NEW data / thinking on insulin – from Alzheimer’s to PCOS - Prof Ben Bikman

0:00This show is sponsored by Primidine, a clean, natural and science-based spermidine supplement that's been a long-time staple in my own longevity stack. Because studies suggest that through autophagy, spermidine increases healthspan and upregulates a range of health markers, from memory and cognitive function to heart health, hormone balance, fertility and even hair growth. Plus, you can be assured that all ingredients undergo rigorous third-party testing. Buy Primadine now at OxfordHealthSpam.com and use the discount code DrSophie, that's D-R-Sophie for 20 % off. This show is sponsored by Microbes, an award-winning liquid probiotic that's now a staple for me, because Microbes, with a Z on the end, is different.

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1:31So together with my producer Fee, I'll be deep diving into the latest research, sifting fact from fiction. I'll also be talking to all kinds of trusted experts tapping into their knowledge, along with bringing you conversations from a range of interesting women and men finding out how they age well. So this is my show. Welcome along. And as always, thank you so much for listening.

2:00Ben, I've been so looking forward to this chat. Let me start by saying that your resume is seriously impressive. You're a metabolic scientist and a professor in cell biology with a PhD in bioenergetics. Just to break that down a bit, your work spans many areas where academia and health education intersect and your primary focus is on insulin resistance and metabolic health. With that in mind, I think it's fair to say that most women, certainly here in the UK and I imagine in the US, are now pretty clued up on hormones such as estrogen, testosterone and progesterone, largely because of this menopause revolution.

2:37But I've noticed that a lot of people, men and women included, have no idea that insulin even is a hormone and only a very vague idea of what it does. So can you give us a quick 101 on insulin just for complete beginners? Yes, of course. Yeah, but please appreciate what you're asking an old professor to do. You're asking me to be brief on the one thing that I know the most about, but I'm going to do my best. When most people hear the word insulin, they actually just think of a drug for diabetes, but it is a hormone that we make from the small little beta cells of the pancreas, which is a big gland tucked beneath our stomachs.

3:16and insulin has a lot of effects in fact it is rare as a hormone because it literally affects every single cell of the body from brain cells to bone cells lung cells to liver cells and all in between insulin is going to come to that cell and tell it to do something now the most famous something is to reduce blood glucose levels commonly called blood sugar but that is just one of insulin's effects. And so maybe just to try to make it a brief answer, insulin's thematic effect is to control metabolism. And that involves a lot of unexpected processes, including, in fact, affecting some of the very sex hormones you just mentioned.

4:00Most people wouldn't appreciate the fact that insulin regulates the production of estrogen from testes and ovaries. It influences blood flow by determining the diameter of blood vessels dictating how dilated or constricted the blood vessel is. And it even affects things like the degree to which the brain is accessing energy to maintain cognition. So from top to bottom, in every cell in between, insulin is telling that cell to do something and that something is going to be very important. So suffice to say, if insulin is not working well, we're not going to be feeling very well. Okay, good start.

4:39A slightly bigger question. Can you talk about the various disease states that your work and the data indicates is connected to insulin resistance? So the two big ones are cancer and Alzheimer's, the latter of which I've heard you talk about as insulin resistance of the brain. So maybe let's start with those two, cancer and Alzheimer's, and perhaps overall brain health, including so-called brain fog. Yeah, those are two disorders that undoubtedly have captured a lot of people's attention because they're just so scary. And with cancer, there's a little less to say, and so I'll start with that one.

5:13Cancer is a disease of growth where cells are no longer responding well to their growth signals. Sometimes cells need to grow, sometimes they need to die, and a cancer cell is not getting that death signal anymore. And in many cancers, particularly the most common in men and women, that is, prostate and breast cancers respectively. We know from biopsies of these tumors in men and women that one of the things that has mutated or changed about the cancer cell is that they have higher insulin receptors than they used to. So these little docking stations for insulin to come to the cell and tell it to do something, well, insulin will often tell cells to eat more and grow.

5:56And now a cancer cell has mutated to respond more favorably to that growth signal. So they've heightened their sensitivity or responsiveness to the hormone insulin, again, giving them a stronger growth signal than they should have. But then on the other side is Alzheimer's, which is the most common form of dementia, the most common form of cognitive decline, and again, a very scary disorder in its own right. Increasingly, we are leaving the old paradigm behind, which is the view that Alzheimer's is a disease of these little plaques that form in the brain and disrupt the ability of the neurons to communicate.

6:35But that is no longer the view. As that view has died on the altar of good science where it needed to die, it was never very well justified. The replacement theory, it has had decades of evidence to support it, now steps to the fore, and that is the energetic origins. And you said it well in framing the question. It is insulin resistance of the brain. Most people don't appreciate the fact that insulin, among its many effects throughout the body, has an effect on various neurons within the brain. And that effect is to come to the neurons and open these transporters or these doors, if you will, whereby glucose can come from the blood into the neurons of the brain to fuel the brain.

7:21The brain is very hungry. It has a very high metabolic rate. Indeed, one of the highest metabolic rates of any organs in our bodies. And that means the brain needs to eat. And the brain has two fuels and glucose is one of them. And if you start to deprive the brain of that glucose, then no surprise that it is going to have to, like an engine that is sputtering as it's running out of fuel, the brain begins to sputter, if you will. And if it cannot obtain sufficient energy to maintain its current performance, then performance will start to drop, and that would manifest as cognitive decline. So insulin resistance of the brain is a very accurate description of Alzheimer's.

8:03And importantly, this is a phenomenon that has been shown to begin to occur in people as early as their 20s. There was a study performed in otherwise healthy young 20-year-old in their 20s women finding that those women who had the lowest levels of brain glucose metabolism had the highest degree of cognitive decline. even though it was modest because they're in their 20s after all, they're young and healthy, but even still it was detectable as early as our 20s. So that should be sobering and my hope is as sobering as it is, there's a little bit of good news in that as you improve your metabolic health, you can improve your risk of Alzheimer's disease.

8:45Staying on the theme of cancer, we heard you talk on a different interview about the fact that while the rate of cancer in men is pretty much staying the same, there's now a rise in cancer among women up to the age of 45 and in particular breast cancer. What's going on here? Right. There is undeniably many things going on here, including ones that would not be metabolic. So I'll just mention those because I need to, because the data is so convincing there. And then I'll come back to my area of expertise being metabolism. But we live in an environment now where there is a shocking number of chemicals that we regularly not only apply to our skin, but we swallow and we inhale that are these chemical estrogens that can mimic the effect of estrogens within the body of a woman.

9:37And that is known to exacerbate certain breast tumors actually mutate to have a heightened sensitivity to estrogen. And then we simply dial that up to an 11, if you will, by flooding the body with these artificial estrogens that are coming in things like plastics and detergents and lotions. And so there's an environmental component that goes beyond the realm of metabolism. But within the realm of metabolism, we do have a strong connection between obesity. Obesity is a very well-known, identified, and rigorously vetted risk factor for breast cancer in women, where there is an interesting overlap between fat cells and cancer cells, which is as fat cells begin to grow, they begin to run out of oxygen and they need more blood flow.

10:27And so the fat cells begin secreting or releasing a bunch of pro-inflammatory hormones in order to enhance its own blood flow. The exact same phenomenon happens with cancer cells. The cancer cells are growing so quickly. They have such a high demand for energy, actually, in the form of glucose. Cancer cells love glucose. And I'll come back to that idea in just a moment. But they also need a lot more just blood and all of the oxygen and everything that's coming with it. And so there's a tremendous overlap between what fat cells need when they grow and what cancer cells need. And it's no surprise that the signal that the fat cell is releasing to try to increase its blood flow can also end up servicing the needs of the growing cancer cell.

11:12But then back to the energy aspect, cancer cells rely primarily on glucose as its fuel. if you attempt to force a cancer cell to use other fuels like fats or ketones, they will die. They don't metabolize those fuels well enough to support their metabolic demands. And so the modern diet being one that is so high in refined carbohydrates, all of these sugars and starches coming into the body almost constantly are a perfect fuel. And so to put all of this in perspective, we have the average woman, as we focus on breast cancer, is gaining more fat mass, she's becoming more insulin resistant. That means she has these pro-inflammatory signals, facilitating enhanced blood flow to the cancer.

11:56She also has elevated insulin, which is a constant feature of insulin resistance. And that elevated insulin is telling the cancer cells to grow faster. But to make matters even worse, we are also flooding her body with glucose because of her constant sipping and eating starchy, sugary things. And so the glucose provides the perfect fuel to fuel the growth of those cancer cells. So there are a host of metabolic variables that have come into play to create a perfect metabolic storm to, I believe, heavily contribute to the increased incidence of breast cancer that we see nowadays. This is all so fascinating.

12:39And for anyone listening thinking, well, what can we do? We are going to get on to lifestyle factors and the good habits that we need to think about. But first of all, let's talk about some of the issues at play. What about PCOS, polycystic ovary syndrome? Can you expand on your viewpoint with this? Oh, yes, certainly. In fact, PCOS is going through a bit of an identity crisis as a term where more and more physicians and clinicians are trying to change the name of this disorder to be something like metabolic infertility, which would be more accurate. So PCOS is the most common form of infertility in women, so it is certainly a topic worth exploring.

13:17The fundamental or the most well-known problem is what gives it its name, which is that the ovaries become filled with these fluid-filled cysts. And each of those cysts was once what's called a follicle, or in other words, a developing egg, which of course is a critical feature of the normal ovulatory menstrual cycle, the fertility cycle in a woman. What happens over the course of the month is actually remarkably fascinating and complicated. I sometimes joke that female fertility is like a 200-piece orchestra, while male fertility is like a barbershop quartet. It is so simple. Not that it's not important, but the female fertility cycle is much more complicated.

13:57And so it's no surprise that her system is more sensitive to metabolic demands or to metabolic signals. After all, she's the one who has to carry the baby, that metabolic marathon of gestation. And so if there is a metabolic component, no surprise that insulin, the master metabolic hormone, plays a role in all of this. And at the very beginning of our discussion, I mentioned how insulin even affects the ovaries, and this is where it matters, because all estrogens were once testosterone. Very few people appreciate that. In men and women, the first hormone that the ovaries and the testes produce will be testosterone in that pathway of events.

14:40And then the testosterone will get converted into the estrogens, the main one being estradiol, but we commonly just call it estrogen. But estradiol is the main estrogen that matters for these processes. And the testosterone will be converted into estradiol via the actions of an enzyme called aromatase. And that whole process is called aromatization. So insulin now comes in and inhibits that process. So if a woman is living a life that is bumping her insulin up constantly throughout the day, that has myriad effects throughout the body including in the brain and cancer risk like we described but it will also be inhibiting her ovaries ability to create estradiol from testosterone and in the absence of a heavy degree of conversion of testosterone into estradiol she fails to get what is called an estrogen surge and that estrogen surge is a critical absolutely essential event right leading up to and indeed what is causing ovulation, the release where one of the follicles becomes the main follicle, the dominant follicle, and actually releases its egg to go into the fallopian tube to be fertilized with normal fertility.

15:59And if that can't happen, then all of the other follicles that were also developing, because there are multiple follicles where the ovaries are waiting to see which one becomes dominant. If one of them doesn't ovulate, then they all stick around. And that's where you end up having the ovaries that have too many of these little cysts because they didn't get the signal to go away and die actually in the absence of one becoming dominant and actually ovulating. So all of this is, I guess, to say in the normal orchestra of the fertility cycle, if insulin is too high, it disrupts the conductor and the conductor is unable to give the big signal being the estrogen surge in order to allow ovulation and as a result ovulation fails.

16:46I'm particularly fascinated by your views on cholesterol. I had a Swedish grandmother who had high cholesterol, actually probably the highest I as a physician have ever seen, but she never went on to have any associated issues. I know there's a study, coincidentally a Swedish study, that says that some of the longest living people do in fact have high cholesterol. And clearly this is totally counter to what we think about cholesterol. Can you tell us more? Oh yes, gladly. I'm thrilled to revisit this topic because it's one that I feel so strongly about. Indeed, I believe that one of the mistakes we've made globally with modern medicine is to vilify cholesterol.

17:26And there is, in fact, a fascinating history of how cholesterol became viewed as a villain. But in the absence of getting into that history, after all, you didn't bring me on here because I'm as a history professor, it is an instance, it's a wonderful case study of bad science, where some conclusions were determined almost ahead of time. And then the scientists made sure that they played around with the data. This is literally what happened in order to ensure that the cholesterol story became the dominant one. So yeah, the Swedish study, and there are similar studies, the Shanghai aging study, the Honolulu longitudinal study, there are multiple studies from around the world at this point to confirm showing that this is something that appears to crop up in multiple ethnicities through multiple countries.

18:16But the main finding was that in the Swedish study was particularly well done. And that is perhaps no surprise given the Scandinavian caution and care and rigor with their centralized medical care. What they were able to do was look retrospectively over decades at people who at one given moment in time were manifesting with diseases and even dying so they can actually measure mortality. What they did was they were able to look back in time and review the health and the medical records of these individuals, coming to one central conclusion, that those with the highest cholesterol tended to be the longest lived.

18:58This is indeed not an uncommon feature. And it is, I believe, reflective in part of just how important cholesterol is. Cholesterol is a molecule of life, and the further we are pushing it down, the more we are compromising life. I just got done talking about sex hormones. Most people don't appreciate that every single sex hormone is built on a backbone of cholesterol. The gonads, the testes and ovaries, will literally take a cholesterol molecule and then turn it into the sex hormones. Same thing happens with vitamin D. this hormone that is so critical it's not a vitamin it's a hormone really but it's so critical for calcium metabolism for immune function even for insulin sensitivity and diabetes risk if you don't have enough vitamin d you're going to have problems with all of those things vitamin d is built on cholesterol the body will take cholesterol and then tweak it around a little bit like a lego set and then turn it into vitamin d you also have just for the sake of time i'll just mention one more.

20:01A critical component of the mitochondria is a molecule called ubiquinone, and ubiquinone actually acts as a central electron carrier in a process of the mitochondria called the electron transport system. There's no production of energy in the powerhouse of the cell, as the mitochondria are commonly called, unless you have sufficient ubiquinone to carry these electrons across the mitochondria. And that is once again, a molecule that is built on cholesterol. So these processes that are so fundamental to life, from fertility and normal sexual development and reproduction to mitochondria, and even with vitamin D, our response to the sunlight, even, they are dependent completely on the body's having sufficient cholesterol.

20:49And so when we have someone like your Swedish grandma come to a clinic and the, in fact, my own grandma, she was one who was, had elevated cholesterol her entire adult life and had multiple physicians throughout her life tell her that she needed to be on a cholesterol-lowering medication. She would go on it thinking she needed to do this to live a long, healthy life, and she would feel so miserable and really experienced muscle pains from it, which is not an uncommon consequence, and would always get off the drug. And then the last 30 years or so of her life, and she lived to 102, was spent off the drug because she just said, I don't want to feel so weak and miserable and achy.

21:31And I know that's just an anecdote. And we would say, well, your grandma is too. But the evidence does support it if we're willing to think contrary to the prevailing views. As a fellow clinician, I'm also really interested to hear your viewpoint on modern day medicine in relation to what we measure in healthcare. And what you just said about cholesterol also sings to this. So as you say, when it comes to clinical markers, so what our doctors and GPs test us for, why are we so obsessed with glucose? Why not insulin? And why are we so obsessed with cholesterol? Why not triglycerides, which is another lipid that's far more predictive of heart attacks.

22:14Does all of this relate to what the pharmaceutical industry is able to produce and therefore sell? I'm not saying that is the case, but I'd certainly love to hear your thoughts. Right. Well, in fact, I will be a little more bold and say I think it is the case. I do believe that much of modern medicine is practiced because we develop a drug that has a target. And so we then focus on that target. And you certainly see this with these ones you just mentioned. My view very strongly is that our glucose-centric paradigm leads to late diagnoses, late detection of problems, and very poor treatments. Because if we focus solely on lowering the glucose, then we may end up taking very unhealthy interventions.

23:01Like, just as an example, type 2 diabetes is a disease of both high glucose and high insulin. The insulin just isn't working very well because they're so insulin resistant. And so a glucose-centric paradigm would say, it would lead the clinician to say, well, we just need to lower your glucose at any cost. And so let's put you on an insulin therapy. I don't even know where your insulin levels are because I haven't measured them, but insulin doesn't matter in that glucose-centric paradigm. And so let's just give you more insulin. And it will lower the patient's glucose, but tragically we make them fatter and we kill them faster.

23:36Basically the risk of every chronic disease increases as we push their insulin up even higher. Let me just put a fine point on that. The more we give a type 2 diabetic insulin to lower their glucose, they become three times more likely to die from heart disease and twice as likely to die from cancer. We are killing them faster because of our lacking an appreciation for insulin. But we can lower glucose with a drug, whereas we cannot do that very well with insulin. So let's focus on the one we can sell a drug against. And then the same thing would apply to cholesterol versus triglycerides. Triglycerides are a much stronger marker of heart disease and cardiovascular mortality than cholesterol is.

24:20In fact, cholesterol is a terrible marker. There was a study published at the UCLA Medical School, a very big hospital system here within the U.S., And they had looked at, I think, 110-ish thousand people who had come to the clinic with a heart attack, the most obvious sign of heart disease. And in measuring their cholesterol levels, even the dreaded LDL cholesterol, the great villain, they found that it was an absolute, totally normal distribution bell curve. In other words, people coming in with a heart attack were just as likely to have high cholesterol, LDL cholesterol, as they were to have low LDL cholesterol.

24:56It had no correlation, no predictive power whatsoever. Triglycerides, on the other hand, are consistently predicting these sorts of events. But we don't have a drug that focuses on triglycerides. Now, I know that makes me sound a little cynical, but I do think it behooves us to be a little practical when it comes to these things and wonder at some ulterior motives that perhaps sometimes our best health isn't the main priority. Not to say that this is on the clinician. A clinician might be operating with the best of intentions. If it's not something that's been worked into their medical school curriculum or their continuing education material, then how could we expect them to know it?

25:38But someone listening now would certainly have a more informed view. Yeah, these are such important conversations and this is all fascinating. And on a similar note, we also interviewed last year Dr. Nathan Bryant, whose work you may be aware of. His focus is on nitric oxide. he explained to us why he's antistatins and we'll link into that particular episode in the show notes and he also talked about erectile dysfunction and at the time of recording Sophie has just finished an episode on erectile dysfunction and libido and things like that can you tell us your viewpoint on erectile dysfunction yeah gladly of course I will be coming at that from the view of a metabolic scientist and in fact that does even include nitric oxide so with erectile dysfunction which is the male counter to PCOS, although very different diseases, but each is the most common form of infertility within the respective sexes.

26:30Nitric oxide matters tremendously, so it's appropriate that Nathan would have mentioned this and focused on it. Nitric oxide is a powerful vasodilator. It will dictate or indicate to blood vessels that they need to expand and extend themselves out to increase blood flow. No surprise that there needs to be a substantial change in blood flow in the man to have normal erectile function. And testosterone plays a part of this, by the way. And so if a man is on statins and he is destroying his ability to produce testosterone because he's waged war on cholesterol, that there is going to be a problem.

27:05And one other comment on testosterone in the modern man is that as his fat cells begin to grow, they actually begin to act like ovaries in that they begin to express that enzyme aromatase, which starts to quite literally take in the testosterone that the testes have worked so hard to produce and then convert it and release it as estradiol. His fat cells begin doing the exact opposite. They begin acting like ovaries when the testes are working so hard to produce testosterone. So they have a bit of a battle and the fat cells win as they get bigger and bigger just by sheer mass. The testes have no chance.

27:44So all of that contributes. But just to stay, come back to insulin resistance, where I'm most comfortable, insulin is a signal that when it comes through the blood vessel, it will actually activate an enzyme called nitric oxide synthase. And as the name suggests, that results in the endothelium or the blood vessel creating nitric oxide. So if the blood vessels become insulin resistant, which they do, then they are not responding as well to insulin's vasodilating signal, and there's going to be less nitric oxide produced. In fact, There was a paper published a little more than 10 years ago now by physicians, and they noted in the title, it was something like, is erectile dysfunction the earliest manifestation of insulin resistance in otherwise young, healthy men?

28:33And they were making the case that if you have a male patient who is experiencing erectile dysfunction, it might be a sign of a metabolic problem. And so let's measure the metabolic problem. Let's actually measure insulin to understand insulin resistance. And then maybe before we put him on some blood vessel specific medication, let's have a conversation about improving his metabolic health. So whether it's insulin resistance affecting the blood vessel, whether it is the statin destroying his ability to produce sufficient testosterone, or it's the fat cell working against the testes and stripping away the testosterone and making it even worse by flooding his body with estradiol.