The Subcellular Processes That Belie All Chronic Disease. The Hateful (or Grateful) Eight #lustig

Foreign.

It is a true pleasure having Professor Lustig here at Emory Pharma. And for those of you who are here, we're grateful for you trekking over here on this rainy, crazy day. And thank you again for coming from San Francisco. And those of you who are online, again, thank you for joining us. So, Professor Lustig, I first came across his presentation at UCSF Grand Rounds and was very impressed and learned a lot about the hazards associated with sugar and fructose. Of course, as always, dose makes the poison, and it's true in almost everything. But Professor Lustig has written books, authored lots of papers. He's been at UCSF for the last 20 some years. He's a native of New York. He did his undergraduate at MIT and his medical degree at Cornell. And we're honored to have you today. And I'm going to pass on the microphone.

Thank you, Ron, and thank you for the invitation, for putting up with me today. I appreciate it. So Ron asked me to talk about chronic disease, and obviously you have more than a little bit of a vested interest in that. Well, everyone has a little bit of a vested interest in that because it's running rampant, you know, throughout the population. Guaranteed, you know, someone with diabetes and even more people with heart disease. And I guarantee you lots of people with fatty liver disease, you just don't know because they don't know it. And all of these are basically compounding our medical and mental health care problems to such an extent that, in fact, Medicare will be broke by the year 2029, no matter what the Republicans do. And so we've got a big problem, and we need to understand what the problem is in order to be able to fix it. And I guarantee you the problem that you think it is is not. So I'm going to try to explain to you what the problem really is today. So, title of the talk is the Subcellular Pathologies that Belie All Chronic Disease, the hateful or grateful 8. And with apologies to grateful Quentin Tarantino, who produced this movie back in 2015, I'm going to basically describe these eight pathologies that are listed here and how they all fit in. All right, so just disclosures, you know, to start with, I did write these books for the general public. Most recent, which is Metabolical, came out in 2021, which lists all of these very, you know, specifically. And I am also the chief medical officer for these four companies and a paid advisor to these other four.

And.

And I will not be mentioning any of these for the rest of the talk. All right, this is A paper that came out in the year 2001, based on 2000 data, looking at how many diabetics there were in the world at the time. And what they said was at that time in the year 2000, there were 151 million diabetics. And what was predicted would be that one decade later in the year 2010, we would be up to 221 million. That. That's a 46% increase, or an annualized inflation rate of 3.88%. This is not what we saw. What we actually saw was 285 million. That's an annualized inflation rate of 6.55%, doubling over what was anticipated by 2014, up to 422 million. That's an annualized Inflation Rate of 10.3%, a tripling over what was anticipated. So as we've learned about the obesity epidemic, as we've been throwing obesity drugs and various other diabetic agents and gym memberships and everything else under the sun at the problem, it has only gotten worse. By the year 2019, we were up to 463 million. 2021, 537 million. And now what is predicted for 2030? 568 million diabetics? WTF. Okay, what is going on? And how is it that this is just getting worse when we're actually trying to do something about it, except it ain't working? Okay, is it possible we're actually making things worse? Well, in fact, we are. And that's part of why we're doing this. And it's not just in adults. This is true in children, too. Now, remember, once upon a time, type 2 diabetes was called adult onset, and type 1 diabetes was called juvenile onset diabetes. But now juveniles get adult onset, so they had to change the name. Right? That's the only reason they went from to type one and type two, because kids were getting it. And in fact, 10 to 14, 15 to 19. Pick your demographic group. It's gone up over the last 20 years. So when kids get adult diseases, something else is going on. Kids are the canaries in the coal mine. They are more sensitive to any perturbation. And so the fact that children get adult diseases says something that children are exposed to is causing this problem. This is not a behavior problem. This is not a diet and exercise problem. This is an exposure. But what's the exposure? Now, if you look at the data on hospital costs in red, physician costs in green, and pharma costs in purple, they do not add up to the total cost because the rest of it is due to the care and treatment of chronic metabolic disease, of which diabetes, of course, is the sentinel disease. And if you look at healthcare expenditure per person against life expectancy, what you'll notice is all the OECD countries, all 37 developed countries, you know, they're sort of keeping themselves to the, you know, within the pack here. But we fell off the rails here in 1980 and have just been going off ever since. And as you know, lifespan is actually going down for the last five years in a row. And this is the reason, because everyone wants the pill. And I am here to tell you there is no pill. There never will be a pill. There can't be a pill. And the reason is because there's no pill that can get to where the problem is. There is a problem and we know where it is. And no medicine gets there. And we're going to talk about that as we go. The only way to deal with this is prevention. But of course, nobody believes in prevention. Everybody wants the pill. So this is not going to get better. It's only going to get worse for this reason. So here's the way I think about it and the way I try to explain it to people so that they get the picture. This is a Venn diagram of the entire US population. 260 million adults, 42.4% obese. BMI over 30, 57.6 normal weight, BMI under 30. Okay, so two mutually exclusive circles. Every one of you is in one of the two circles and you know who you are. Okay, here's what the doctors and the nutritionists and the Institute of Medicine and the National Institutes of Health and the Surgeon General and the White House and Congress and the food industry all say. They say 80% of those 42.4% obese. These 86 million people here, they're sick. They're fat and they're sick. And they're sick because they're fat. And if they would only just diet and exercise, we could solve this problem. Garbage. Total. Complete trash. Sounds right. Sounds like common sense, but it's wrong. Why is it wrong? It's on the slide. Why is it wrong? Well, it is true that 86 million people are obese and sick. That's true. Okay, but that means. And that's 80% of the total. That means 20% are not. They are metabolically healthy. We have a name for them. Mho. Metabolically healthy. Obese. They will live a completely normal life. Diet a completely normal age, not cost the taxpayer a dime. They're just fat. They have Increased subcutaneous fat, which turns out to be protective against chronic metabolic disease. Nothing wrong with them, you know, other than fitting into a swimsuit. Conversely, and this is the important part, 60% of the normal weight population have the exact same diseases as did the obese. Normal weight people get type 2 diabetes, hypertension, dyslipidemia, cardiovascular disease, cancer, dementia, fatty liver disease, polycystic ovarian disease. 2. Now they get it at a lower BMI, and it's true that it's 60% versus 80%. So, in fact, obesity is a risk factor for chronic metabolic disease. And I don't argue that that is absolutely true. Obesity is a risk factor, but it is not a cause. There's a difference between risk factor and cause. And what we are talking about today is cause that's not the same. Tell the nih. So there are plenty of thin sick people out there, okay? And there are plenty of fat, healthy people out there. And so the question is, which are you? Well, can I prove it? The answer is, yeah, here, I'll prove it right here. So here are two equally weighted people, CT scans through the abdomen of two equally weighted people. Notice trunk fat, 12.8. 12.8. One's healthy, one's sick. Which one's sick? B. B is sick. A metabolically healthy obese. He's got big love handles. Subcutaneous fat. Not dangerous. In fact, might be protective in many cases. Protective? This guy's got fat all around his organs. Intra abdominal fat, okay? And we have a name for this. It's called tofi. Tofi. Thin on the outside, fat on the inside. Real medical term, 1500 Medline citations. Coined by Dr. Jimmy Bell at University College London, Neuroimager. So my question to you sitting here right now, all of you, are you a tofi? How would you know? How could you know? Does your doctor know? If your doctor knows, why hasn't your doctor told you? And what would your doctor do about it if they did know? And it goes even further than that, because it turns out it's not just the visceral fat, it's the liver fat. So here's a histological micrograph of normal liver. And you can see the sinusoids and the biocanalliculi and the Kupfer cells, all nicely ordered. And over here, we have fatty liver disease. And you can see the fat vacuoles, and you can see the beginning of scarring. You can see all the macrophages infiltrating. Okay? Now, prior to 1980, if you saw this under the microscope, that was alcohol, alcoholic fatty liver disease. The problem is, if you look at this now, in 25% of children, you will see the same thing. And children don't drink alcohol. That is called non alcoholic fatty liver disease. Or now a new name, metabolically associated fatty liver disease. So nafld maffled all the same. So the question is, how come something that causes disease in alcoholics is causing disease in children? What's that about? What's the exposure there? Because everyone's got it. 45% of adults have non alcoholic fatty liver disease, 25% of children. Now, I didn't say obese total. In fact, fatty liver disease is now the leading cause of liver transplant in the United States, having overtaken hepatitis C. And that's not just in obese people. Now it is true that the more obese you are, the more fatty liver disease. I'm not arguing that again, obesity is a risk factor. I didn't say it wasn't. It is. Okay, but you'll notice, take a look at the prevalence in the normal weight population, and that's around the world. So this is not a uniquely American problem. This is a global problem because of a global exposure. And the question is, what is that global exposure? And if you look here, here's BMI bind here. And this is the hazardous ratio for fatty liver disease. And you'll notice here's the overweight category. And you can see very clearly a signal, you can even see the signal a little bit in the normal weight category. But if you have diabetes, take a look even in the normal weight. In fact, turns out if you have fatty liver, you are 3.5 times more likely to develop diabetes because of your fatty liver causational. And it makes sense because after all, when the pancreas releases insulin, where does it go? Goes to the liver via the portal vein. Now the rest of the body, you know, when a hormone is made, it goes into the systemic circulation, right? But pancreas goes to the liver. And the reason is because the liver is the primary target of insulin action. And so when your liver is sick, guess what? So is your pancreas. So the question is, what's going on in the liver? So here we have an obese person. Notice the love handles on the side. But take a look at this guy's liver. Notice 2.6% liver fat. This is fine. This is MHO, metabolically healthy obese. Nothing wrong with this guy. Now take a look at this guy over here. Notice obesity. But take a look at his liver. 24% liver fat. Ground glass appearance. See, okay, this guy's got metabolic syndrome. This guy's got nafld. This guy's going to die. Now take a look at this guy over here. Notice, no obesity. Normal amounts of subcut fat. But take a look at his liver. 23% liver fat, thin, sick fat, sick fat, healthy. In other words, it's not the fat you can see that counts, it's the fat you can't see, and particularly the fat in the liver that you can't see. And so the question is, how did the fat get in the liver in the first place? And why is it children have it? So my point is that obesity is not the problem. It is a symptom of the problem. It is downstream of the problem. And so we are treating the symptom of the problem and not doing a very good job of it, mind you. So what is the problem? Metabolic syndrome, Defective metabolic health, metabolic dysfunction. And that's where all the money goes. 75% of all health care dollars go to all of these diseases, of which, of course, diabetes is the sentinel disease. Now here's the real problem. None of these diseases have any cures. They just have treatments. And in fact, the treatments don't work because they are just treating the symptoms, they're not treating the cause. Okay? It's like giving an aspirin to a patient with a brain tumor because they have a headache might help the headache ain't gonna do a damn thing for the brain tumor because the pathology is still there. The only way to fix the problem is to remove the pathology, not to cover it up, not to band aid it over, but get rid of it. And we're not doing that because we don't understand it. We think obesity is the problem. No, obesity is a symptom of the problem.

Is mental health part of the issue?

Mental health is metabolic health. So anything that happens. And we're going to talk about mitochondria in a minute, okay? You got mitochondria in your liver, and when they don't work, you get fat in your liver. You have mitochondria in your brain, and when that those mitochondria in your brain don't work, you get mental illness. And the same things that affect your mitochondria in your liver affect the mitochondria in your brain. So, in fact, metabolic health and mental health go hand in hand and often not just overlap, but are, you know, due to the same problem. Okay, now example, ldl. Everybody's chasing ldl. Everybody thinks, get the LDL down right and you'll fix heart disease, right? Garbage. Total garbage. Now, it is true that LDL levels do correlate with cardiovascular disease. That is true. The hazard risk ratio is 1.3. You see it right here, 1.3. Now, the public health community has settled on 1.3 as when it's a public health issue. So if it was 1.29, it wouldn't be a public health issue, but it's right there on the edge at 1.3. And there's your data, okay? And it's true, and it does correlate. And I'm not saying it doesn't. It does, okay? But there's something that correlates way better, and that's serum triglyceride. Serum triglyceride correlates with a hazard risk ratio of 1.8. And there's the data right there. 1.8. So serum triglyceride is actually 50% more informative in terms of heart disease than is LDL. Now, turns out your serum triglyceride is your very low density lipoprotein. It is made by the liver and it is made from the conversion of sugar to fat through a process called de novo lipogenesis. Your triglycerides are your VLDL and your chylomicrons. But if you're fasting, your chylomicrons should be zero. So your VLDL and your serum triglycerides are the same, which means that your serum triglycerides are a measure of liver function. And so if your serum triglycerides are high, it means your liver is sick. If you've got fat in your liver, it means your liver is sick. And if your liver is sick, that means your pancreas is sick. And that's what drives the chronic metabolic disease. Now, we give statins for people with high LDL in an attempt to drive the LDL down because we think the LDL is the problem. The question is, is the LDL the problem? Well, if it were the problem, then the statins would work, but they don't. And there you can see right there, there's your diamond on the identity line. It's not on the favorable side. There's a Cochrane review. This one's for total mortality, this one's for fatal cardiovascular events. Again, virtually no, non existent, okay? And if you look at the data on LDL lowering as a primary, not secondary, but primary prevention for heart disease, like if you go to your doctor and your doctor says, oh, your LDL is high, you need a statin that's Primary prevention. Okay, as opposed to, oh, you've had a heart attack here, you need a statin. That's different. That's secondary prevention. Everybody see the difference? Okay, so primary prevention, you're not self selecting for people who already have a problem. When you look for primary prevention, turns out the RCTs do not show any benefit on mortality. Do you know what the mean increase in lifespan is from treating high LDL with a statin is? 4 days. 4 days. None of these trials reduced CVD events and some of the drugs actually reported harm. This just came out three days ago. And so you're looking here, sorry, at all cause mortality. And this is the degree of LDL cholesterol reduction. And it doesn't matter if it's statins or ezetimibe or diet or anything else. That's your, that's your benefit. Zero. This is for myocardial infarction. Okay, about a 5%. And here's for stroke, about a 2%. And more importantly, on this side, we have number needed to treat. How many people do you have to treat with a statin to actually get one patient with benefit? 754. Ridiculous. Number needed to treat. Maybe 10. Might be cost effective. Really? 5 might be cost effective. 754. Really? You get the picture. And statin use is associated with development of diabetes. And the reason is because it's a mitochondrial toxin. That's where it works. Works at 3 beta hydroxymethylgluteryl COA reductase. It's a mitochondrial enzyme causing damage. So why should you be surprised it's associated with diabetes. All right, let's take a different marker, not LDL. Let's take hemoglobin A1C. Everybody says high hemoglobin A1C bad. Get it down. Give insulin, give oral hypoglycemics, give glutinides, give SGLT2 inhibitors. Right. Well, here are five studies that show that lowering A1C didn't help, didn't make a difference in terms of morbidity mortality. So here's the original UK PDS data looking at talbutamide versus placebo. And the mortality rate was actually higher with the talbutamide. And the cardiovascular disease was higher with the talbutamide, even though the A1C went from 9 to 7. This is the famous rosiglitazone data from the New England Journal that you're all familiar with. Okay? Take a look at the odds risk ratio for myocardial infarction. Not a whole lot better. Just as bad and for cardiovascular death, 1.64, not very good. Okay, this is the Accord trial, the intensive trial. It was in the New England Journal. Here's standard therapy and intensive therapy for A1C. You can very clearly see the benefit. But when you look at the primary and secondary outcomes, here's mortality notice, intensive therapy, worse, statistically worse, and CVD death, statistically worse. So just getting the A1C down doesn't necessarily translate into metabolic and or cardiovascular benefit. So we can't fix chronic disease with medicines we haven't been able to. We're not going to be able to. And the reason is because we are not addressing the problem, we are papering it over. Which then leads us to, well, what is the problem? And that's where this concept of the hateful or grateful eight comes in. These are the eight subcellular pathologies that you can't measure. In fact, there's no ICD11 code for any of them. Your doctor can't bill for any of them. Your doctor doesn't know what the hell they are anyway, wouldn't discuss it with a patient. Their lives depended on it because it basically just be blowing smoke because they can't do anything about it anyway. And so no wonder no one's heard of them or cares about them. And here they are listed. Okay? Now, some of you are medical, Some of you have heard of these eight, Some of you are not medical and have not heard of them. But these are what's going on inside your cells. Glycation, oxidative stress, mitochondrial dysfunction, insulin resistance, membrane instability, inflammation, methylation, and autophagy. The point is that not one of these pathways is druggable, except maybe inflammation. And that's a question mark all by itself. Depends on what's inflamed. But they're all foodable. You can use food to fix all eight of these. I will show you at the end how you do that. So let's start with number one, glycation. Here we have five pictures of food.