Food for Thought: The connection between type 2 diabetes and Alzheimer’s

Image result for alzheimers and diabetes

Both Alzheimer’s disease (AD) and type 2 diabetes are products of insulin resistance. Type 2 diabetes has insulin resistance in the peripheral organs, muscle and adipose tissue, while in AD, the insulin signaling pathway in the brain is impaired. This common molecular mechanism between the two diseases is theorized as the reason why 70% of individuals diagnosed with Type 2 diabetes will eventually develop Alzheimer’s. This connection has led to nicknaming AD as Type 3 diabetes. So what is insulin resistance? Is it actually a good theory for the risk of developing Alzheimer’s? Let’s take a look.

Insulin Resistance

Insulin is a hormone that regulates the amount of glucose in the blood. When insulin binds to a tyrosine kinase receptor, the phosphorylation or activation of proteins occurs, sending a signal down the pathway. This signal allows for the uptake of glucose, fatty acids and amino acids into cells where they are stored in the liver, adipose tissue and muscle as nutrients. If these nutrients are not able to be taken up, diabetes occurs. In the case of Type 2 diabetes, the body becomes resistant to insulin, so the signaling pathway never occurs to cause the uptake of these nutrients. The body’s resistance to insulin can be due to the inability of the insulin receptors to bind insulin and unlock the cells to allow glucose and other molecules into the cell.

Type 3 Diabetes

The term “type 3 diabetes” is given to Alzheimer’s because it has the insulin pathway impairment that is a trademark of diabetes, but in AD it occurs in the brain. The brain dysfunction occurring in AD has similar molecular and biochemical mechanisms as type 1 and type 2 diabetes. The reason why AD would be another form of diabetes and not just a symptom of type 2 diabetes is due to the brain specific issues that are disrupted. These issues stem from abnormalities in gene expression that encode insulin, insulin growth factor (IGF), insulin growth factor peptides, receptors and more signaling mechanisms. Problems with gene expression lead to the disruption of signaling pathways that control insulin and insulin growth factor neuronal survival, along with problems with tau expression, energy metabolism, and mitochondrial function. Together, these abnormalities create the symptoms observed in Alzheimer’s.

Is it a viable hypothesis?

There are multiple different studies showing that abnormalities with insulin and IGF signaling mechanisms occur in the early stages of Alzheimer’s, so they likely play a large role in the disease’s pathology. While AD and diabetes have a lot of similarities, it has not yet been entirely determined what the role of having type 2 diabetes plays in the development of AD. However, there are obvious conclusions that can still be drawn. Since issues with insulin pathways stem from poor diet, excess weight and inactivity, having a healthy lifestyle will keep you out of risk for issues with these pathways. Therefore, if these pathways stay healthy and functional, you will be less likely to develop both type 2 diabetes and Alzheimer’s disease. Alzheimer’s does have a genetic component to its development as well, so staying healthy may decrease the chances that these genetic abnormalities causing the development of the disease. While the research into disease pathology continues and more and more connections are found, it is important to remember the role you play in your own health.

Image: https://www.google.com/search?biw=1392&bih=684&tbm=isch&sa=1&ei=BhO9W9ycNc_8jwT6sLz4Bg&q=alzheimers+and+diabetes&oq=alzheimers+and+diabetes&gs_l=img.3..0i10i24.62947.69763..69890…2.0..0.104.1675.24j1……1….1..gws-wiz-img…….0j0i67j0i10.oPF5crPJtJc#imgrc=_0-B23ouAi8HlM:

Bridging the gap between Alzheimer’s disease and type II diabetes

100 million American adults either have type II diabetes or prediabetes (if left unregulated will lead to type II diabetes in 5 years).

It is estimated that 5.7 million Americans are living with Alzheimer’s.

Both represent a significant physical and economic burden to both the impacted individual as well as the remainder of society. At first glance, it may seem like these two diseases are unrelated, however, recent studies have identified a link between the two.

How is type II diabetes characterized?

Type II diabetes is characterized by insulin resistance. Insulin is a hormone your body releases as a response to increased blood sugar levels (which are directly dependent on eating habits). After a meal, blood sugar levels rise, and the body sends insulin to tell cells to store sugar inside the cells rather than in the surrounding bloodstream. Initially, the body will release more insulin to accommodate the increased blood sugar levels, but overtime the body cannot make enough insulin to keep blood sugar levels normal.

How is Alzheimer’s characterized?                                              

Alzheimer’s can only be diagnosed for certain by taking tissue samples and observing a build-up of neurofibrillary tangles and amyloid-beta plaques. A brain with Alzheimer’s also experiences significant brain atrophy, as seen in the image below.

These physical indicators are difficult to diagnose short of taking a tissue sample, therefore an Alzheimer’s diagnosis is determined almost exclusively on the presented symptoms of memory loss as well as mild cognitive impairment.

How are they connected?

  • Inflammation

Insulin resistance as seen in type II diabetes is proposed to be a result of chronic inflammation in peripheral tissues of an increased amount of fat tissue. Although not caused by an excess of fat tissues, brains with Alzheimer’s have increased levels of inflammation as compared to a “normal brain.”

Additionally, amyloid-beta plaques in the hypothalamus (part of the brain that regulates hormones) have been shown to cause dysregulation of metabolism in peripheral tissues. Amyloid-beta plaques also mediate the further release of various inflammatory factors causing a cascade-like inflammatory response.

Evidence points to sustained inflammation being a mechanism of insulin resistance which is present in both type II diabetes and Alzheimer’s disease.

  • Gangliosides

The brain has insulin receptors that are involved in pathways in the brain. Proper signaling is highly dependent on certain molecules being in the correct location. A cell can be portioned into different areas that accomplish different tasks- known as microdomains. An important factor of microdomains is cholesterol which acts akin to glue holding proteins together at the membrane, thereby making a more efficient signal, simply because the necessary molecules are close together. Gangliosides are commonly associated with microdomains and facilitate many reactions in the body; notably, the conversion from a single amyloid-beta molecule to a full blown plaque by having many aggregate together, a trademark of Alzheimer’s.

Diet has been shown to directly modify the type and frequency of gangliosides that become incorporated into a cell. Insulin receptors can be displaced from its proper location in a microdomain, essentially making it ineffective and modifying proper insulin signaling.

Important Takeaways:

  • Type II diabetes and Alzheimer’s disease are related, and one increases the risk for the other
  • Establishing a link between the two provides insight into two very prevalent diseases in the United States, which in turn could be helpful in finding particular therapies or treatments for one or both diseases
  • Inflammation plays a critical role in the development of type II diabetes and Alzheimer’s alike
  • Gangliosides have the potential to displace insulin receptors in the brain contributing to insulin resistance
  • Taking measures to ensure you do not develop type II diabetes lowers your chances of developing Alzheimer’s at an older age

Sources:

https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet

https://www.alz.org/alzheimers-dementia/facts-figures

https://www.cdc.gov/media/releases/2017/p0718-diabetes-report.html

http://www.diabetes.org/diabetes-basics/type-2/

https://www.ncbi.nlm.nih.gov/pubmed/29129775

Insulin and Alzheimer’s: Bridging the Link Between Degeneration, Diet and Diabetes

Source: https://www.ecowatch.com/dr-mark-hyman-why-scientists-now-call-alzheimers-type-3-diabetes-1882174730.html

Alzheimer’s Disease (AD)

Alzheimer’s Disease (AD) is seen throughout popular culture today and is one of the most well known neurodegenerative disease there is. AD is the most common type of dementia, and is what most people often associate the disease with. Symptoms of AD include memory issues, confusion, problems speaking and writing, alterations in mood and personality. Despite how prevalent AD is and how much research is been put behind it, there is still very much that is not known about the progress of AD and why individuals with AD are being affected.

Neurofibrillary tangles

In understanding AD there are several aspects of disease that are essential to bigger picture. Neurofibrillary tangles (NFT) are one of these. In AD one of the major issue that occurs is proteins in the brain called Tau are hyperphosphorylated. This is one of the markers that is used to diagnose AD, as the malformed Tau proteins build up there is so malfunction associated with the cells. Exactly how this happens in not known but scientists are investigating how NFTs are directly associated with AD. It is believed that some or most of the communication between neurons are blocked because of these.

AB plagues

Amyloid is often used to describe proteins that are naturally produced by the body. The specific amyloid that is observed in AD is referred to as beta amyloid (BA) and is built up because the of incorrect cutting on amyloid precursor protein (APP). This incorrect cutting causes there to be longer BA in the brain which accumulates together to form plaques that cannot be broken down.

Figure 1: This image depicts the two most common identifiers of AD in the brain. There is also an observed loss of mass of brain mass, especially in the hippocampus which is an area associated heavily with memory.

Source: http://weeklyhealthtip.blogspot.com/2015/11/the-link-between-type-2-diabetes-and.html

What else do we know?

One of the major players scientists associated with AD are the cytokines of the immune system. Inflammation is seen in individuals who have AD and the response of the immune system to lower this inflammation is to send in cytokines. These are cells that have response on another cell, in this instance to give a response to inflammation. Thinking about the relationship between AD and cytokines is much like pondering the age old question of the chicken and the egg. Increased amounts of cytokines are associated with mutated APP molecules and Tau phosphorylation and eventually leads to neuron death which is a major culprit in neuroinflammation. So was it the inflammation and BA plaques that called the cytokines or excess cytokines that started the inflammation? A bigger question lays behind this, why is there a strong relationship between AD and type 2 diabetes? What about the two strings them together?

Type 2 Diabetes (T2D)

What is it?

Type 2 Diabetes (T2D) which is also known as adult onset diabetes, is when the body no longer processes glucose properly because of insulin resistance or the lack of the production of insulin. Insulin is the molecule in the body that is response for regulating the sugar molecule glucose in and out of the cells. Although T2D is more common in adults, as childhood obesity increases so does the chance of developing the disease. There is no cure for T2D but can be regulated through healthy eating and exercising.  

Figure 2: The connection between the brain and body is undeniable but eating healthy not only helps with the regulation of T2D it also increases the overall sense of wellbeing and may help the brain in the long run, much longer than some people may think.

Source: https://www.medindia.net/patients/lifestyleandwellness/diet-and-alzheimers-disease.htm

Diet and Diabetes

As seen through ways to live with T2D, diet plays a large role. It is important for individuals with T2D to take insulin shots to increase the amount of insulin in the body but in addition to this, as stated above, taking careful notice of the food that you put into your body. As seen with younger individuals, those who experience or are on the verge of obesity are at risk of developing T2D, suggesting there is some relationship between T2D and food associated with obesity. Although the exact reason for T2D diabetes is unknown to researchers there is some evidence to suggest that weight gain and unhealthy eating are apart of the cause. What most people don’t associate with this however, is AD even though there is a clear link between the two.

Figure 3: A venn diagram shows the relationship between T2D and AD by comparing the similarities between the two. As seen above, there are more things in common than many people realize. The major classifiers of AD are seen listed as well but are not observed in T2D.

Source: https://www.mdpi.com/2072-6643/7/9/5341

Insulin in Alzheimer’s Brain: Type 3 Diabetes

Insulin is so well known in the development of T2D, as well as type 1, that many people do not often realize that it plays a major role in other parts of the body, including the brain. Insulin can increase spatial memory, is essential in cognitive and memory functions, as well as influencing feeding behavior. In patients with AD less insulin is seen as well. There is also a correlatory 80% of individuals who have AD also have insulin resistance of T2D, prompting AD to be called type 3 diabetes. Although there is much more research required behind this notion, scientists urge individuals (especially those with T2D or at risk of developing it) to eat better.

Another culprit in the development of both diseases is leptin. Leptin is a hormone that is made by the body to regulate caloric intake and feeding behaviors. In one study in particular, researchers found that there mice with high fat diets did not allow leptin to bind to neurons which never alerted the body that it was full and the mice continued to eat until they were overweight. Leptin also plays a role in the insulin pathway in the brain. Mutated leptin pathways often led to insulin resistance in individuals. This suggests that high fat diets that change the structure and purpose of leptin are not only associated with diseases related directly to insulin, such as T2D, but others like AD that have less information but what is known is the lack of insulin in the brain. This shows that there is no one common link between the three but rather may remain interconnected to each other.

Figure 4: Many individuals with T2D or at least insulin resistance are at risk of developing AD.

Source; https://ediblearia.com/2016/09/11/alzheimers-disease-is-type-3-diabetes/

Many people don’t realize that changing diet now may make a difference later in life. Not only in AD and the progression of the one not only the most debilitating diseases known to man but also the hardest to watch a loved one endure. It is so important for people to understand the connection between these diseases because in doing so it may aid for them to alter their lifestyle now so that they are able to experience the best possible future.

 

References:  

https://www.alz.org/alzheimers-dementia/10_signs

https://www.brightfocus.org/alzheimers/infographic/amyloid-plaques-and-neurofibrillary-tangles

http://www.diabetes.org/diabetes-basics/type-2/

The Brain-Pancreas Connection: An Insulin Resistance Story

 

http://www.mwhomecare.com/diabetes-alzheimers-study/

What is Alzheimer’s Disease? Most likely when you first encountered Alzheimer’s, you heard that it was an individual forgetting things that they had previously known, such as names, events, or even large portions of their lives. The first thought after that is probably: Why? How does this happen in a person’s head? There are two big things that have been found to contribute to Alzheimer’s: neurofibrillary tangles and Aβ plaques.

Neurofibrillary tangles are hyperphosphorylated aggregates of tau protein that come together as insoluble clumps due to problems caused by insulin resistance. These insoluble tangles increase toxicity in the brain and cause neurons in the brain to die. With less neurons in the brain, connections are less easily made and symptoms of Alzheimer’s start to show.

Aβ plaques are collections of amyloid beta peptide oligomers that clump together because of improper cutting of an amyloid precursor protein (APP). This improper cutting is due to a buildup of the GM3 ganglioside. This also causes the insulin receptor to be unable to receive insulin. Then insulin resistance increases.

https://healclinics.com/a-relationship-between-diabetes-and-alzheimers-disease/

Now how does this relate to Type 2 Diabetes? The answer is insulin resistance. Type 2 Diabetes is characterized as your body being unable to use insulin in the correct way. When it can’t be used, it can’t regulate our blood sugar levels causing hyperglycemia, or higher blood sugar levels than normal. We know that insulin is important in maintaining our blood sugar levels; but being a big part of the brain? That is a new idea. Insulin is made in two parts of the body: the pancreas and the brain. It is an important regulator of brain physiology and works as a cognitive enhancer. So if there is resistance to this cognitive enhancer, there will be breakdown in the brain: Alzheimer’s Disease. We see that both the neurofibrillary tangles and Aβ plaques are fundamentally involved in some way, shape, or form with insulin resistance.

http://www.drugood.com/2018/05/30/is-alzheimers-disease-called-type-iii-diabetes/

Now that we have talked a little bit about both Alzheimer’s and Type 2 Diabetes, we can see that there is a connection between the two. That connection being insulin resistance. However, it goes even deeper. Studies show that 70% of all individuals that have Type 2 Diabetes will develop Alzheimer’s Disease at a later time in their lives. That number is staggering to me and it makes me think we need to make some changes at both the individual and societal levels. Individually we need to think about what we eat and get more exercise. Since Type 2 Diabetes is largely characterized by unhealthy eating and lack of exercise, this would be the obvious place to begin. At the societal level, we need to have healthy options available as fast options, not only unhealthy options. Though much of our society is in a “go-go-go” mode, we still need to have a healthy food to fuel us through our days. Though this won’t completely fix the problem, it will likely be worth it to slow down the large numbers that are developing Type 2 Diabetes and in the future Alzheimer’s. I feel that this ‘risk’ of healthy eating and exercise is worth it to remember loved ones and large events that happen in your life.

Alzheimers and diabetes, the consequences of our lifestyle

Alzheimers is a neurodegenerative disease in individuals that are usually of an older age. One of the major components to Alzheimers disease (AD) is the role of insulin. Insulin functions in our bodies to regulate uptake of glucose for cellular processes. In neurological functions, it breaks down Aβ amyloid plaques. though if there is a lack of insulin, this results in plaque formations leading to tau plaques. These plaques result in loss of neurons, as these can prevent the proper function of the neurons.

Insulin resistance develops from an excess of GM3 gangliosides building up in the phospholipid membrane, causing dissociation of the GEM insulin receptors from the caveolae.

This lack of insulin signaling leads to a lack of glucose in individuals with type 2 diabetes, a disease that is more common in obese and overweight individuals. These diseases share many components, such as a resistance to insulin. These diseases prevalence will only become more taxing on our society, as the projected numbers for the US ranks 50% of the population to be classified as overweight or obese by 2030. This increase in the affected population will also increase the number of individuals that are at a much higher risk for AD and type 2 diabetes. The State of Obesity lists the average percentage of adults in the US is 30% in most states. With several states having 35+% of the population being considered obese. In a projected 13 years for that percentage to gradually increase to encompass more of the population.

So what can we do to prevent this?

Our lifestyle choices play a major component in the development of bad habits, which can result in becoming overweight. Once overweight, this greatly increases the risk for type 2 diabetes. Since the relationship with type 2 diabetes and AD, this also increases the chances for someone who has type 2 diabetes or is overweight to be at risk for AD.

So to take preventative measures at a younger age, as preventing one from becoming obese or overweight by being active and eating a healthy and balanced diet. As these factors become more substantial at an older age.

 

Can you EAT your way into Alzheimer’s?

Did you know that 70% of people with type II diabetes are later diagnosed with Alzheimer’s? That is a ridiculous percentage to be coincidental, but what could these two diseases possibly have in common? Well, recent studies have linked both diabetes and Alzheimer’s to unhealthy diets high in fats and sugar. These unbalanced diets can then lead to detrimental factors such as insulin resistance, the degradation of your blood-brain barrier, and inflammation. Let’s take a closer look at how your diet can affect these three ailments.

Insulin Resistance:
Insulin is a natural hormone produced in the body when blood glucose levels are too high. It signals for the uptake and storage of glucose from the bloodstream to cells on the brain, liver, muscles etc. It is a very important biological function that can be disrupted if too many gangliosides (specifically GM3) have been incorporated into one’s diet. Glycosides are modified lipids that are found inside cell membranes and play an important role in cell signaling and communication. Unfortunately, if there becomes an abundance of GM3s in the membrane, they can disrupt insulin signaling by separating insulin receptors from their secondary proteins. This halts the signaling cascade and prevents the cell from intaking excess glucose resulting in insulin resistance. Excess GM3s also play a crucial role in the feedback production of amyloid beta (Ab) peptides. Once GM3 is degraded into GD3, it signals for more Ab peptides to be produced into the extracellular matrix (ECM). Therefore if there is a continuous integration of new GM3 into our membranes, the concentration of GD3s will rise leading to an increase of Ab peptides in the ECM. This can then lead to aggregation of these peptides which results in Ab plaque formation which is a classic trademark of Alzheimer’s.

Blood Brain Barrier and Chronic inflammation:
Another important factor in both Diabetes and Alzheimer’s is chronic inflammation that causes irreversible cell damage over time. The million dollar question is what causes the inflammation? Some research has pointed to clues within the gut-brain-axis which is a model showing how the gut can affect brain function. Simply the gut-brain-axis states that toxins, molecules, or anything else we digest can more easily get into our bloodstream if our gut’s microbiota is out of whack. This then can lead to extreme problems if our blood brain barrier (bbb) is damaged letting dangerous chemicals enter into our brains and cause inflammation. Microbiota imbalance can be caused by numerous factors including genetics and our daily diet. A diet high in fat, sugar, and sodium can also lead to fat accumulation which has also been shown to degrade our bbb. Without the protective covering of astrocytes around our blood vessels, which make up the bbb, the foreign molecules are free to wreak havoc on our brains. The inflammation response then hyper-activates the processing of Ab Proteins placing a higher concentration of Ab peptides in the ECM. With a higher concentration of Ab peptides, comes plaque formation and eventual neuronal death causing impairment in brain function and Alzheimer’s.
Besides the accumulation of plaques, Ab peptides trigger the production of cytokines which are the signaling molecules for inflammation creating a vicious cycle. If we could one day stop the cycle of inflammation in the brain before serious damage has occurred then we could theoretically treat Alzheimer’s. Other interesting fields of study could include bbb repair, fixing the gut microbiota in Alzheimer’s patients, and the degradation of excess Ab peptides.
However, for now, the biggest preventative strategy for Alzheimer’s and type II diabetes is a healthy lifestyle and diet. What we put into our body’s today will come back to affect our quality of life in the future.

From Alzheimer’s to Diabetes: What is the Connection?

 

picture created on wordart.com

It is no secret that Alzheimer’s Disease can be debilitating to an individual as well as to their loved ones. People look for genetic ties to the disease and early signs of memory loss or decline. However, what if there are more connections to Alzheimer’s other diseases that we thought? Below we discuss Alzheimer’s Disease and Type 2 Diabetes, the connection between them, and why this connection really matters.

Alzheimer’s Disease: What is it, really?

Alzheimer’s Disease (AD) is a progressive disease of the brain which destroys memory and cognitive and mental functions. AD accounts for 60 to 80 percent of dementia cases, according to the Alzheimer’s Association. Unfortunately, the cause of AD is still not greatly understood despite years of research. This is mainly because of the multiple factors that contribute to AD. With other diseases, researchers have found one to two causations for that disease. But AD has so many possible causations that there is no set cure. Symptoms for AD include difficulty in remembering events, in finding commonly used words, in multiple-step tasks as well as signs of depression, agitation, and apathy.

Type 2 Diabetes:

Type 2 Diabetes is a metabolic disorder where your body either does not produce enough insulin to maintain glucose level or it resists the effect of insulin. Doctors find Type 2 Diabetes in patients by looking at laboratory tests of glycemia levels. Symptoms for Type 2 Diabetes can range from blurred vision, increased hunger and thirst, and fatigue. Similar to Alzheimer’s Disease, there is no cure for Type 2 Diabetes. However, in contrast to Alzheimer’s Disease,  people with Type 2 Diabetes can manage their disease well by exercise, a healthy diet, and insulin therapy and medication.

 

How are these two connected?

Many longitudinal research studies have shown that adults with Type 2 Diabetes have a higher risk of developing Alzheimer’s Disease later on. There have also been studies showing that Type 2 Diabetes may develop due to a high-fat and high-sugar diet as well as obesity. These studies have been helpful in linking factors such as poor diet to high blood sugar and high blood sugar to inflammation in the brain. In both diseases, insulin and inflammation play major roles in the development. In AD, amyloid-beta plaques require more production and eventually lead to response in the cell to maintain overproduction. This inflammation can lead to more production of cytokines and eventually to stress and cell death, which is common is brains of AD patients. You can see the outcome of cell death in the cross-section pictures of the brain where the AD brain has deteriorated greatly. Inflammation in Type 2 Diabetes mainly is derived from over-nutrition or overeating. This excess nutrition induces insulin resistance, thus adding to one of the biggest problems in Type 2 Diabetes.

Studies have show that insulin interacts with amyloid-β protein and tau proteins. These are the proteins that eventually make up those plaques and neurofibrillary tangles that are found in brains of those with Alzheimer’s Disease, especially those with early-onset Alzheimer’s Disease. Combining this information with the face that people with insulin resistance in their body has 5-7 times more insulin than a body without insulin resistance. To learn more about insulin and its connection to these two diseases, watch this video. https://www.youtube.com/watch?v=NlbdMb8oGDo

So what?

Some might be wondering why all of this matters. Why should we care about the link between these diseases, especially if there aren’t any members of our families that have a history of Alzheimer’s Disease or show signs of Type 2 Diabetes? The answer is that this matters for our health and for our loved ones. Most people reading this have witnessed, first-hand, the impact that Alzheimer’s Disease and dementia have on the one enduring it as well as those surrounding the patient. This disease affects far too many aging people. In addition, this matters to people dealing with Type 2 Diabetes. If one has been struggling with this disease for a decade and is beginning to struggle to retrieve short-term memories, this can be incredibly alarming to them. Informing people about the warning signs of the two diseases as well as the connection between them can alert their families to focus more on diet, exercise, and being mindful of the factors leading to these two diseases. As research continues to develop for these diseases, our hope is the community surrounding those suffering will be willing to be more proactive.

 

“Grandma… it’s October”: What is happening to our relatives with Alzheimer’s Disease?

We all know someone who has been affected by Alzheimer’s disease: maybe a neighbor, a family member, or even a teacher/mentor. Alzheimer’s is a terrible disease that slowly takes away a person’s ability to function by increasingly disintegrating the neurons and their connectivity. But what IS happening when a person has Alzheimer’s disease? Why is this illness almost inevitable in the United States? And how can we stop it?

It is believed that Alzheimer’s occurs in people when there is plaque build-up from neural tangles in the brain. In recent studies, scientists have found a correlation between those with type-2 diabetes and Alzheimer’s. People with type-2 diabetes (T2D) have a resistance to insulin, the hormone that decreases glycogen levels in the body. Studies have found that the insulin signaling pathway is also essential to forming memories and preventing Alzheimer’s disease (AD). Here are a few theories on why:

TNF-alpha (a cell signaling protein involved in systematic inflammation and is a cytokine that reacts to danger) mediated inflammation:

  • ABOs cause inflammation
  • Cause insulin resistance
  • Brain inflammation mediated by microglia
  • Impairs synaptic function
  • Intersects with ER stress

Unchecked PTP1B activity:

  • Upregulates neuroinflammation-PTP1B positive regulator of microglia-mediated neuroinflammation
  • Down regulates brain insulin, leptin ( found in hippocampus and prevents plaque build-up) and BDNF (growth of neurons) signaling
  • Impact synapse dynamics and stability and cognition
  • ER stress is associated with peripheral insulin resistance in inflammatory conditions

Deregulated mTOR signaling:

  • Increase uncoupling of IR and IRS (insulin receptors)
  • Retro inhibits IRS-1 (insulin receptor substrate)
  • Impairs synaptic plasticity and cognition
  • Deregulates autophagy
  • Causes cell cycle re-entry

Aberrant ganglioside metabolism:

  • Increase of GM3 & GM1 (gangliosides) causes the uncoupling of IR & IRS-1 and accumulation of ABOs which can turn into tangles which then turn into plaques
  • Impairs AB aggregation
  • Serves as receptors for AB in the membrane
  • Required for ASB synaptotoxicity

What can we do to fix it?

Because we are seeing a correlation between T2D and AD, why not use T2D medications to treat AD? Insulin and Metformin are two drugs that scientists are experimenting with to see if they decrease the risk of developing AD in the future.

  • Insulin:
    • It is recognized that in patients with AD, the amount of insulin signaling in the insulin signaling pathway is very low. Using insulin injections, typically used for diabetes patients, studies have shown improvements in memory. For many of the studies, the insulin is more effective for older patients compared to younger ones. The insulin can be delivered two different ways: intravenously and intranasally.
      • Insulin infusion “is achieved using the hyperinsulinemic-euglycemic clamp method, where circulating insulin levels are raised by a controlled infusion of insulin while glucose levels are monitored and maintained constant through glucose infusion” (Morris, 2012).
      • The intranasal is a new process that is still being tested of its effectiveness. Instead of using the bloodstream to deliver the insulin, administration of the drug is done through the olfactory and trigeminal pathways. This new way of delivery is thought to be better as it is less invasive and less painful. By avoiding the bloodstream, intranasal delivery of insulin does not risk causing hypoglycemia in the patient.

Caption: “Insulin signaling deficits in AD brain. Several studies have compared insulin signaling in nondemented and AD subjects in postmortem brain tissue. Deficits in insulin signaling associated with AD include decreased expression of insulin receptor, insulin receptor substrate (IRS), phosphoinositide 3-kinase (PI3K), and AKT and decreased AKT activity (phosphorylation). Preclinical studies have also shown that amyloid beta (Aβ) can compete with insulin for insulin receptor binding and impair interaction of AKT and phosphoinositide-dependent kinase (PDK1). Because glycogen synthase kinase-3 (GSK-3) lies downstream of AKT, it is possible that these effects could influence tau phosphorylation” (Morris, 2012)31

  • Metformin:
    • After seeing the correlation between those with T2D and AD, the thought was to use other medications that alleviate the effects of diabetes to potentially help with Alzheimer’s. Metformin is a common drug used in cases of mild diabetes. It works by activating the AMP-activated protein kinase with then proceeds to inactivate the mTOR/p70S6K-mediated negative feedback loop to insulin receptor substrate-1 (IRS-1) , thus enhancing insulin signaling. AMPK also regulates tau phosphorylation, Aβ production, and autophagy, all of which are critical processes in AD. Metformin has also been shown to cross the blood-brain barrier. There has been some controversy over whether or not metformin is an effective way to treat AD. A study in Taiwan took people with T2D and treated them with various types of diabetes medications. Compared to all of them, metformin did the best in reducing the hazard ratio, decreasing from 1 to 0.76 (Koenig, 2017)32. However, metformin can also decrease the amount of vitamin B12 in the body, which is a risk factor to developing AD. In a study where vitamin B12 was regulated, metformin made no difference in preventing AD33.

 

I sincerely hope that a cure for Alzheimer’s disease is discovered very soon. I was recently on the phone with my best friend, my great-grandmother, who is 92 years old. She has been doing great for her age, still living alone in a duplex apartment. I notice that she often tells the same stories to me every time I visit, but I have never been too worried about that. The last time I talked to her on the phone, she completely forgot what month it was. She thought it was still summer and that school had not started yet. Once I corrected her and she was no longer confused, she told me to not tell anyone that she made that mistake. It scares me because I know that AD is a fast-moving disease and it won’t be long until Grandma forgets more important things. I hope a cure can be found so that no one has to go through the pain of taking care of a loved one with Alzheimer’s Disease.

Citation:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476214/

https://www.alzdiscovery.org/cognitive-vitality/ratings/metformin

https://moodle.cord.edu/pluginfile.php/723477/mod_resource/content/0/2018%20AD%20and%20insulin%20signaling.pdf

The Missing Piece: Linking Alzheimer’s Disease and Type II Diabetes

Linking Alzheimer’s Disease and Type II Diabetes

The Link

When picturing an individual suffering from Alzheimer’s disease (AD) and one suffering from Type II Diabetes (T2D), these pictures look greatly different. However, zooming in past the physical symptoms and appearances, we can look closely at the specific ways these disorders work. Tied together by the mechanisms of neuroinflammation, insulin resistance, and ganglioside function, AD and T2D are more similar than we might imagine.

Image 1: The biological connections in grey can be studied between AD and T2D and represent the two-way street these disorders pave in our brains.

What is Insulin?

Insulin is a hormone generally made in the pancreas that helps our body take in glucose, which is processed and used for energy and stored in our cells for future use. In diabetes, this process does not function. In type II diabetics, insulin is produced but not able to complete the signaling pathway to intake glucose.

The Pathway:

Insulin leads to the uptake of glucose through the pathway represented in the above image. Insulin binds to the transmembrane insulin receptor (IR). This activates the IRS1, leading to a phosphorylation cascade ending with the translocation of GLUT receptors to lipid rafts (compartmentalized sections) in the membrane.

Understanding Alzheimer’s:

Alzheimer’s disease is characterized by the buildup of amyloid plaques and neurofibrillary tangles in the brain. The pathway to these malformations is complex, but has many connections to neuroinflammation and insulin resistance.

Connecting the Pieces

The pathways of AD and T2D connect through insulin resistance and neuroinflammation. The two figures below detail the complex mechanical connections between the diseases. More specific information on these topics can be found at source links 1 and 2 below.

Image 3: Insulin resistance affects the production of glucose peripherally. This dysfunction in the CNS contributes to the formation of amyloid beta plaques and neurofibrillary tangles in the brain.

 

Image 4: This pathway shows that many factors (ex: PKR, S6K, PTP18, GM3) directly inhibit the processing of insulin. The buildup of GM3 molecules physically disassociates the IR from its connection with IRS 1/2, causing reception to be halted. The GD3 molecules that are made from GM3 perpetuate the buildup of Amyloid Beta plaques, showcasing the connection to AD.

So what?

Using the connections in mechanism between T2D and AD can inform future treatment options and research in both conditions. Seeing the parallel nature in pathophysiology between the conditions, it isn’t surprising how often the two disorders overlap. The knowledge gained from a dual-perspective view at both AD and T2D can influence further research in not only these conditions, but also other neurodegenerative conditions involving neuroinflammation due to the buildup of malformed molecules in the brain. This research has the potential to impact a large community of individuals and family members who are affected by neurodegenerative diseases or Type II Diabetes.

Sources for further research

The Genes of Alzheimer’s Disease

The Concordia College Neuroscience Program aims to consider and connect as many interdisciplinary perspectives as possible. As students, we are taught to think critically and connect our experiences to the curriculum. This perspective helps in discussing the possible causes and connections in neurodegenerative diseases. When discussing Alzheimer’s Disease this week, the class considered the similar pathways and concepts we learned last week with Autism Spectrum Disorder (ASD). Students also considered their personal connections and experiences with neurodegenerative diseases.

Although we have all learned about Alzheimer’s Disease in our courses, many of us also have personal connections to the neurodegenerative disease. According to the 2018 facts and figures released by the Alzheimer’s Association, 5.7 million Americans currently live with Alzheimer’s Disease. The number of deaths related to Alzheimer’s Disease has increased by 123% from 2000-2015. The association notes that every 65 seconds, another individual develops Alzheimer’s Disease in the United States. Cases of dementia, including Alzheimer’s Disease, are responsible for the death of 1 in 3 senior Americans–this is more than Breast Cancer or Prostate Cancer combined.

Like a few of the other students in the class, I have a familial connection to Alzheimer’s Disease. Due to many members within the older generation of my family developing Alzheimer’s Disease, I fear that I too may develop the disease in the later years of my life. We know from previous research that there is a hereditary factor linked to Alzheimer’s Disease. Previous research has shown that mutations in genes APP, PSEN1, and PSEN2 have linkages to early onset Alzheimer’s. Likewise, research on late-onset Alzheimer’s Disease found 20 different genetic loci associated with the disease. Specifically, APOE4 is a gene correlated with the familial development of Alzheimer’s Disease–one that shows the heritability of the disease. Regardless of the heritability and genetic factors of dementia, previous research has also shown the importance of the environmental factors associated with the development of the disease–and in many cases, the genetic and environmental factors both contribute to the development of Alzheimer’s Disease. Paying attention to these environmental factors may decrease my chances of developing this neurodegenerative disease.

These environmental factors include:

  • Diet
    • Type 2 Diabetes has been linked to Alzheimer’s
    • The insulin resistance leading to Type 2 Diabetes likely stems from a fatty diet
    • Other popular media articles have discussed how red meat might lead to Alzheimer’s
    • The prevalence of Alzheimer’s Disease in the United States more than likely is due to our diet and lack of exercise.
  • Exposure to toxic chemicals
  • Serious brain injury
  • Air pollution

When discussing Alzheimer’s Disease and many other neurodegenerative diseases, it remains important to note the vital interaction between genetic and environmental factors resulting in the development of disease. With the prevalence of genetic testing in today’s society, specifically through companies like 23andMe, people can know in approximately 6-8 weeks if they possess some of the genes associated with Alzheimer’s Disease. Without proper consideration or education, members of society may be mislead to think that they are destined to develop the disease. That may not be the case. It is more likely that even if an individual possesses the gene associated with a disease, environmental factors play a large role in whether or not that gene is transcribed or “turned on.” Research has shown that paying attention to the environmental risk factors above, and changing lifestyles to match, may reduce a person’s risk for Alzheimer’s Disease.

https://moodle.cord.edu/pluginfile.php/723477/mod_resource/content/0/2018%20AD%20and%20insulin%20signaling.pdf

https://www.alz.org/media/HomeOffice/Facts%20and%20Figures/facts-and-figures.pdf

 

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