THE LINK BETWEEN TYPE 2 DIABETES AND ALZHEIMERS DISEASE
The 1st case of Alzheimer’s Disease (AD) was reported in 1906 in Germany . According to Alzheimer’s Association (www.alz.org) as of Oct 2016 there are more than 5 mil. Americans living with AD while in 2017 it is estimated to cost US $274 billion.
Over the last decade there has been a lot of research associating the development of Alzheimer’s Disease with Type 2 Diabetes.
There are 2 ways in which T2D influences the risk of AD:
1. by contributing to small vessel disease. T2D can disrupt the healthy function of brain vasculature and lead to dementia and AD 
2. by interacting with key proteins & pathways (such as Aβ and tau), T2D influences the development of AD.
In this article I will discuss the 2nd link.
1. THE HALLMARKS OF T2D AND AD
Alzheimer’s Disease (AD) is a neurodegenerative disease characterised by selective neuronal cell death. Two hallmarks of AD are:
– the intracellular neurofibrillary tangles (NFTs)
– extracellular amyloid deposits forming senile plaques.
The accumulation of neurotoxin amyloid β peptide (Aβ) in the hippocampus and cerebral cortex appears to be a major pathological step in the progression of AD [1, 10]. Based on the tau hypothesis excess phosphorylation of tau proteins result in the transformation of normal tau proteins to NFTs.
Diabetes mellitus is a metabolic disorder characterised by hyperglycaemia. In type 2 diabetes (T2D) the main effect is insulin resistance causing relative insulin deficiency. Pancreatic β-cells co-secrete insulin and amylin (also known as islet amyloid polypeptide IAPP). One of the hallmarks of T2D is:
– β-cell loss  due to amyloid deposits (composed primarily of amylin) .
Similar with AD in T2D degeneration of pancreatic islets has been associated with NFTs formation .
2. INSULIN’S IMPLICATIONS IN Aβ BREAKDOWN
Both Aβ peptide and insulin are amyloidogenic peptides sharing a common sequence recognition motif. Together with other amyloidogenic proteins (i.e. glucagon and amylin) they are degraded by Insulin Degrading Enzyme (IDE)* [3, 13]. IDE highest expression is in the liver, testes, muscles and brain . Aβ is also broken down through Neprilysin (NEP) .
Both Aβ peptide and insulin compete with each other not only for their degeneration through IDE but also for binding to insulin receptors .
Insulin plays a key role in the healthy metabolism of Aβ peptides. It up regulates the transport of AβPP/Aβ from trans-Golgi to cellular membrane  promoting the transport of Aβ outside the cell  and has been shown through different mechanisms to contribute to the increase of extracellular Aβ levels and decrease of intracellular Aβ levels .
As I will discuss later insulin seems to counteract many of the toxic effects of Aβ in the mitochondria.
In the only study so far that measured insulin levels in the brain** it was shown that insulin reduces with age in both healthy subjects and patients with AD  indicating that low brain insulin is not a direct cause of AD pathology. On the other hand though there is consistency in the findings of insulin resistance in AD patients .
The following mechanism has been speculated to contribute to that:
1. IDE expression decreases with aging  reducing the breakdown capacity of Aβ peptides; leading to higher intracellular Aβ levels.
2. Sequentially the relatively higher levels of Aβ 1-40 & Aβ 1-42 peptides by binding on insulin receptors reduce insulin’s binding capacity and promote insulin resistance .
The fact that insulin resistance is not specific to insulin in AD brain is supported by the fact that both insulin-like growth factor (IGF) I & II (50,51) and lectin (52) are reported to be lower.
3. OTHER LINKS THROUGH WHICH INSULIN RESISTANCE CAN CONTRIBUTE TO ALZHEIMER’S
Insulin also regulates the phosphorylation of tau proteins with insulin resistance been shown to cause  tau hyper-phosphorylation  and the formation of NFTs.
4. HYPOMETABOLISM OF GLUCOSE (IN CEREBRAL CORTEX)
In areas of the brain with high glucose demand and insulin resistance, AD patients have been shown to have compromised glucose metabolism . 44% reduction in cerebral glucose metabolism has been reported in the early onset of AD .
Hypo metabolism of glucose leads to:
A. the inhibition of glutamine synthase, creatine kinase, aconitase, pyruvate dehydrogenase & α-ketoglutarate dehydrogenase [17,18,19] Sequentially the lower levels of pyruvate dehydrogenase lead to lower levels of acetyl-CoA, the compromised production of acetylcholine  and the decreased formation of intracellular cholesterol  (which is necessary for normal cell function).
B. reduced ATP production. In sporadic AD patients*** there is a 50% ATP decrease at the beginning of the disease . Reduced ATP production leads to the activation of erk36 & erk40  and subsequently tau hyperphosphorylation .
Glucose hypometabolism of early-onset AD was shown to be much more severe than in late-onset patients .
5. IMPAIRED DETOXIFICATION & COMPROMISED Ca2+ BUFFERING (MITOCHONDRIA)
Aβ42 protein was shown to inhibit cytochrome oxidase in human mitochondria in a dose depended manner . The effect was dependent on the presence of Cu2+. Studies in cybrid cells demonstrated a deficit of cytochrome oxidase in AD platelets as well as impaired intracellular calcium buffering and elevated basal cytosolic calcium concentration in AD [27,28]
Mitochondria serve as a high capacity Ca2+ sinks, supporting cellular Ca2+ homeostasis . Excess Ca2+ uptake in the mitochondria has been shown to [34, 35, 36]:
1. Increase ROS production
2. inhibit ATP synthesis
3. release cytochrome c
4. induce mitochondrial permeability transition (MPT)****
The maintenance of Ca2+ homeostasis represents a major expenditure within neutrons . In high oxidative stress there is an increase in cytoplasmatic Ca2+ . MTP is enhanced by increased Ca2+, oxidative stress, and low membrane potential, while Mg2+, ADP, high membrane potential [38, 39], CoQ10, vitamin E, reduced glutathione, melatonin and nicotine oppose that effect [41, 42].
Diabetes decreases the capacity of mitochondria to accumulate Ca2+ thus leading to MPT opening [31, 32]
6. INSULIN’S PROTECTIVE MECHANISM IN THE PRESENCE OF Aβ (MITOCHONDRIA)
Insulin has been shown to support mitochondrial function in skeletal muscles . It seems to impact the function of neuronal mitochondria in multiple ways :
1. prevents the depolarization of mitochondrial inner membrane 
2. increases CoQ9 antioxidant 
3. modulates glutathione redox cycle 
4. increases the capacity of mitochondria to accumulate Ca2+ 
5. promotes clearance of Aβ 
“ Although insulin does not affect basal mitochondria function, in the presence of Aβ insulin prevents a drastic decline in mitochondrial OXPHOS efficiency and avoids an increase in the oxidative stress, improving and/or preserving the function of neurons under adverse conditions.” 
While genetics indisputably play a role in the development of AD; with 50% of patients being carriers of the APOE4 gene , there is enough research showing the link between T2D and AD. Non-APOE4 carriers have 535% (1.4 -> 7.5%) more chances of developing AD if their fasting blood insulin is > 89.4 pmol/l [54, 55].
The relationship between T2D and AD is intricate though if you consider the following:
1. One of the hallmarks of T2D is insulin resistance causing elevated insulin levels.
2. One of the hallmarks of AD is elevated Αβ peptides.
3. Insulin counteracts many of the toxic effects of the Aβ peptides in the brain of patients with AD.
3. Aβ peptides appear to contribute to the development of insulin resistance independent of insulin’s action, by binding on insulin receptors.
AD -> high Aβ peptides -> Insulin Resistance / T2D -> elevated insulin -> Protect from Aβ toxicity
Could T2D be a defense mechanism against the brain’s degeneration in AD?
* IDE is a zinc-metallopeptidase. It is also known as insulysin.
** It is not clear if insulin is produced in the brain or transferred there through the bloodstream 
*** Sporadic AD are the patients without a genetic predisposition to develop AD
**** The mitochondrial permeability transition (MPT) is the sudden increase of inner mitochondrial membrane permeability to solutes with a molecular mass less than 1500 Da [29,30]
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