Type 2 Diabetes Related Dementia: Neurodegeneration the Path to Prevention Part 3

Type 2 DiabetesWelcome to part 3 of Neurodegeneration: The Path to Prevention.  So far, in part 1, I have provided an overview of neurodegeneration and,  in part 2, I provided an in depth look at Frontotemporal Lobar Degeneration.  Today, in part 3, I will be focusing on another form of neurodegeneration, Type 2 Diabetes (T2D) related neurodegeneration.  This is also a good primer for my next post on Alzheimer’s disease because, as you will see, the 2 conditions are related.

Specifically, what I hope to cover in this post is that cognitive decline/dementia risk is much higher in T2D patients; T2D is associated with brain shrinkage;  T2D is associated with Alzheimer’s like neurodegenerative changes in the brain; and that T2D is linked to metabolic dysregulation, chronic inflammation, and leaky gut (i.e. all the wonderful things that a paleo lifestyle helps with).

What is Type 2 Diabetes

I don’t want to spend too much time on this as most everyone these days knows what Type 2 Diabetes is.  Basically what happens is when you eat carbohydrates (like sugar), your blood sugar rises.  However, high blood sugar levels are toxic to us, so our body releases insulin.  Insulin signals our muscle and liver cells to take in the sugar and store it as glycogen (another form of sugar).  But, we only have limited storage space for glycogen, and once this space is taken up, any excess sugar is turned into fat and stored as fat cells.  This is a normal process; however, where the problem lies is when we chronically eat way too much sugar (or carbohydrates for that matter), than what we use up in our daily activities.  You see, the signal for insulin release is high blood sugar, and if we always have consistently high blood sugar we will have consistently high insulin; however, what happens when our muscle and liver cells are already full of glycogen? Well, they begin to ignore the insulin signal.  So, the body says “what’s going on, we need to reduce blood sugar levels or we have some serious issues”, and then it releases more insulin, and the cells ignore it again because they are full, and eventually this process leads to our cells becoming resistant to the insulin signal (i.e. insulin resistance).

So that is the basic model, and most well understood model, of T2D.  However, much recent research is beginning to reveal the contribution of autoimmunity and chronic inflammation to T2D (1), as well as to obesity and metabolic syndrome.  Here you can find a respectable blog post on this exact topic.  Another interesting point to make is that a recent study has tied leaky gut to T2D is human patients (2). This is a very important finding relating to the autoimmune/inflammatory T2D model since much recent evidence is showing that the gut is a major regulator of our immune system (3).  Now lets move on to how T2D relates to neurodegeneration.

Type 2 Diabetes and Cognitive Decline Risk

It is fairly well documented these day that Type 2 Diabetes is a risk factor for dementia and Alzheimer’s disease (4).  Multiple studies have shown that people with T2D consistently score lower on tests of cognition (4, 5, 6).  Another interesting point to make here is that this occurs even at subclinical levels of T2D markers (6).  One study (6), found that HbA1c levels inversely related to cognitive performance.  Basically, the lower the HbA1c levels, the higher the score on cognitive performance tests, and vice versa.  This finding still held up even when HbA1c levels were below the level of a clinical T2D diagnosis.  HbA1c is a blood marker that is used to determine blood glucose levels over the last 8-12 weeks.  This is a very interesting finding and important to note, because although we may not have a diagnosis of T2D, if our blood sugar is on the high end of normal, it appears that we may be doing damage to our brain in some way.  The researchers in this specific article hypothesize that such a decline in cognition could be due to structural changes in learning areas of the brain. On that note, we have a great segway to discussing possible mechanisms of cognitive decline in T2D population.

Type 2 Diabetes and Brain Shrinkage

Type 2 Diabetes patients seem to consistently show levels of brain shrinkage (atrophy). What studies have shown is a clear reduction in brain volume, across multiple regions of the brain, in T2D patients (7, 8, 9).  It is even noted that the pattern of T2D related brain atrophy is similar to what is seen in Alzheimer’s disease (9).  Once again, this finding is not specific to clinical T2D diagnosis,  as it was with cognitive performance, subclinical diabetic blood sugar levels are also associated with brain atrophy (8).  Obviously, brain shrinkage is a mechanism of cognitive decline, so no explanation required here; however, the question remains as to why brain atrophy is occurring in T2D patients? This is the same question that researchers have been trying to answer relating to all neurodegenerative conditions.  Brain cells are dying causing the brain to shrink, but why?

Type 2 Diabetes Related Dementia – Possible Causes

A simple explanation for T2D related dementia is that vascular disruption occurs in the blood vessels supplying oxygen to the brain; and therefore, decreased brain function occurs due to reduced oxygen delivery.  While there is some evidence of this (1), there are many other suggested mechanisms which appear to be much more complicated.

One theory suggests that high blood sugar levels themselves can lead to cell death via osmotic stress (1).  Another suggestion is that high blood sugar levels can lead to oxidative stress via the creation of advanced glycation end products (AGEs) (1).  Basically, sugar and certain proteins react to create AGEs, AGEs can then interact with free radicals in the body which then cause oxidative damage.  The idea here is that the higher your blood sugar, the more AGEs you are likely to have.  Interestingly, aside from the direct toxic effect AGEs can have on nerve cells, another suggestion is that AGEs can actually activate microglial cells in the central nervous system (CNS) (1).  Microglial cells are a major part of the CNS’s immune system.  So, if we have constantly high blood glucose, leading to constantly high levels of AGEs, that can cause activation of the CNS immune system (inflammation), we have effectively created a state of chronic inflammation in the brain.  As we know from my previous posts on neurodegeneration, this is a hallmark sign of all neurodegenerative conditions.  One further note on oxidative stress is that individuals with T2D have reduced antioxidant systems, which leads to a reduction in the body’s ability to deal with oxidative stress across the whole body, including the CNS (1).

Another area of focus for a suggestive mechanisms of T2D related neurodegeneration is regarding insulin itself.  Insulin is not only a signalling hormone for glucose storage, it is also involved in the production of a specific CNS neurotransmitter, as well as possessing protective properties against amyloid beta oligomers (involved in Alzheimer’s disease) (4).  Interestingly, in T2D patients, CNS insulin levels are depleted due to changes in blood brain barrier function.  Therefore, all the above protective and homeostatic (i.e. normal) actions of insulin in the brain are also depleted.

Type 2 Diabetes Take Away         

While the mechanisms may vary, and possibly all combine to produce the final result, it is clear that Type 2 Diabetes increases the risk of neurodegeneration, and subsequently, the risk of cognitive decline.  Not only that, there is plenty of evidence that Type 2 Diabetes itself can cause neurodegeneration.  As new evidence is revealing autoimmunity and chronic inflammation as major players in the disease, it’s also fairly clear that Type 2 Diabetes is not simply a metabolic condition.  With all of this in mind, we have even more reason to make sure we are taking care of our bodies properly and ensuring our metabolism and immune system are in check.  Again, these are just the things that an ancestral lifestyle seem to improve for most people.

Now it’s your turn, did I miss anything in the above post? If so, I would love to here about it and be more than happy to learn more about it!


The Barefoot Golfer


1.) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671680/

2.) http://www.ncbi.nlm.nih.gov/pubmed/?term=Increased+intestinal+permeability+to+oral+chromium+(51+Cr)-EDTA+in+human+Type+2+diabetes.

3.) http://www.ncbi.nlm.nih.gov/pubmed/?term=The+gut+microbiota–masters+of+host+development+and+physiology.

4.) http://www.ncbi.nlm.nih.gov/pubmed/22411248

5.) http://www.ncbi.nlm.nih.gov/pubmed/24103900

6.) http://www.ncbi.nlm.nih.gov/pubmed/?term=Higher+glucose+levels+associated+with+lower+memory+and+reduced+hippocampal+microstructure.

7.) http://www.ncbi.nlm.nih.gov/pubmed/?term=Changes+in+subcortical+white+matter+and+corpus+callosum+volumes+in+patients+with+type+2+diabetes+mellitus.

8.) http://www.ncbi.nlm.nih.gov/pubmed/?term=High+%22normal%22+blood+glucose+is+associated+with+decreased+brain+volume+and+cognitive+performance+in+the+60s%3A+the+PATH+through+life+study.

9.) http://www.ncbi.nlm.nih.gov/pubmed/?term=Brain+Atrophy+in+Type+2+Diabetes%3A+Regional+distribution+and+influence+on+cognition.

1 Comment

  1. drjocelyn

    Type 2 diabetes is one of the few diseases that can affect all the parts of the body including the brain. To prevent dementia from developing in patients with diabetes, controlling the blood sugar level is a must.

    About the shrinkage (atrophy) of the brain the patients with diabetes: I just wonder if this is because of possible intracellular dehydration because of the relatively high levels of sugar in the blood. As we all know, sugar attracts water, which could possibly pull fluids out of the cell into the blood vessels to be excreted in the urine.
    drjocelyn recently posted…Earlier Diabetes Diagnosis Decreases Cardiac Complications, Say ResearchersMy Profile


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