Saturday, April 16, 2011

Brain Diabetes: Why The Dr. Oz Show Makes Me Wish I Had Alzheimer's

Thanks to some truly excellent work by Orac, I am now highly skeptical of just about anything that comes out of the Dr. Oz show. I made the mistake of expressing my distaste to my parents, who are Dr. Oz devotees. Now, every new show is a chance for them to challenge my knowledge of physiology.

A true scientist, when faced with something that is beyond their knowledge and experience, will humbly state that fact. This is respectable, and opens the lines of scientific inquiry. Curiosity is a lovely thing, and a good scientist will combine it with an interest in investigation. 

If one does not know the answer, however, one should not make shit up. And frankly, that was the take home message from Dr. Oz's latest guest, Dr. Suzanne DeLaMonte. I was alarmed to discover that this woman is a neuropathologist. And she is making some rather insipid and outrageous claims about the way insulin interacts with the brain.

I was informed of this episode by my mother. I grew increasingly suspicious the more she explained about the show, and I resolved to do some research. First, let's take a look at what Dr. DeLaMonte claims is happening in Altzheimer's patients, and then let's take a trip through neurophysiology. Neurophysiology is my passion; I was frankly excited to be able to use my knowledge to see what this woman was talking about.

"Although we’ve always known that Alzheimer’s disease is typically associated with numerous tangles and plaque in the brain, the exact cause of these abnormalities has been hard to pin down. Now, we may be closer to an answer.

In many respects, Alzheimer’s is a brain form of diabetes. Even in the earliest stages of disease, the brain’s ability to metabolize sugar is reduced. Normally, insulin plays a big role in helping the brain take up sugar from the blood. But, in Alzheimer’s, insulin is not very effective in the brain. Consequently, the brain cells practically starve to death."

Alarm bells immediately rang in my mind. I'm not an MD (yet) but I do know neurophysiology, and my degrees cover two different types of physiology. This just made no sense to me whatsoever. 

Insulin is a protein hormone synthesized in the beta cells of the pancreas, in a structure called the Islet of Langerhans. Like most proteins, it is a polar molecule and has an overall charge.  Most importantly, it is not lipid soluble because of this polarity. 

When a meal is consumed, the food is broken down into much smaller molecules that circulate in the blood; mainly glucose but some fructose as well. When the concentration of glucose reaches a certain threshold, insulin that is already circulating in the blood both signals insulin receptors in cells to upregulate glucose transporters to get the glucose into the cell, and signal pancreatic beta cells to make and release more hormone. 

Thus you have glucose circulating through the blood until they find more transporters and insulin circulating until the molecules find receptors or transporters to bind with and activate. All of this cellular activity occurs on the surface of cellular membranes, which are rather like a slippery film of oil that prevents substances that are not similar to it (also oily or fatty) to pass through unless it has its own special 'door', called channels or transporters.

Only very small or lipid soluble molecules pass through the blood brain barrier, a series of tight junctions that prevents unwanted substances from passing through. Insulin, as is, cannot pass. Oxygen and carbon dioxide can, because they are small gasses. Glucose, surprisingly, cannot either, without help. This is important: the only water soluble molecules that can cross the blood brain barrier MUST have transporters in order to do so. For a great refresher on the blood brain barrier (hereafter abbreviated BBB) see here. 

It is true that glucose metabolism is impaired in Alzheimer’s patients, which can lead to a sad downward spiral of dementia, but not for the reasons that the good doctor says. Insulin is not necessary, and indeed is not used, for glucose uptake and cellular metabolism in the brain. Thus, insulin’s decreased efficacy is irrelevant in the brain. Once one understands this, the entire argument falls apart. 

The good doctor continues. 

"These days, most people with diabetes have Type 2 diabetes mellitus. Basically, cells throughout the body become resistant to insulin signals. In an effort to encourage cells to take up more sugar from the blood, the pancreas increases the output of insulin. Imagine having to knock louder on a door to make the person inside open up and answer. The high levels of insulin could damage small blood vessels in the brain, and eventually lead to poor brain circulation. This problem could partly explain why Type 2 diabetes harms the brain. In Alzheimer’s, the brain, especially parts that deal with memory and personality, become resistant to insulin."

Since insulin doesn’t circulate through the brain, and is kept in very tight quantities in a very small portion of the brain, the idea that insulin could damage small blood vessels in the brain is questionable at best.

However, since the brain literally consumes a massive portion of the glucose that we eat, up to 70%, any disruption in the body’s ability to control and monitor glucose intake can have a devastating effect on the brain. A disruption in overall body metabolism can definitely affect the brain because the brain uses so much of the body’s energy. There is evidence that brain function is impaired in diabetes and other metabolic disorders. But Alzheimer's? There just isn't any evidence for this.

 "Why does the brain need insulin?
As in most organs, insulin stimulates brain cells to take up glucose or sugar, and metabolize it to make energy. Insulin also is very important for making chemicals known as neurotransmitters, which are needed for neurons to communicate with each other. Insulin also stimulates many functions that are needed to form new memories and conquer tasks that require learning and memory.

 The alarms became sirens, drowning out everything around me. I was reminded of the line from Tim Minchin's amazing poem 'Storm': "I'm like a rabbit suddenly trapped in the blinding headlights of vacuous crap."

Insulin, again, is not required for brain cells up uptake glucose. There are specialized transporters in the blood brain barrier that undergo facilitated diffusion with a chemical gradient that allows glucose to pass on through. Once there, cells with their own transporters bring glucose inside for metabolism. No insulin necessary; the transporters do not need signaling or upregulation. 

I hunted through the literature looking for a link between insulin and neurotransmitters, to no avail. I have to conclude that insulin, seeing as how it doesn’t circulate and doesn’t cross the BBB freely, is not involved in neurotransmitter synthesis whatsoever. 

Again, no circulating insulin = not necessary for any of the stuff that the doctor says it is essential for. 

Where does the insulin come from in the brain?
Very sensitive tests showed that insulin is made in the brain. It’s made in neurons, and the hormone made in the brain is the same as that produced in the pancreas. This point may seem surprising, but if you consider the fact that every other gut hormone is also made in the brain, it only makes sense that insulin would be among them. Insulin that’s made by the pancreas and present in blood does gets into the brain as well."

 Claxons were going off in my head if I didn't stop this nonsense.  I stopped right about here, because frankly, I felt like my brain cells were going to undergo apoptosis just to spare themselves the misery of having to read on. 

Insulin is not made in the brain. It isn’t necessary, so why would it be synthesized? 

The only function I found for insulin in the brain was as a signal to the hypothalamus for satiety and the feelings of fullness from the gut. It’s sort of as if the hypothalamus ‘sips’ the insulin, tests it and measures it, and tells the body how full the gut is. But insulin gets to the hypothalamus via a transporter, much like the one at the BBB. So again, it isn’t free circulating. 

In fact, the more I dug, the more I found that insulin really doesn’t do anything in humans. The role of insulin in the hypothalamus in humans remains unclear. Glucokinase, a protein on pancreatic beta cells that sense the presence of glucose, is on the hypothalamic membrane, and so can tell when there is sufficient glucose in the brain or not. 

Every other gut hormone is made in the brain? Really? Incretin, ghrelin, fibroblast growth factor19, cholecystokinin, secretin, gastrin, leptin, and others are all made in the brain? My, I never knew that the brain was a digestive organ as well as a control and computational organ. Did you? 

And now we return to the point of her insipid little diatribe: the effect of insulin resistance on Alzheimer’s patients. We now know that insulin really has nothing to do with it. So what does?

Well, it’s tough. There is an awful lot we don’t know about Alzheimer’s. Each group researching the disease has their own pet theory and project that they hope will explain everything. Many of them have found just enough correlation that makes them think they are on the right track. One group that my neurobiology professor is acquainted with is studying possible viral causes of the disease. The big idea when I was an undergrad was that pesticides might be a cause since there seemed to be a larger than average rural population with the disease. 

This is a very excellent review article on Alzheimer’s disease, which sums up much of the current thinking on how it works. 

Basically, similar to prion diseases, normal proteins in our brain mutate at a certain point and contribute to the breakdown of our cognitive function. There are a couple of competing hypotheses, two of the strongest  involve the buildup of amyloid beta plaques or tangles in the axons of neurons made of a protein called tau. There is some evidence to suggest that it may even be a combination of the two. 

In any case, the degeneration of the brain is quite clear, with advanced cases involving dementia, severe memory loss, and the inability to form new memories. This is an excellent illustration of the types of differences that are apparent in Alzheimer's patients compared to a normal brain.

We do know that genes seem to have a big role to play. But we are not sure how big of a role, and what other factors may be at work. Heritable cases tend to have an earlier onset and be mostly genetic in nature, while 'sporadic' or those that don't have a clear heritable lineage are perhaps 25% genetic. And the number one risk factor seems to be age.

Can Alzheimer's be prevented? Well, seeing as how metabolic diseases can affect onset and severity of Alzheimer's, balancing your diet, exercise, and controlling your diabetes is definitely a good idea. The phrase 'use it or lose it' definitely seems to apply here, as keeping an active mind during your later years seems to reduce the severity or even the occurrence of the disease. 
However, the good doctor goes a bit further than I would. 

Could diabetes and Alzheimer’s be caused by some types of exposures?
We have reasonable evidence that human exposure to nitrosamines is at the root cause of not only Alzheimer’s, but several other insulin-resistance diseases, including Type 2 diabetes, fatty liver disease, also known as NASH, and visceral obesity. 

Again, since Alzheimer's is unrelated to insulin, this is quite a claim. She is basically saying that the nitrates in our food, used as preservatives, are causative factors in the disease. After a search in PubMed for 'nitrosamines+Alzheimer's' came up with only her own work, I am suspicious of this link, to say the least.

She goes on to discuss diet and exercise as preventative measures, something which is definitely supported as being useful to making sure the brain gets the nutrition it needs to keep going in a healthy fashion. However, she goes off the cliff of woo when she talks about antioxidants, Omega-3s, and other substances that are purported to keep Alzheimer's at bay. No one is arguing that fresh fruits and vegetables are an essential part of a healthy diet. The role of Omega-3s and other fats are less well indicated.  But if you think that supplementation with these is either going to prevent Alzheimer's or extend your life, you are sadly mistaken.

It seems as if this doctor had settled on her own pet idea, but I am frankly alarmed at the gross misunderstanding of neurobiology that has led her to these conclusions. 

This all cycles back to the idea that if you are a scientist and do not know the answer to a question you should A) do some research and B) if there is no information out there you test it using, you know, science. It honestly seems as if this lady made some shit up based on some pet theory. 

Alzheimer's is an important and debilitating disease. I have seen first hand the devastation it can cause in families that lose someone a piece at a time. But we are not going to get anywhere in terms of a diagnosis and a cure if we continue to entertain these fashionable theories based on sheer nonsense. 

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