Key blood test results explained that tell you about your pancreas health
In this episode of A Whole New Level, Levels editorial director Mike Haney talks with Dr. Robert Lustig, a neuroendocrinologist and professor emeritus of pediatrics at UCSF, about pancreatic health and the markers that reveal how well this critical organ is functioning.
The pancreas is often overlooked in conversations about metabolic health, yet it plays a dual role that makes it uniquely important: it's both an exocrine organ that produces digestive enzymes and an endocrine organ that secretes hormones like insulin and glucagon to regulate blood sugar. When the pancreas malfunctions, the consequences can range from diabetes to life-threatening pancreatitis.
In this conversation, Dr. Lustig and Mike discuss why the pancreas is considered "no man's land" in medicine, how blood markers like fasting insulin, amylase, and lipase reveal pancreatic health, the mechanisms behind type 1 and type 2 diabetes, what causes pancreatitis, and why pancreatic cancer is so deadly. They also explore the role of mitochondrial dysfunction in pancreatic disease and what we can do to protect this vulnerable organ through lifestyle choices.
The pancreas is the only organ in the body that is both exocrine and endocrine. There is no other organ in the body that does both of those at the same time.
— Robert Lustig, MD
Why the pancreas is "no man's land" in medicine
Mike Haney: The context for this episode is that Levels is expanding our blood testing into many more markers. We're doing a series of shows grouped around functional areas of markers, really to help people make sense of some of these results they're going to get back and have some context for what does this marker mean, what does it do in my body. Today we're going to talk about the pancreas. Maybe where we'd start is your background. Why am I talking to you in particular about the pancreas? How does it intersect with what you've done professionally?
Robert Lustig, MD: The pancreas is sort of no man's land in medicine, and there's a reason it's in no man's land. The first reason is because it's in no man's land in the abdomen. It is between the spine and the stomach. It's actually very hard to see, very hard to image, very hard for the surgeon to actually be able to go in and look at it or operate on it. It's very hard for MRI to see it. It's very hard for people to know what's going on with the pancreas. Because of where it is, between the peritoneum and the retroperitoneum, it is in this space where it can get really sick and it can get tumors and you don't know it until it's too late. So the pancreas is kind of a problem organ to start with.
It's also no man's land physiologically. The reason is because it's the only organ in the body that is both exocrine, meaning it makes enzymes that go through ducts into someplace else to chew up the food, and also endocrine---it secretes hormones into the bloodstream. There is no other organ in the body that does both of those at the same time. The endocrinologists claim the pancreas, but also the gastroenterologists claim the pancreas, and so a lot of stuff actually falls in between. When there's a problem with the endocrine part, sometimes it will affect the GI part, and sometimes when there's a GI problem, it'll affect the endocrine part. You really have to be on your toes to know what's going on with your pancreas.
Mike Haney: The study of the pancreas then typically falls into one of those two camps. You're either an endocrinologist or you're a gastroenterologist. There's nobody who's a pancreatologist.
Robert Lustig, MD: Well, there are, but they are super specialized and very few and far between. To be honest with you, you wouldn't necessarily want one because they're so specialized, they're not even going to be able to help you.
Mike Haney: Your background is obviously on the endocrine side. Talk a little bit about your background. How did you come to endocrinology? What did you do in your career in that space?
Robert Lustig, MD: I became a neuroendocrinologist when I was in seventh grade. How's that? The reason was because it was 1968 and Guillemin and Schally, two famous scientists, one at the Salk Institute, one in Texas, had separately within a week of each other isolated the first hypothalamic releasing factor and it made a big splash because it showed that the brain controlled all the hormone secretions of the body. It was called thyrotropin releasing hormone, or TRH, and I had to write a term paper in science and I said, "Wow, this is cool," and it captured me. I said I'm going to be a neuroendocrinologist when I grow up, and indeed I did.
Endocrinology was particularly interesting to me because of the concept of negative feedback. The thing about endocrinology is that a gland will secrete a hormone and then that hormone will react with a receptor and then that hormone receptor complex will then regulate how that hormone is secreted in the future. From a physiologic, from a mechanistic standpoint, it was very attractive to me. It made sense to me.
The biggest advances in endocrinology
Mike Haney: It feels like there's a lot that's happened in endocrinology in the decades you've been practicing. What have been some of the biggest advances or biggest things we've learned in that space?
Robert Lustig, MD: The first one that I'm most interested in is that behavior is really biochemistry. Pretty much every thought is a protein phosphorylation. Every thing we do is driven by some neurotransmitter which is then susceptible to either a hormonal signal or a dietary signal. We are just products of our environment when it comes right down to it. I think that is probably the most important thing we've learned over the last 40 to 50 years.
Other people would say that other things were important, like for instance we now have a good handle on this phenomenon of diabetes, both type 1 and type 2. We understand the causes of them. We don't yet have cures for them, but we do have treatments for them that work. Given the importance of diabetes in terms of metabolic health, in terms of healthcare costs going out the window, and the fact that it keeps rising, I would say this is probably the single most important clinical development over the past 40 to 50 years.
There are others, like osteoporosis and learning about what's going on with the adrenal gland and cortisol and stress has been extremely valuable. But for me, the behavior part was the real interesting part.
Behavior is really biochemistry. Pretty much every thought is a protein phosphorylation.
— Robert Lustig, MD
How the pancreas works: exocrine and endocrine functions
Mike Haney: Let's dive in a little bit more and talk about the mechanistic chain on both that exocrine and endocrine sides. What's actually happening?
Robert Lustig, MD: We really need to break the pancreas apart into its two pieces, the exocrine and the endocrine. Let's do the exocrine first. When you eat, you need enzymes to break down the food. The stomach makes some of them and then the pancreas makes the rest of them. The pancreas makes them in cells called acinar cells, and those then go via the pancreatic duct which exits into the small intestine at a place called the sphincter of Oddi in the duodenum. It can mix with the food from the stomach and then it can digest all of the nutrients and be able to chop up, for instance, proteins into their component amino acids and triglycerides into their component fatty acids so that they can be absorbed, appropriately packaged, and then delivered to wherever they need to go---usually the liver, sometimes muscle, sometimes brain.
Bottom line is, if you don't have those enzymes, you can't digest your food. It's just that simple. We know this because there are disorders of the pancreas like cystic fibrosis. In fact, that's where the term cystic fibrosis comes from---it's cystic fibrosis of the pancreas. We always think of cystic fibrosis as a lung disease, and it is, but in fact the term cystic fibrosis was coined because of what it looked like under the microscope when looking at the pancreas. They can't make the enzymes and so they are unbelievably malnourished and have to take pancreatic enzymes by mouth to basically do the job that the pancreas would do but it can't.
The acinar cells make the enzymes. The enzymes travel through the pancreatic duct and end up in the intestine where they do their business.
Mike Haney: What signals those acinar cells to create and release those enzymes?
Robert Lustig, MD: Components of food and specifically hormones that the GI tract are making that then tell the pancreas what to do. That becomes an endocrine phenomenon because it's going through the blood to communicate that information. So it's a very complicated set of phenomena that occur all at the same time.
That's the exocrine part. The endocrine part, the hormone part---nestled within those acinar cells are sets of what are known as islets. They're islets of Langerhans and you can only see them on microscopy when you stain for them. They are little microarchitectonic marvels because every type of cell in that islet, there are three types, have to be touching each other because there's information going back and forth between them.
The three main hormones that the islet secretes are insulin, glucagon, and somatostatin. Insulin lowers your blood glucose. Glucagon raises your blood glucose. Somatostatin is the brake on both of them. I'm very interested in that because how I got into obesity research was by giving an analog of somatostatin called octreotide to suppress insulin release at the level of the pancreas to lower insulin levels to induce weight loss in kids with brain tumors. So I have a real affinity and interest in that story.
Obviously, when the beta cells of those islets are attacked, you end up with type 1 diabetes. When those beta cells can't make enough insulin for whatever reason, you end up with type 2 diabetes. When you have a problem with glucagon, usually you don't have enough glucagon and that will end up giving you hypoglycemia. Glucose control is dependent on that islet of Langerhans working properly. To be honest with you, that's what we do at Levels---we basically monitor what the pancreas is doing. We just use the glucose level as the readout.
The constant balance of alpha, beta, and delta cells
Mike Haney: I know sometimes we tell a pretty simplified version of the story---food comes in, glucose goes up, insulin goes up. We don't really talk about glucagon that much. My understanding is that there's really a constant balance. It's not that insulin is high and glucagon is gone and then 5 hours later your glucagon comes in. They're always sort of in balance. All three of these cell types, your alpha, beta, and delta cells are always releasing some combination of these three hormones, right?
Robert Lustig, MD: Absolutely. That's correct. In general, glucagon is not a problem until it's not there. Then it's a problem and you find out the hard way. Glucagon will raise your blood glucose when you become hypoglycemic. It is one of the emergency mechanisms. There are three emergency mechanisms that the body uses to try to raise the serum glucose so you don't die from blood glucose going too low.
One is glucagon, which works on the liver to release whatever glucose is stored as glycogen into the bloodstream, just to flood the zone with glucose. The second one is the sympathetic nervous system, the adrenergic nervous system releasing norepinephrine, which also causes the release of glucose, usually from other organs like muscle. Adrenaline will stimulate other organs to release their glycogen. Finally, the third is cortisol. What cortisol does is it engages in this phenomenon called gluconeogenesis. It will turn proteins or amino acids into glucose, or even glycerol into glucose, in order to raise the blood glucose.
So you have three counter-regulatory hormones to deal with hypoglycemia. We don't talk much about hypoglycemia, but hypoglycemia is a real issue. In fact, I am an adviser to a nonprofit called the Hypoglycemia Support Foundation. It turns out that lots of people have reactive hypoglycemia. They don't know it. They don't understand it. They just know that they feel lousy about one and a half to two hours into a meal. They don't understand what the problem is. Almost assuredly, it's because of a problem of these counter-regulatory hormones, the fact that insulin's lasting too long and glucagon's not coming up to meet the moment. It's actually very important for routine physiology to understand how these work.
Mike Haney: How is that dance of those three hormones regulated?
Robert Lustig, MD: Those three cell types, the alpha, the beta, and the delta cells are all touching each other. There's information, there's communication going on directly in what we call a paracrine fashion from one cell to another that's actually making changes in the output of that next cell. When glucagon's high, that means insulin's going to get shut down because glucagon is going to be the brake on insulin. Insulin's also the brake on glucagon. So you have that reciprocal relationship and then somatostatin's the brake on both of them. It's a complicated dance to say the least.
When you have problems with the endocrine part of your pancreas, you're going to get into all sorts of trouble, whether it be diabetes with high blood glucose or reactive hypoglycemia with low blood glucose. You will feel it.
Why we measure insulin but not glucagon or somatostatin
Mike Haney: Why don't we measure glucagon and somatostatin? Why do we always just measure insulin?
Robert Lustig, MD: Glucagon only means something when your blood glucose is low. You'd have to catch it when the blood glucose was low. What are the chances that you're going to be in the emergency room getting a blood draw at that exact moment when your blood glucose is low? It wouldn't tell you anything in the face of a normal or high blood glucose. It's one of those things that only occurs in the emergency room and only in the face of hypoglycemia.
Often what ends up happening is you didn't even know the patient had a low blood glucose. You find it out after, and then you ask, "Did you draw the glucagon tube? Did you get the red-top tube?" That's the very important tube in the emergency room that you get just in case. Once you find out, you end up getting the glucagon out of that if you were smart enough to get it.
We measure insulin because understanding something about our insulin level and our insulin response will tell us something about beta cell function. But the same is not necessarily true for glucagon or somatostatin. We're not trying to uncover alpha or delta cell dysfunction. There may be, but you're not going to see it from a biomarker. At least for glucagon, it has to be when the blood glucose is low. It won't mean anything any other time.
For insulin, it does mean something, at least when you're fasting. If you're fasting and insulin's high, that means that your insulin is not doing its job and your pancreas has to make more to make the liver do its job. That means you are insulin resistant. That means you have one component of metabolic syndrome and possibly are on your way toward diabetes. So there it is a biomarker and it works as a biomarker and it makes sense to draw it.
Mike Haney: What's going on with your glucagon and your somatostatin when you're getting the hyperinsulinemia?
Robert Lustig, MD: The reason that you're hyperinsulinemic is because your glucose is high. That's why your pancreas is making extra insulin to try to bring your glucose down. If your glucose is high, your glucagon doesn't need to go up because it's already high. Your glucagon only goes up when your plasma glucose falls. So there's no reason to measure it.
Type 1 diabetes: an autoimmune attack on beta cells
Mike Haney: Let's talk a little bit more about some of the things that can go wrong in the pancreas. Maybe diabetes is a good place to start because that's the obvious one. We've got type 1 and type 2. I also want to talk about type 3c to the extent that that's interesting. Let's talk about what's going on in the pancreas, what's going on in the beta cells in type 1 diabetes.
Robert Lustig, MD: In type 1 diabetes, you have these cells in the islets called beta cells. For reasons that are still unknown and we're just still trying to figure out what this is all about, the body decides for its own reasons that are unapparent to us that those cells don't belong, that somehow those cells are foreign. They aren't, but the immune system screws up. It makes a mistake. It decides something that is self, that you were born with, all of a sudden is not self, is in fact a foreign invader. This is the basis of all autoimmune disease.
What causes autoimmune disease? There are a lot of autoimmune diseases. There's Hashimoto thyroiditis, there's multiple sclerosis, there's diabetes, there's Crohn's disease---pick an organ, there's an autoimmune disease to go with it. We don't know what causes any of them still. We have some ideas. We have some clues.
One thing that we know is that T cells, which are part of the immune system that recognize foreign invaders, screw up. We know that there's a dysfunction of T cells and those T cells then tell the rest of the immune system, "See that protein? That's a foreign protein. It must be on a foreign body, whether it be a virus or a bacteria or a microplastic or something that doesn't belong. Immune system, go kill it." And the immune system then does. If that's a beta cell, you end up with type 1 diabetes.
That part we know. So we know the how. We don't know the why. Why does this happen is anybody's guess even to this day. One thing we do know, I think, maybe it's still a little controversial, but I think we know this---these foreign antigens, these proteins that ultimately T cells get turned on to, are coming in through the gut due to gut inflammation, due to what we call leaky gut. We've talked about that in the past as well because leaky gut is one of the primary drivers of metabolic syndrome.
If your gut, which is supposed to be a barrier to the stuff that's in the lumen of the gut, it's not supposed to end up in your bloodstream---if your gut can't protect you because it's dysfunctional, then proteins or peptides in your gut will make their way into the bloodstream. Then the T cell will recognize it as foreign. You will end up with a clone of T cells against that protein and then you're off to the races in terms of destruction. Usually it takes three to five years to destroy the beta cells in the pancreas once the process has gone on.
The good news is we can actually monitor that because we have biomarkers for that destruction. We have antibodies that we can measure in the blood---IA2, anti-GAD 65, zinc transporter 8, things that we can see that will actually predict if and when a patient will get type 1 diabetes. We even now have a medicine that can block that T cell phenomenon by basically boosting regulatory T cells. This is called teplizumab. We worked on it here at UCSF. My colleague Dr. Steve Gitelman basically headed that project up and that is now a medicine that's on the market for delaying the onset of type 1 diabetes.
Mike Haney: That's pretty new, right? In the last few years.
Robert Lustig, MD: About three years. Yeah.
Mike Haney: Why is type 1 so often diagnosed in youth? Why is it that---I've never quite understood this progression of it. It's often diagnosed in youth but often in sort of adolescence, right? Why does it take your body 10, 15 years to figure out that it has an autoimmune reaction to your own beta cells?
We've seen type 1 diabetes in as young as 6 months of age. You can see it anywhere from six months to 85 years.
— Robert Lustig, MD
Robert Lustig, MD: Hell if I know. What I can say is that we've seen type 1 diabetes in as young as 6 months of age. By the way, there's a neonatal diabetes, which is not usually immune-mediated. There's transient neonatal diabetes of the newborn. Sometimes it can be permanent, but that's a different phenomenon. That's usually a genetic phenomenon. But you can see type 1 diabetes anywhere from six months to 85 years. You can see it in adults. It has a different name in adults. They call it LADA---latent autoimmune diabetes of adults. But it occurs.
Why it occurs around the time of puberty, why it occurs in that 10-year-old age group mostly, is I think still one of those questions for the ages. We still don't know why.
Mike Haney: From a diagnostic perspective, typically the way you're going to start to understand that you might have developing type 1 diabetes is symptomatic. It's not going to show up in your normal blood test that you're getting, is that right?
Robert Lustig, MD: Usually. Usually what happens is that your beta cells start getting destroyed, start getting destroyed, start getting destroyed and they knock them down, knock them down, knock them down. But the insulin-secreting cells that are still there will just release more insulin. So it will maintain your blood glucose. You still don't know that you've got the problem until you finally run out.
When you get to 90% destruction, when you only have 10% residual, that's when you don't have enough insulin to be able to keep that blood glucose under control. Then your blood glucose starts to go up. The usual way that you find that out is you start ending up in the bathroom every two hours through the night. If you're lucky, you get to the doctor, they measure your urine glucose, it's high, they measure your serum glucose and it's high and now you get diabetes. If you're not lucky, then you'll end up in the ICU in diabetic ketoacidosis, and that would be really bad.
So that's type 1 diabetes.
Type 2 diabetes: mitochondrial dysfunction and beta cell exhaustion
Mike Haney: Let's talk about type 2 in relation to the beta cells in the pancreas.
Robert Lustig, MD: Type 2 is a different phenomenon entirely. It is not autoimmune. Has nothing to do with autoimmunity. What it has to do with, I've said this on our podcast before, it has to do with mitochondrial dysfunction.
The cells of the body have mitochondria. Every cell has mitochondria. The cells that work the hardest have the most mitochondria. Those are the brain and also the glands and the muscles. Those are the three types of tissues that need the most energy and therefore have to manufacture the most ATP, adenosine triphosphate, and so they have to have the most and the most functional mitochondria.
Now if your mitochondria are working and they're doing their job, you can make enough ATP for whatever your needs are, whether it be physical, whether it be cognitive, whether it be cardiac, whatever it is. You can make enough ATP for your needs because your mitochondria are working. If your mitochondria need a boost, the sympathetic nervous system will give them a boost and will tell the body to make more mitochondria so that you can make more ATP. So you have a negative feedback pathway there so that you never run out of ATP.
But what if something poisons your mitochondria? What if something keeps your mitochondria from working properly? Well, turns out air pollution, microplastics, chemicals in the environment, chemicals in the water, chemicals in the food, obesogens, fructose---my favorite---all impact on the mitochondria and cause them to work less well.
When that happens, now your cells can't make as much ATP as they need to. That causes two problems. The first is you don't have the energy you need, so you feel lousy. The second is you have a lot of substrate that needs to get through that can't because your mitochondria are screwed. Something has to happen with the excess substrate that can't make it through on the front end. What happens is that gets turned into fat. In this case, the substrate we're talking about is glucose.
Mike Haney: Glucose gets turned into fat.
Robert Lustig, MD: Exactly. And then that fat has to make its way out of the liver or the muscle, wherever. That fat can contribute to high triglyceride levels, which is a sign of poor mitochondrial function, or that fat will precipitate in the liver as a lipid droplet. Now you've got fatty liver disease.
In either case, the point is your mitochondria being defective or dysfunctional tells the pancreas through mechanisms we still don't understand what the reflex is that I need more insulin to deposit this extra energy that I can't turn into ATP. So your insulin rises because your liver can't handle the excess. So your fasting insulin rises. Your high fasting insulin is a marker, a biomarker for defective mitochondrial function.
Now that keeps going on, keeps getting worse, keeps getting worse. Ultimately, the pancreas makes so much insulin that it starts to actually cause those beta cells to either overwork, overexhaust, or die. When that happens, now you don't have enough insulin. Now you've got insulin deficiency on top of insulin resistance. Now you have diabetes.
Mike Haney: So both type 1 and type 2 ultimately are a reflection of beta cell death, beta cell dysfunction, but coming from two different places.
Robert Lustig, MD: Coming from two completely different places. Type 1, the immune system. Type 2, metabolic problem.
Challenging the traditional carbohydrate-insulin model
Mike Haney: In that narrative, you're taking in---there are things that are essentially poisoning your mitochondria, causing them to not function as well. You're not making as much energy. You're using that glucose that you're bringing in through the natural processes of eating. Glucose builds up, has to go somewhere, and that's leading ultimately to too much insulin. Beta cells overwork, beta cells get dysfunctional. I feel like the traditional story we tell about what leads to insulin resistance is the simpler one of you just eat too much glucose. You just have too many carbs coming in. You got consistently high glucose, lots of insulin release. Cells become numb to insulin.
Robert Lustig, MD: There's no question that carbs drive insulin. That's old news. As we've talked about, there are two models for obesity. There's the energy balance model that you eat too many calories, and there's the carbohydrate-insulin model that says you eat too many carbs. Turns out they're both right and they're both wrong. The reason is not that they're right or wrong. It's that they're downstream of the actual problem. The actual problem is the dysfunction of the mitochondria in the first place. That's where the real problem is. So the question is what's causing that? And that's upstream.
We know now that the only way to prevent disease is by working upstream. We have to actually assess and ultimately treat what's wrong with the mitochondria. Whether it's the too many calories because your reactive oxygen species in your brain are making you eat more, which it does, or it's because of the reactive oxygen species in your pancreas telling you to make more insulin, which is driving the weight gain, which then drives insulin resistance further---it's sort of irrelevant. The point is you got to fix the mitochondria where the problem is. And we haven't. We have not.
This is what I'm devoting my retirement to understanding. I just gave a talk a week and a half ago at Auburn University on exactly this point. The fact is that until we solve that problem, we're not going to get anywhere. Now, how do you solve that problem? Well, it turns out there are a lot of mitochondrial toxins as we talked about. Some of them are in the food. Some of them are in the air. Some of them are in the water. Some of them are ionizing radiation that you can't get away from either. The one we could fix tomorrow is fructose. The one sugar that we could fix tomorrow and no one would miss it. That's what I think we should start with. But other people will think otherwise.
What insulin and glucose markers tell us about pancreatic function
Mike Haney: Getting back to this marker-centric view of all this, we talked a little bit about the diagnosis of type 1 and how that typically comes about. What am I learning about my pancreatic function from my insulin and my fasting glucose and my A1C or maybe even an OGTT if I get that?
Robert Lustig, MD: You're probably learning more about your liver by looking at your insulin because the liver is the primary target of insulin action. When your insulin is high, it's usually because your liver has the problem, not your pancreas. So you're actually learning more about your liver.
Now, if you get to the point where your pancreas is starting to fail and can't produce enough insulin, then you want to be looking at other markers. Not insulin per se, but you want to look at other markers. What markers do you want to look at? Well, you want to see whether or not your beta cells can release insulin in response to a glucose load.
The problem is you don't know if the insulin was hanging around from being insulin resistant or it's being made new by the pancreas. That's kind of a problem. So insulin won't answer that question because it doesn't tell you if it's old or new. You need something that tells you new. That is C-peptide.
C-peptide is a piece of the insulin molecule that gets cleaved out in order to make the mature insulin. The way your beta cells work, for better or worse, is they make a pro-hormone and that pro-hormone is called pro-insulin. Pro-insulin has very little activity of its own. But what happens is there are two disulfide bridges that have to be formed and then there has to be a piece that has to be cut out. That's called C-peptide. When you do that, then you make the mature insulin molecule. Then that can be released and that will have activity at the level of the liver and elsewhere in the body.
If the pancreas is stressed because the blood glucose is high, because you're insulin resistant, because things are not going well, your pancreas tries to get that blood glucose down any way it can. What it does is it releases everything it can, including pro-insulin. So you can measure pro-insulin in the blood. There's a pro-insulin assay. You can see hyper-pro-insulinemia. That will tell you that you've got a problem with your beta cell because your beta cell shouldn't be releasing pro-insulin. It should be releasing insulin.
The C-peptide will tell you, "Here's how much reserve I've got. Here's my capacity for being able to make insulin properly." So those two are biomarkers that will tell you that your beta cells are on the way out. You can use those, but insulin itself won't tell you.
Mike Haney: From a patient perspective, I go and I see some of these metabolic markers are high, insulin in particular. That's not necessarily telling me I've got a problem with my beta cells.
Robert Lustig, MD: No, not yet.
Mike Haney: When is it starting to tell me? When as a clinician would you start to look at some of these other tests to go, "Oh, maybe this is a beta cell problem"?
Robert Lustig, MD: When you end up with high blood glucose in response to a glucose load, so glucose tolerance---the point is you should be able to make enough insulin to bring your blood glucose back into range. But if you've got impaired glucose tolerance, not frank diabetes, but on the way, that's usually telling you you have a secretory defect. So you might want to look at C-peptide, you might want to look at pro-insulin, depending. So that would be when I would suggest drawing those. But those are only valuable at the time of the high blood glucose.
It's all about when you draw it. You can't draw glucagon unless the blood glucose is low, and you can't draw a C-peptide or pro-insulin unless the blood glucose is high. So you have to know what the blood glucose is before you draw it. And usually you don't know. So it's another reason why these biomarkers are problems.
Type 2 diabetes can be reversed
Mike Haney: Is it true that one of the things we've learned in the last however many years is that once you've got burgeoning type 2 diabetes, you start to get some beta cell dysfunction. That can actually be reversed. We can actually make beta cells work again if we reduce the carb load, if we reduce the stress on them, if we improve the mitochondria.
Robert Lustig, MD: Yes. Reducing the carbs will do that and losing weight will do that and reducing the mitochondrial toxins, whatever they are, will do that. So yeah, we have plenty of data to show that you can do that. One way we do that is the ketogenic diet. The ketogenic diet basically takes the glucose away, takes the fructose away. Remember, fructose is a mitochondrial toxin. It inhibits three enzymes that the mitochondria need to be able to generate that ATP. So a ketogenic diet means no sugar, no fructose. That's a great way to start to see whether or not you can reclaim your mitochondrial function and maybe turn this whole thing around.
There's no doubt, there is absolutely no doubt that type 2 diabetes can be reversed because those beta cells are still there. They're not dead. They're dormant. They're not happy. They're basically running for cover under the onslaught of all this glucose that it can't handle. So they involute, but you can bring them back. They are not dead dead. That's an old wives' tale that was told by diabetologists for 40 years, which we now know is not true.
Mike Haney: This seems like a really important distinction to underline. In type 1, we can slow the progression, but it is an autoimmune reaction that is killing the beta cells and once they are dead, they are not coming back. But in type 2, they go dormant, which means that there is a level of reversal that you can get. You can get back beta cell function that you have lost.
Robert Lustig, MD: Exactly right. And that's why it's so important to monitor it, to know what's going on, because you could potentially recoup that capacity. We used to say that type 2 diabetes was a chronic, progressive, inexorable, non-stop destruction of pancreatic beta cells over time. Every single thing I said is garbage. It's all not true. None of it's true. It can be reversed. You have to take away the toxin that caused it. And there are many toxins that can cause it. Which one for any individual patient? That gets complicated. But if you do them all, it should work. Great way to start: get rid of the substrate.
Amylase and lipase: markers of pancreatic enzyme function
Mike Haney: We've talked a lot about the endocrine side. Let's talk about the exocrine markers that are there. The two that are in the blood tests that we're offering that you often see in these expanded blood tests are amylase and lipase. Remind us what those two do. They have different functions and different enzymatic functions. What are they doing in the body and why are we testing them?
Robert Lustig, MD: We're talking about now the exocrine pancreas, those pancreatic acinar cells. We're not talking about the islets anymore. We're talking about the cells that make enzymes that help you break down your food.
The pancreas makes enzymes that break down protein into individual amino acids. It also secretes an enzyme that breaks down starch into its component glucose molecules. That's called amylase. And it also secretes an enzyme that breaks down fats into its component fatty acids. That's called lipase. So amylase and lipase are two enzymes that the pancreas makes, go down the pancreatic duct, get released into the duodenum in order to work on the food, in order to be able to digest the food so that you can absorb the stuff you need.
When your pancreas is faced with a starch load, it will make amylase. When it's faced with a fat load, it will make lipase and will dump it in. It should dump it into the pancreatic duct. It shouldn't dump it into the bloodstream. So when you eat, your amylase and lipase go up very little unless you have a problem, unless those pancreatic acinar cells, those exocrine cells that are making those enzymes, unless they are damaged.
Unfortunately for us, there are a lot of things that can damage those pancreatic acinar cells. The main one: alcohol. Alcoholic pancreatitis. Alcohol can cause acute pancreatitis and can cause chronic pancreatitis. Pancreatitis is sort of part and parcel of alcoholism. Pretty much everyone who was a chronic alcoholic---and that's 10% of the US population and another 10% are binge drinkers---have had some bout of pancreatitis. Abdominal pain, vomiting, turning yellow due to jaundice, whatever. It's a bad scene.
The way you know that that's what's going on is you measure amylase and lipase in the blood. They will have spiked because of the damage to the cells in the pancreas and will spill it into the bloodstream.
Mike Haney: The damage means it's not going where it's supposed to.
Robert Lustig, MD: Right. It's not going into the intestine. It's going into your blood.
Mike Haney: So it's actually making too much of those enzymes. It's just putting them in the wrong places.
Robert Lustig, MD: Exactly. Because they're damaged. Exactly. And then they're not doing their job. Not only are they not doing their job, but they're actually then working on the glycosylation on your cells. There are glucose molecules on each cell called glycosylation. That's bad. In addition, lipase will damage membranes. These are not things you want floating around in your blood. You want them in your intestine, not in your blood.
You can measure both amylase and lipase in the bloodstream. Normally, amylase and lipase should be anywhere from 40 to 140 or maybe even 160. Lipase is specific for the pancreas. Amylase is made in two places. It's made here in the salivary gland because it's working on the starch that you consume right away to turn it into individual glucose molecules, and also in the pancreas.
If your amylase goes up, you don't know if it's your salivary gland that's got the problem, like a virus or a salivary stone, or whether it's your pancreas. The thing that tells you is the lipase. The lipase is the specific marker for the pancreas. The amylase is the non-specific marker for the pancreas.
Mike Haney: Does it happen that you would then maybe get an out-of-range amylase reading without pancreatitis-like symptoms?
Robert Lustig, MD: Exactly. If you have pancreatitis, you should have a high lipase. I've never heard of a pancreatitis without a high lipase. That's your better marker. But if your amylase is high and you're not having symptoms, it might be something else. Then you should just recheck.
But if you've got pancreatitis, they'll be up in the hundreds. They'll be sky-high comparatively. And that will tell the doctor in the emergency room, "Hey, this person has pancreatitis." And if you have pancreatitis, you got a problem. You got a big problem. You don't have a little problem. You got a big problem.
The reason you have a big problem is because those enzymes that are leaking out into the bloodstream can do damage to cells. They can do damage to the pancreas. They can make your pancreas not work. They can make your pancreas fibrose so that it won't work in the future. It can basically dissolve pancreatic cells so that you will have less pancreatic reserve later on. You won't be able to make the enzymes that you need to digest your food. You may not be able to make the hormones that you need to regulate your blood glucose.
So chronic pancreatitis can result in diabetes also because the exocrine output is damaging the endocrine output because they're right there together. This is why this no man's land is so problematic because you got these two completely different phenomena, different functions, in the same space. This is not good.
Treating acute pancreatitis
Mike Haney: If you have acute pancreatitis, you don't want it to become chronic pancreatitis.
Robert Lustig, MD: So you have to be admitted to the hospital. You have to get a nasogastric tube. It has to stay there and you're not going to be able to eat anything probably for at least two weeks, if even then. Might be longer, might even be up to six weeks, while you basically take that inflamed pancreas and put it to rest. And hopefully you didn't develop fibrosis. You didn't develop a pseudocyst, which is basically a conglomeration of fluid inside the pancreas that could burst at any moment and cause enormous pain and difficulty and possibly even death.
If you've got a pancreatic inflammation, you got big-time problems. You need to protect your pancreas. And people don't even know what it is.
Why alcohol is so toxic to the pancreas
Mike Haney: Alcohol's kind of the big kahuna in terms of pancreatic damage. Why is alcohol so damaging to the pancreas? Why does that beat up the acinar cells?
Robert Lustig, MD: Alcohol is ethanol, ethyl alcohol. What happens is it gets turned into an aldehyde, acetaldehyde. Aldehydes are extremely reactive. They're extremely toxic. Formaldehyde, for example, you know that, but acetaldehyde is just as dangerous. What it does is it basically binds to proteins. It binds to lipids. It causes damage. It basically kills cells.
The goal is not to make aldehydes, and alcohol goes straight to an aldehyde every time. So we have a limited capacity to metabolize alcohol because we have a limited capacity to clear that acetaldehyde. The reason it happens at the pancreas is because pancreatic cells are very fragile. They're very susceptible. You don't want that.
When alcohol or something else damages the acinar cells, you've got your enzymes then spilling out into the blood, which is problematic. The only way to resolve that in an acute case---that's what we call acute pancreatitis---the only way to resolve that is to essentially not make your acinar cells work at all for a while.
Mike Haney: Why is a high-fat diet often part of a treatment for pancreatitis?
Robert Lustig, MD: Oh, no, no, it's a low-fat diet.
Mike Haney: Low-fat diet. Okay.
Robert Lustig, MD: Low-fat diet. There you go. A high-fat diet is what causes it. There you go. I know it has something to do with fat.
We don't understand this yet. I don't think we've gotten a handle on this yet, but if you have a high triglyceride level in your bloodstream, that triglyceride can basically end up in the pancreas. So not only will you have this phenomenon called non-alcoholic fatty liver disease, but you can have this phenomenon called non-alcoholic fatty pancreas disease.
We saw this in our patients with metabolic syndrome, our pediatric patients with metabolic syndrome. We set the windows on the MRI machine to be able to see the pancreas and we could actually see the fat in the pancreas. And when we got rid of the sugar in their diet because that reduced their triglyceride, their non-alcoholic fatty pancreas got better.
We know that the fat that's in the blood ends up taking residence in the pancreas. We don't know why and we don't know why it's a preferential place for fat to want to hide, but that's a bad idea. You don't want to have fatty pancreas because it in and of itself can stimulate this acute pancreatitis. It's one of the reasons why when you get your lipid profile, if your lipids are super high, your doctor will call you up and put you on fish oil in order to get those triglycerides down so that you don't get pancreatitis.
Chronic pancreatitis
Mike Haney: Is chronic pancreatitis just an accumulation of bouts of acute, or acute that has not healed, or is there a different pathogenesis to what we call chronic pancreatitis?
Robert Lustig, MD: There are enzyme defects like PRSS1 that can cause chronic pancreatitis in kids. We take care of them. This is one reason why we do pancreatic transplants in kids with genetic chronic pancreatitis because it's affecting their growth. It's affecting their life. They can't go to school because they're always in pain. It's a disaster. But they have a genetic reason, in general.
We are trying to maintain the pancreas in the best condition it can be in because when your pancreas is sick, whether it's acute or chronic, you're in trouble. The goal is to never---to prevent the acute, and if you have the acute, prevent it from becoming chronic. That's the calculus here.
Mike Haney: I think you mentioned earlier that thinking back to the blood test part of this, it is unlikely that I'm going to go to get my blood test, see a very high amylase and lipase without any accompanying symptoms. If I've got pancreatitis, I sort of know it and then the amylase and lipase are kind of confirming it for the clinician.
Robert Lustig, MD: That's right. That's right. There's no point in measuring your amylase and lipase as a standard biomarker because it will be normal as long as there's no pancreatic damage. The question is what is the sign of pancreatic damage and the answer is pain, vomiting, jaundice. That's the sign of pancreatic damage. So it's a biomarker for the doctor. It's not necessarily a biomarker for you.
Mike Haney: If I've got some of those symptoms and then I see the high marker, that's a sign that there might be something going on there.
Robert Lustig, MD: Yep. And then you are admitted to the hospital, NG tube in, and good luck to you.
Why pancreatic cancer is so deadly
Mike Haney: The last condition I want to talk about, even though it's not necessarily directly related to markers, but is the one that we think about when we think about the pancreas, is pancreatic cancer. Why is pancreatic cancer such a death sentence?
Robert Lustig, MD: We don't know. Pancreatic cancer is resistant to every chemotherapy we've thrown at it. And I can't explain why, but it just is.
One thing that's very interesting about pancreatic cancer is that many pancreatic cancers can turn fructose into glucose. Normally, fructose only goes to mitochondria in the liver. But there is an enzyme that can turn fructose into glucose. That enzyme is called transketolase. It will turn fructose into glucose, but only in the cells that have the transketolase. Well, pancreatic cancers have the transketolase.
If that's the case, if you're giving sugar to a patient with pancreatic cancer, you are feeding the cancer because the rest of the body can't use it, but the cancer can. That's kind of a dumb thing to do. This is work from Anthony Heaney at UCLA, who demonstrated this. Pancreatic cancers are notoriously drug-averse and they basically generate their own glucose source that you have a hard time taking away.
Those are two reasons why pancreatic cancer is bad. The other reason pancreatic cancer is so bad is because it's in that no man's land. Usually you end up with stage 4 pancreatic cancer before you even know you have a problem. And by that time it's usually too late because pancreatic cancers seed into the liver and into other tissues very rapidly. So catching a pancreatic cancer early is just stroke of luck. So these are all the reasons why pancreatic cancer is so bad.
Mike Haney: Is there a relationship between the other conditions we've talked about---pancreatitis and diabetes and cancer? Does having those make me more likely to develop pancreatic cancer?
Robert Lustig, MD: Yes. Metabolic syndrome increases your risk for pancreatic cancer. Alcohol increases your risk for pancreatic cancer. Yeah. So anything that damages the pancreas increases your risk for pancreatic cancer.
Mike Haney: It's basically creating an environment in which those tumors can start to grow.
Robert Lustig, MD: Exactly. Right.
How to protect your pancreas
Mike Haney: Maybe where we'll end it, so as not to end it on pancreatic cancer, is we've talked about some of these things in specific instances, but maybe we'll just wrap up with what can we do to take care of our pancreas? Everything's normal and healthy. We don't have anything diagnosed but we don't want to get there. What are the lifestyle habits, the foods, the diet that are going to keep the pancreas working?
Robert Lustig, MD: Get rid of the toxins. The pancreas is unbelievably susceptible to these toxins. Anything that causes mitochondrial dysfunction is going to cause pancreatic dysfunction for the reasons we talked about. Mostly it's going to cause liver dysfunction, which is going to cause the beta cells to have to work harder. So that's one way to take care of your pancreas is by helping your liver.
But in addition, the toxins that directly affect the pancreas---alcohol being sort of chief, number one on the list. But having a high triglyceride level, not letting that wander off without taking care of it, is extremely important as well. Basically, pancreas care is preventative care. There is no medicine for the pancreas.
Mike Haney: Lifestyle stuff. We want to eat a whole foods diet. We want to avoid excess, particularly excess fructose and excess sugar. Keep the triglycerides down. I assume sleep, stress, exercise, all of those same markers that are going to support the rest of our system.
Robert Lustig, MD: All the above. The point is there's no medicine that gets there. The goal is take care of it because I guarantee you if you don't take care of it, you're going to be really miserable. Nothing is more painful than acute pancreatitis except maybe a kidney stone.