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. 

Residencies

I promised you content... and here is the first of many, I hope.

Recently there was a kerfuffle over allowing medical residents to work shorter hours. In the end, the law remained the same such that residents are only permitted to work 80 hours a week; the major change was that the shifts went from 30+ hours to about 16, though senior residents can do 28 hour shifts with "strategic napping".

This would seem to be painfully obvious to anyone halfway paying attention: tired doctors don't necessarily make the best calls for a patient that needs and deserves excellent care. Especially if the tired doctor in question is, in fact, in training.

With good reason, there has been public outrage about the number of hospital-associated mistakes. Unfortunately, the bandwagon has been made available to sensationalist media coverage of the number of times that people at hospitals screw up. It seems as if the culture that loves to find fault with an educated elite absolutely adored punching holes in the godlike facade of doctors. People like Faux news seemed to take childlike glee in exposing the idea that yes, doctors are people too. Yes, doctors are not infallible. Mistakes are made, and it is a shame, but the best that humans can do is to try an minimize the potential for such mistakes.

Now mind you, there are all kinds of systems in place to minimize mistakes. Nurses ask for I.D. and papers before drawing blood or doing any kind of procedure, due to a mishap at Mt. Sinai in New York with a woman going in for the wrong surgery. It is awful and deeply regrettable, and so we learn from these mistakes. We ask for I.D., discuss the patient's understanding of the upcoming procedure, answer questions, and try to have redundancy programs where if one nurse or doctor misses something, then someone else might be able to catch it. Much of the wait and drag of a hospital can involve running these types of checks. Yes it can get bogged down in bureaucracy, but I would rather have accuracy than speed when it comes to my health. 

Which is why I simply did not understand the hue and cry raised about lowering the number of hours that residents can work. Exhausted students that work 30+ hour shifts, go home to study more, and then must return to the hospital for more work simply makes no sense to me whatsoever if a patient's life is on the line.

Put simply, safety is put into jeopardy. I don't really see that as being an option, really.

Arguments against cutting back hours and shifts are kind of ridiculous, in my opinion. The one good argument against cutting hours was made by Orac a few weeks back, and it is somewhat compelling. We'll visit it by and by.

A residency is a paid apprenticeship. A resident gets paid very low wages for a lot of work, but it is expected because the resident is learning their profession and their craft. An attending doctor oversees their work and makes sure that they are learning what they need to learn, but in a lot of ways they are basically practicing medicine.

Because the resident is working for very low pay, certainly less than she can command as a full doctor, she pumps a lot of free work into the hospital. More patients can be seen quicker because there is a larger staff of doctors that can cover the demand, and thus the hospital brings in more revenue. The hospital benefits from this, much like when you volunteer somewhere. You are performing a service for free because it helps the organization you are working for, and you personally are possibly learning or devoted to a cause. The teaching hospitals objected to the proposed changes because it would cost them revenue.

My question to them is this: if it meant fewer mistakes, fewer lawsuits, and lower malpractice insurance, wouldn't you do it? I'd love to see numbers where the cost/benefit analysis was done, with an estimation of how much the hospital can save in lawsuits and/or eating the costs associated with mistakes, vs. how much revenue is lost from either requiring more residents to cover the lost shifts or not having that many residents.

The next objection was safety. I worked veterinary emergency for years, and I know what happens when shifts change. You hand patients off to the next oncoming shift. In many cases, to promote safety and make sure that things go well, you have the shifts overlap significantly (by perhaps 2 hours) to make sure that nothing comes up. The oncoming shift reads the chart thoroughly to make sure that they understand the case and ask questions to make sure that they get it.

The process takes perhaps 20 minutes TOPS. WHY is this so difficult for human doctors to do? What, precisely, is wrong with handing patients off to another doctor?

There was all of this noise made about "continuity of care" nonsense that really irked me. I've sen it done. It isn't that hard. Why is this kind of continuity so flippin' important that it was raised as a major safety objection? If there is something here that I've missed, please let me know, because I frankly don't get it.

Dr. Wachter's article above made some good points, which kind of coincide with Orac's argument. One is the idea that even though a shift is technically over and the resident is free to go, that the resident might need to stay for whatever reason. I do get this. I've done it myself, because I had a project or issue in the back of my mind that I had to handle before I left, and explaining it might be too complicated or take too long. This I do understand.

The other is the "swinging door" mentality, that the resident might be too eager to leave or know that the shift is over and that things might get dropped just because the resident knows they have to go. Appropriate care to detail and discussions with the attending or oncoming attending physician, in conjunction with staying to make certain that cases are being handled adequately or to handle the case yourself, can probably settle this issue. Knowing the kind of sacrifice, hard work, and discipline involved in getting into and graduating from medical school, I think that this concern really doesn't give residents enough credit for being mature adults. Communication is the key when it comes to patient care, and not being communicative enough with your team will raise all kinds of problems, not just this one.

And we come, finally, to Orac's objection, the one that I think carries the most water. There is a massive amount of information necessary to becoming a doctor, and a good one at that. Book learning can only take you so far, which is why there are residencies and internships. Residencies can be anywhere from 2-5 years long, because there is so much to learn. Orac's problem with decreasing shifts is that there is less actual time to learn what you must in order to pass the boards and be a fully accredited and independent doctor.

I understand and agree with this point of view: there is a huge amount of material to learn, and less and less time in which to learn it. There will be a critical point, with short shifts and a very long residency, past which students will be unwilling to devote their education to a particular discipline simply because of the time involved.  I also think, however, that there are ways to increase the efficiency of a program so that you can indeed learn more effectively. Due to the shift restrictions, this conversation about restructuring the residency programs offered at teaching hospitals is already happening. I think that that is a great idea, because learning medicine is like trying to hit a moving target: it is constantly changing and updating itself.

There are good objections to changing the shift requirements and allowances for residents, but I honestly think that the most important ones are being lost in the shuffle. In addition, creative solutions to solving the aforementioned objections are also being lost because of a seemingly stubborn adherence to a fixed curriculum.

I'm Alive, I Swear!

Between finals, my belt test in karate (Shaolin Kempo, in case you are curious) and moving and selling furniture I have been incredibly busy.

I hope to come back soon with new material. But something occurred to me today.

I started this blog because I did not see any med school hopefuls (or students, for that matter) discussing their experiences trying to get into school or their experiences in school. And I feel like I have basically lost sight of that.

So what I am going to try to do is keep on top on new developments in medicine and various other things that I think are important to me as someone beginning a medical career.

A good place to start is the health care bill and new hours for residents. From there I will see what I come up with. As a member of the American Medical Student Association I get access to forums and newsletters, so I want to start talking about things that I think are important.

Part of doing this is finding my own voice. I think that I should try and reclaim that.

Topics In Medicine

Man there is a lot that I want to talk about, from topics from class, to filling out my applications, (which feels more and more like I'm playing to my audience in a vaguely guilty fashion) to medical ethics.  I'm not 100% sure if I'm going to get to all of them, really (I want to finish complement, talk about heart physiology, do a quick and dirty overview of eicosanoids, and whine about filling out rather tiresome applications) but I'm going to try and get to the more time-sensitive ones first, like the ones that affect my grades and my application deadlines.

White Coat Underground is a wonderful blog about topics in science-based medicine and medical ethics. I particularly enjoy his posts on the latter, because I think that in our litigation-happy culture, we need to think about these things. We also don't want to repeat mistakes of the past.

I worked in veterinary clinics for years. I saw a lot of disease and suffering and death. When one is exposed to such things on a regular basis, you have to figure out how to justify it somehow. How do you get through a day when you have to euthanize parvo puppies because the owner can't afford the treatment? It is difficult and can be heartbreaking.

Euthanasia isn't part of the medical dialogue (yet) like it is with veterinary medicine. In emergency cases people just work the best way they can, as fast as they can. A patient's life must be saved. Period.

In situations where the person is sick and lingering, the decision must be made about how to spend those last few months. Doctors approach the situation from the perspective that every bit of extra time is worth it in order to allow the patient to spend it with loved ones, doing the things they enjoy, and the illness is managed rather than treated.

I think that it is very important to have and maintain an open dialogue with your patients. Telling someone that they are going to die soon cannot be easy, but it is important to make certain that the patient understands all of the options, even at the risk of overwhelming them with information. They need literature to take home, something to discuss with their loved ones, and your phone number. Tell them that you can talk to them and make sure that their questions are answered. This is the only way that they can make an informed decision.

The ability of patients to have that kind of informed decision-making, to be able to enjoy those last few months with their families and friends, is, in my opinion, what makes it a little easier. All doctors have to be around and see suffering on a daily basis. Death isn't easy for anyone, but it is comforting to know that the patient knew the options and was able to go for the one that best suited them. That situation is impossible without informed consent.

And PalMD did an excellent job of framing the question. Go have a look-see.