been found between the two conditions, there is evidence to suggest that AD represents a brain-specific form of diabetes. The idea that insulin deficiency and insulin resistance are fundamental to the development of AD pathology has led to the proposition that AD may be a neuroendocrine disorder and thus could be termed ‘type 3 diabetes’.11
Whilst there is considerable overlap between the physiological processes of type 2 diabetes and AD, the impaired insulin signalling seen in AD is unique and brain-specific, so cannot be classed as either type 1 diabetes or type 2 diabetes. Potentially the strongest evidence in support of type 3 diabetes is the effect on the cognitive and pathological features of AD following the use of Insulin sensitizers (IS).
Currently, treatment for AD is only able to slow the progression of AD symptoms, rather than prevent the disease itself.33 A promising new avenue for therapeutic intervention is to combat the insulin resistance found in the brain in AD.34 Peripheral insulin resistance in type 2 diabetes is prevented by the use of IS.
The main drugs currently used as IS are metformin and the thiazolidinediones - rosiglitazone and pioglitazone. The exact mechanism of each of these drugs is not well understood, but as sensitizers, they reduce insulin resistance by increasing glucose uptake and enhancing the sensitivity of insulin receptors.34 Consequently, if used in AD, IS may be effective at counteracting insulin resistance in the brain and thus repairing insulin signalling.35 This would potentially reduce the cognitive decline and characteristic AD pathology shown to be a consequence of this pathological process.
However, studies investigating the use of thiazolidinediones to improve cognition in mild-to-moderate AD patients have produced conflicting results. Early phase II36 and phase III37 double-blind, randomised, placebo-controlled trials showed improved cognition upon rosiglitazone treatment. However, more recent phase III clinical trials 38,39 have found no effect of rosiglitazone treatment on cognition. Similarly, smaller clinical trials for pioglitazone disagree on the efficacy of this drug in mild-to-moderate AD patients. Two pilot clinical trials showed improved memory and cognition in patients with mild AD and type 2 diabetes40,41,42 whereas no benefit was found in a similar study which used patients with AD but not type 2 diabetes.42 This suggests that pioglitazone may only have an effect in patients with diabetes. There are currently no clinical trials on the use of metformin in patients with AD.
In summary, there is an increasing awareness of the importance of insulin in the development of AD. The impaired insulin signalling found within the brain of those with AD has been linked to the development of the characteristic cognitive and pathological features seen in this disease.
Type 2 diabetes demonstrates similar insulin impairment peripherally, as well as sharing numerous pathological processes with AD. Consequently, AD may represent a brain-specific form of diabetes and could thus be classified as type 3 diabetes. Attempts to combat this insulin resistance provide an interesting new avenue for therapeutic intervention.
Amy Craig, 4th Year Medical Student, The University of Manchester
Conflict of interest: none
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