Your Gut Microbiome And Type 2 Diabetes Management

Orville Kolterman, MD

Thank you.

Beverly Yates, ND

We’re glad to have you here. Would you give us just a little overview of your background and your work with Pendulum?

Orville Kolterman, MD

It’s been my pleasure. I’m an internal medicine doctor, trained as an endocrinologist, and have spent my entire professional career working in the area of diabetes, with a focus on Type 2 diabetes. I was on the faculty at the University of Colorado and the University of California, San Diego, before moving to the biotech industry, where I worked with a company called Elin Pharmaceuticals, developing peptide-based drugs for the treatment of metabolic conditions. We were the company that brought the first GLP1 analog, to market, and very soon Elin was purchased. It was bought out in 2012, and I thought I was going to retire, but I became bored and was approached by Colleen Cutcliffe, the CEO of what’s now Pendulum, about diving into the microbiome, which I agreed to do and spent ten years as a Chief Medical Officer, still enjoying every minute of it.

Beverly Yates, ND

Now, that’s great. I’m glad that Colleen Cutcliffe, the CEO, is connected with you. Your background is so specific and wonderfully rich for exactly what Pendulum’s doing in its mission to help people have better glycemic regulation and better blood sugar control and results. Would you share with us that you touched a little bit on that microbiome topic, we’re going to explore it more in-depth here because it is central when we think about how the body regulates blood sugar, promotes insulin sensitivity, and gets a better response to the interaction of glucose and insulin? The gut metabolic axis, it’s an exciting, emerging, and growing area of study. A lot is going on. We know a lot, and we’re learning even more. I don’t know that everything has been discovered. I doubt that yet. How does the gut play a role, specifically with metabolic diseases like Type 2 diabetes?

Orville Kolterman, MD

There are a couple of different ways that the gut microbiome impacts this. With the adoption by our society of the so-called Western diet, which is low in fiber and high in refined carbohydrates overloaded with simple sugars, the dietary fiber has gone missing from that diet, and the bacteria that make up a healthy microbiome rely upon those fiber sources as their energy supply. If you starve the microbiome, the bacteria that live off of those fibers diminish in amounts and sometimes disappear completely, that has two major, and I say major because we’re learning more and more every day. I expect that there will be even more connections that will be worked out over the coming years. But the two that play critical roles that we know about today are the bacteria in the microbiome that digest or ferment the dietary fiber and produce short-chain fatty acids. One of those short-chain fatty acids is butyrate, which is important because it’s an energy source for the cells that line the islet line and the intestinal tract. But it is also a signaling molecule that binds to the cells. In the gut, this would be the secrete GLP-1, and GLP-1, as you just pay attention to the lay media today, is critically involved in the regulation of metabolism, particularly as it relates to glucose control, and also plays a major role in terms of astrocyte control, satiety, and the maintenance of a healthy weight. The other axis that is well worked out is a specific bacteria in the microbiome, namely akkermansia muciniphila. It maintains the integrity of a mucin layer that lies on top of the inner interstitial, or lining, of the gut, and the cellular lining plus this mucin layer forms a barrier that keeps in bad actors that shouldn’t get into the bloodstream in the interior of the gut. They pass through and out of the body. If akkermansia becomes starved, it decreases in amount. I guess with the butyrate producers’ decrease, akkermansia tends to induce a decrease if you lose akkermansia’s ability to maintain that mucin layer, a so-called leaky gut syndrome. What that means is that things shouldn’t get into the bloodstream, get across and get into the bloodstream, various toxins, etc. Those substances create inflammation throughout the body. As it relates to inflammation, it’s become clear over the last five or six years that generalized inflammation plays a significant role in driving insulin resistance throughout the body.

Beverly Yates, ND

Makes sense. All of these things are so interrelated. I’ve always thought that the good news is to find a key area or two to focus on, and you’ll get benefits systemically. But we always have to be able to plant our flag and get some results. What are the two main dysfunctions that occur in the gut microbiome of people who are living with Type 2 diabetes? How is that related to missing bacterial strains? 

Orville Kolterman, MD

You mentioned the fact that there are strains in the healthy microbiome that ferment the dietary fiber and produce these short-chain fatty acids. And again, as it relates to metabolic diseases, butyrate is particularly important. For almost anyone who has components of metabolic syndrome, multiple studies have shown that there is a deficiency of butyrate producers in the microbiome. In parallel, as I mentioned earlier, there tends to be a decrease in akkermansia. Its actual role is that it digests damaged mucin, which interestingly, by akkermansia digesting that damaged mucin and stimulates the formation of new, healthy mucin by increasing the number of mucin-producing cells in the lining of the gut. So those are two things that happen that play a very significant role as they relate to metabolic syndrome and Type 2 diabetes in particular.

Beverly Yates, ND

These things are important. I remember that in the nineties, some research came out around the importance of butyrate, the role of butyric acid, and what goes on for the gut and the gut lining. Then people talked about the interstitial permeability of the cell lining, and then it became more popularly known as leaky gut syndrome. Now here we are in full circle with understanding the impacts, specifically on blood sugar regulation. I think this is a very fertile area for continued growth in research and understanding, and I’m glad for the kinds of products the Pendulum has because they make a tangible, provable, and objective difference in people’s lives. 

So then, how does this gut metabolism access and regulate this glucose metabolism, and what role does GLP-1 play in this process? GLP-1 is something that people are starting to hear more and more about, whether it’s commercial drugs like Ozempic or Mounjaro, Zepbound, etc. What role does it play here? Then, can we optimize GLP-1 production through the gut microbiome in a natural way?

Orville Kolterman, MD

GLP-1 is what’s known as an incretin hormone, which means that it’s stimulated by the ingestion of food and it augments insulin secretion. So if GLP-1 production falters or lags, there’s not adequate production of insulin, which is key to regulating your blood sugar. The GLP-1 is sort of an amazing peptide, which not only impacts insulin secretion but also impacts the rate at which food moves through the stomach. I like to think of it as turning the stomach into or maintaining the stomach as a reservoir that holds food. Instead of just dumping it all into the small intestine for absorption at once, it sort of trickles it in over time. That’s another contributing factor to improving metabolic control. Then it also works centrally in the brain. It turns out that even bigger impacts. There are two parts to this. One is, is that GLP-1 which makes it into the bloodstream can enter the brain. I learned in medical school that there was a blood-brain barrier that nothing got across. 

Beverly Yates, ND

I did too.

Orville Kolterman, MD

Back in our days, you came to understand that in the brainstem there’s this area postrema that has a finer straight blood-brain barrier, which means that it has holes in it that peptides of certain sizes can get across, and they cross over into the area postrema, which is rich in GLP-1 receptors. It then plays a major role in satiety by what happens in the area postrema triggers, a whole network of neural circuits in the brain, all of which are impacting your appetite, control, and satiety. There’s still a lot to be learned about that. It’s the knowledge level that is exploding right now and something that I think is equally important. It ties back to how the microbiome can influence because it’s now known that there are nerve endings in the lining of the gut that have GLP-1 receptors. GLP-1 which is secreted locally can interact with those receptors. Those receptors trigger signals that travel up, and those nerves end up entering the vagus nerve, which is a sort of superhighway, directly to the brain. Again, when those signals get to the tollbooth, if you will, going into the brain, they sort of trigger several signals that, again, fan out and have an impact on various satiety centers. So that means that GLP-1 has two different lines of attack if you all trigger, and improve metabolic control, satiety, and weight control.

Beverly Yates, ND

Those are important relationships. I think that one of the things I’ve heard people commonly express is that they talk about food noise, or they can’t stop thinking or obsessing about food, or they feel like they’re never full, that they’re always hungry, things like that. This GLP-1 peptide relationship in the body makes a huge difference in whether or not someone can be at peace with food or if they’re just going to struggle. So whatever we can do to help promote GLP-1 functionality is going to be a good thing for human health. It’s a place where we have to win because we see profound metabolic changes happening in people. many more people with pre-diabetes, Type 2 diabetes, which is what affects the brain and dementia, and Alzheimer’s, type 1 diabetes, showing up in adults, Type 1.5. This is just a moment in human history. We have got to have more answers. I appreciate you explaining this. 

Orville Kolterman, MD

Another aspect of that that I think is going to be big is that you mentioned people making peace with food. There’s some very intriguing literature evolving as we speak, showing that the GLP-1 impacts not only the satiety centers but also the craving centers of the brain. For me, it goes across nicotine, alcohol, and even hard drugs. I think those are going to be very rewarding areas soon. This was a Pendulum. We’re very pleased to see that studies are showing that in akkermansia, there are also impacts and cravings. We’ve just completed a study with akkermansia, where people were provided with akkermansia and used state-of-the-art questionnaires to assess food cravings. The data show that food cravings decreased in over 90% of people. Interestingly or importantly, I think that the stronger the food cravings were at baseline, the greater the impact of the akkermansia.

Beverly Yates, ND

That’s great. I’m a fan of giving people control over their lives through human agency, so they can make good decisions and not constantly be at war with themselves, because that’s kind of what it seems like it is for the person who has the issue.

Orville Kolterman, MD

Which is, one of the sets of questions in that questionnaire target fast food and demonstrate that there was an impact on people’s desire or drive to stop by McDonald’s on the way home. which certainly is a helpful and a health-positive step forward.

Beverly Yates, ND

Highly processed, ultra-refined food is never, ever a good thing for human health. That statement stands alone. Now that we have this context, we’re talking about the gut microbiome and optimizing GLP-1 production, helping people to make peace with food and to be able to have a real tool around success with battling cravings, making good food choices, and wanting to do it right. Because once a person turns that order, they tend to stay there, which is great news. Is there evidence for the use of probiotics and prebiotics in glucose management for individuals who have Type 2 diabetes?

Orville Kolterman, MD

The good news is that, yes, there is. Some of the traditional probiotics have been shown to have some impact. But even with glucose control, these are things like lactobacillus and bifidobacterium. The founders, Colleen, and her colleagues have a background in DNA sequencing. That’s the technology that opened up the microbiome to doing their sequencing work in their former lives. They noticed that there were certain patterns of changes in the microbiome that were associated with Type 2 diabetes. Other investigators were making similar observations, or at least in the literature. It points out that the thing that sets a pendulum apart is that lactobacillus and bifidobacterium are bacteria that can grow in the presence of oxygen. But there are several keystone strains—key players in the microbiome. It turns out that the ones that ferment the fiber are anaerobic bacteria, meaning that they cannot tolerate the presence of oxygen when they’re actively metabolizing. But historically, those are bacteria that have not been leveraged for any kind of use because it is such a challenge to grow them. Colleen and her colleagues noticed that bacteria were decreasing in patients with Type 2 diabetes. So we use that data to target a sweet formulation, no pun intended, that would target the efficiencies that we’ve seen. Those deficiencies were the ability to ferment fiber and produce butyrate. The formulation has three different butyrate-producing organisms in it. Also in metabolic syndrome, as you touched on several times in this conversation akkermansia, is decreased. We were able to develop a method by which you could grow akkermansia and successfully launched all of these strains, once they’re grown, they’re frozen dry in the absence of oxygen. They are stable in the presence of oxygen until they become rehydrated. We’re able to make a powder formulation, a probiotic strain of the capsule, and then it’s available for people to use. We conducted a study on patients with Type 2 diabetes, all of whom were using the common drug Metformin. We demonstrated that the introduction of this was a five-strain formulation that’s now known as Pendulum Glucose Control. There was a significant improvement in terms of glucose homeostasis. There’s also some evidence emerging that it’s probably also beneficial in terms of managing and controlling lipids.

Beverly Yates, ND

It makes sense. These things all go together. They’re hand-in-hand. Many people who have Type 2 diabetes also have unhealthy, unfriendly cholesterol profiles. So being able to get multiple benefits is always going to be good news. That makes sense. From a nutritional standpoint, is there anything that individuals with diabetes can do to improve the state of their gut microbiome?

Orville Kolterman, MD

It turns out that the general recommendations that nutritionists have been making for years are the ones that are beneficial for patients with Type 2 diabetes. The challenge has been that diet tends to be rich in insoluble fiber. Things like nuts, berries, and green leafy vegetables—all things that have a good fiber content. The right kind of fiber to feed the microbiome has been recommended. However, the problem has been that the other half of the team has been missing, and that there are deficiencies in the microbiome. If you put those dietary recommendations together with replenishing the microbes in the microbiome, you as I like to say, get the whole loaf; you give both of them the diet, and then you also get the benefit of replenishing the players that can make maximal use of that dietary fiber to replace the processes that we’ve been talking about so far.

Beverly Yates, ND

Getting the full benefit and helping to restore the integrity of the gut’s lining and mucin production, getting better balance and sensitivity responses, if you will, to the protection of GLP1 peptides in the body, and having them do that goodness that puts people at peace with food, reduces cravings, and benefits their blood sugar. The direct thing that we’re after. But aside from all these other benefits. Are there other things that you’d like to share that have to do with the science and evidence for the use of a symbiotic formulation to improve gut health and assist with glycemic management and blood sugar control in people with Type 2 diabetes?

Orville Kolterman, MD

The term symbiotic means that it’s a combination of a probiotic with a prebiotic, or, in this case, a fiber source that the bacteria live all over and use as an energy source. Pendulum Glucose Control, for example, contains inulin, which is a fiber that the bacteria love to chew on and get their energy from. Inulin comes from Jerusalem artichokes, and if you live in the South and are familiar with having chicory root added to the coffee, chicory root is another good source of inulin.

Beverly Yates, ND

That’s good to know. I was recently traveling in New Orleans, Louisiana, and I was enjoying chicory, and there were a lot of beverages available. I’ve always enjoyed that particular herb. You just gave me one more reason. great. As we look towards wrapping up our interview, I wonder what your thoughts might be about the future trends that might be coming and things people should be looking for. I know that Pendulum as a company is a leader and is looking to grow the audience and its impact. We’re all linked together. My personal goal is to help three million or more people reverse Type 2 diabetes because the trickle-down effects will be amazing if we’re able to accomplish that. As a working team, we’re all going towards the same goal, which is helping people to be healthier and to have their health span equal to their life span because a lot of people are living longer, but they’re not living better. So I feel like we have to close some gaps here around metabolic health, and Type 2 diabetes would be right in the bull’s eye of that whole thing. What are your thoughts about things that you’re either working on as a company or about coming trends that you see since you have such a long background in this work?

Orville Kolterman, MD

Type 2 diabetes is a very significant issue. But the precursor to Type 2 diabetes, pre-diabetes, is that millions of Americans are afflicted with the disorder, many not aware that they have every issue. But I think being able to spread these approaches that we’ve been talking about out into the population as a preventive measure as opposed to reacting to a disease state once it’s established is going to be very important, particularly amongst our young people. Many in the audience will be aware that there’s an epidemic of Type 2 diabetes in adolescence. We’ve been seeing that now for about a decade. It’s been long enough that the data is emerging that show that the Type 2 diabetes emerging at that young age is particularly devastating. In terms of anything, those young individuals seem to be more susceptible to chronic complications, particularly cardiovascular disease. If we don’t do something about that, we’re going to see people who have had significant heart attacks before the age of 30, which is just frightening. and then, as you said, Dr. Yates, and multiple times, that this is all connected. I think we’re going to see that, particularly as it relates to neurodegenerative diseases like Parkinson’s disease, Alzheimer’s, and multiple sclerosis, these things that we’ve been talking about are going to be shown or are being shown to have a major impact on neural health, mitigating some of those neurodegenerative complications.

Beverly Yates, ND

I agree with you, Dr. Kolterman. I see them coming right down the pike because, again, these things are related in the same way you can help to heal something and make it better. You can also make it worse. It’s a seesaw thing, this relationship. I think the more we can talk with people and get the word out and educate them via summits, things that we do on LinkedIn or other places, social media, and YouTube, the more we’re reaching folks. We have got to get the word out because otherwise, our young people are going to suffer, and they’re going to suffer seriously. They’re going to have crummy adult lives if they even live that long. It doesn’t make sense for our health progress to go backward so sharply. But that’s exactly what we’re seeing in real-time. We need to have effective answers in real-time to meet the moment and make this better.

Orville Kolterman, MD

We appreciate what you’re doing to help get the word out. That’s very important.

Beverly Yates, ND

Thank you so much. I appreciate your kind words, being a sponsor, and being with us here on this journey very much. Friends, please share this episode and other episodes that you watch with people that you care about. We are trying to impact people’s lives and make a positive difference in a chronic disease that is so sensitive to lifestyle. Everyone, thank you so much for being a part of this episode.

Orville Kolterman, MD

Thank you.