Stopping Metabolic Dominoes Before They Fall: A Holistic Approach to Internal Medicine

2022/11/08

Non-communicable diseases (NCDs) are responsible for 70% of deaths worldwide and include conditions such as diabetes, kidney disease, heart disease, and cerebrovascular disorder. That is why the Department of Internal Medicine (Nephrology, Endocrinology and Metabolism) at Keio University’s School of Medicine is taking a holistic approach to NCD treatment, taking on the many challenges that face modern medicine. Here, Professor Hiroshi Itoh shares the current state of endocrinology and metabolism and reflects on one patient who helped shape his storied career.

Lifestyle-related diseases can cause obesity and lead to metabolic syndrome, a cluster of conditions that can include hyperglycemic spikes after meals, elevated blood pressure, and lipid abnormalities. And the dominoes can continue to fall—from arteriosclerosis to diabetes and then on to other issues like kidney disease, stroke, heart failure, and even dementia. This is the novel “metabolic domino effect” first coined by Prof. Hiroshi Itoh in 2003, followed two years later by the now-common diagnosis of “metabolic syndrome.”

“One of the new concepts that developed from thinking about metabolic dominoes was the accumulation of risk factors in a single individual. At the time, we were beginning to understand that many people with diabetes also had high blood pressure. It is no coincidence that these diseases have a compounding effect. They are both caused by obesity, the first metabolic domino, which increases the risk of developing diseases found in the mid- and late-stage of the metabolic domino effect. Another new concept that developed was that of 'time.' If ignored, these individual “dominoes” can topple all at once, resulting in an unstoppable cascade of disease. The idea of preventive or preemptive medicine has become common these days, but the bottom line is that if we intervene at the stage before a domino falls over—that is, before a patient develops a disease—we can keep that domino from falling.”

It will soon be 20 years since Prof. Itoh first proposed the metabolic domino effect. In that time, diseases like cancer and sarcopenia have been added as new dominoes due to their compounding nature with many other metabolic syndrome diseases. And in 2016, it was shown that gut inflammation actually exists as a domino that foretells obesity. “In experiments with mice models, we found that a continuous high-fat diet leads to intestinal inflammation and that suppressing intestinal inflammation can prevent rapid increases in blood glucose levels and insulin resistance. So it is clear that metabolic syndrome begins with intestinal inflammation.”

Over the years, Prof. Itoh has slowly refined the metabolic domino effect, culminating in his Greedy Organs Hypothesis published in 2022. “The idea is that the ‘greed’ of two organs, the intestines and the kidneys, causes metabolic dominoes to topple, leading to various diseases. Incidentally, the name of this hypothesis was inspired by the phrase ‘greedy guts.’”

Prof. Itoh focused on the intestines and kidneys, both organs that absorb nutrients, a function vital for survival. “Many people may think of the kidneys as excreting waste, but they are actually an ‘absorption' organ. They absorb more than 99% of glomerular filtrate, the substance that becomes urine, into the body for reuse.”

The intestines and kidneys are particularly “greedy.” They absorb sugar to create energy and salt to regulate blood pressure, which helps carry oxygen and nutrients to all parts of the body. And then there are the “carriers” that allow for the efficient absorption of sugar and salt: sodium-glucose co-transporters (SGLTs).

2014 saw the introduction of SGLT2 inhibitors, a class of medicines that directly block SGLT2 in the kidneys and thereby inhibit renal glucose reabsorption. “Many people, myself included, did not expect much from these new drugs. But when they were administered, blood glucose levels dropped significantly. It was completely unexpected. This caused a commotion in the medical community as it was discovered that not only were these drugs effective against diabetes, but they could also treat obesity, help with recovery from kidney disease and heart failure, and even improve vital prognosis. SGLT2 inhibitors are now one the most promising drugs and are being approved to treat diseases other than diabetes, such as kidney disease.”

Excessive intake of sugar and salt overwhelms the “greedy” intestines and kidneys, which are always trying to absorb as much of these substances as possible. This can lead to diabetes, hypertension, kidney disease, heart failure, and cancer. The Greedy Organs Hypothesis hinges on putting a stop to the greed of the intestines and kidneys and could significantly impact the metabolic domino effect first discovered 20 years prior.

The metabolic domino effect is also closely related to the field of anti-aging. “First of all, the metabolic domino effect is thought to result from abnormal mitochondrial function in various organs. In other words, healthy mitochondria lead to longevity.”

In 2000, proteins called sirtuins were discovered at the Massachusetts Institute of Technology. Sirtuins control the function of mitochondria and regulate the effectiveness of insulin, and they have attracted much attention as a potential ingredient for slowing the aging process. Many companies have recently drawn notice for producing NMN (nicotinamide mononucleotide), an anti-aging substance that activates these sirtuins. “Keio conducted the world’s first human clinical study on NMN in 2016, and subsequent trials have shown great promise with the potential to delay organ aging in general. However, the NMN currently available on the market is something of a mixed bag.”

So what does the future of anti-aging medicine look like? “While anti-aging treatments, including NMN administration, are based on the concept of ‘absorbing what is good for the body,’ there is also the contrasting concept of ‘removing what is bad from the body.’ The idea is that aging is caused by damaged cells, so if we can remove those cells, it will lead to rejuvenation. In fact, in the United States, senolytic drugs aimed at eliminating senescent cells (i.e., cells that have reached a stopping point in the cell cycle) are also available, and reports show promising results. This is also part of the reason for the recent argument that aging is merely a disease that we will be able to cure.”

Prof. Itoh, however, is somewhat dismissive of this idea. “The entire body is weakened by aging, and I believe that the method of rejuvenating the body by merely replacing the bad cells will lead to a dead end. I think the conventional method of activating cells as much as possible and replenishing them when damaged is the right approach. In that sense, I’m somewhat uncomfortable with the ‘anti-’ part of the term ‘anti-aging.’ We will be better off working to slow down the aging process rather than fighting it.”

In recent years, Prof. Itoh has proposed the concept of a “happy life expectancy.” This concept contrasts with “healthy life expectancy,” which is the number of years a person can expect to live in good health without disability. “For example, people with intractable cancer may still live full lives, cherishing the days they have left, with a sense of gratitude for those around them. On the other hand, someone in generally good health may constantly complain. Having seen such a range of patients, I felt that there were more important factors at play than physical condition and level of care. I thought the question we should be asking is: ‘Are you living with a source of motivation and a sense of happiness?’ I want to keep thinking about the answer to this question and consider what we can do from a medical and scientific perspective to ensure that everyone can live to enjoy a longer, happier life expectancy.”

Prof. Itoh has been working in the field of endocrinology and metabolism for nearly 40 years, and during that time, he says, he has had one unforgettable patient whom he met while doing his residency at the Japanese Red Cross Fukui Hospital.

“She was the first patient to come to the outpatient clinic, my first case as a clinical resident. She had a very swollen throat, and I knew from the moment I saw her that she had thyroid cancer. She was also sweating profusely and had high blood pressure. Test results revealed that she had Sipple’s syndrome, a rare genetic disorder that results in multiple endocrine gland tumors, mainly medullary thyroid carcinoma, pheochromocytoma, and parathyroid tumors.”

At that time, Red Cross Fukui Hospital didn’t have an endocrinologist on staff, and Prof. Itoh was put in charge of diagnosis and treatment. “I just did whatever I could to help her. I even traveled with her to Kyoto University Hospital, which had the most advanced facilities then, so that we could test for metastases.”

Fast forward to one year later. The end of Prof. Itoh’s residency was approaching, and he didn't want to leave his patient behind. “Sadly, she passed away just before I returned. I still get teary-eyed just thinking about it. And for various reasons, the hospital also put me in charge of conducting her autopsy. It was a real challenge, but it showed me the reality of the disease and how hormonal imbalances can cause such debilitating symptoms.

“It’s hard to put it into the right words, but I really learned a lot from that patient. When I reflect on it now, I often regret how I handled things, as I was still young, and my feelings got the better of me. But without a doubt, it is because of that patient that I chose to specialize in endocrinology, hormones, and hypertension. She was unforgettable.”

Prof. Itoh now heads the Department of Nephrology, Endocrinology and Metabolism. The department is home to doctors specializing in diabetes, hypertension, and endocrinology. They can treat lifestyle-related diseases and metabolic syndrome, as well as less common endocrine diseases related to the hypothalamus and pituitary gland, in addition to the thyroid, parathyroid, adrenal, and gonads. Only a handful of internal medicine clinical departments in Japan can cover such a wide range of areas. “The metabolic domino effect shows us the close relationship that exists between kidney diseases, diabetes, and endocrinology, and I think it perfectly suits our department because it allows us to unite and treat each of these areas holistically.”

“A holistic approach to internal medicine.” This is the slogan and policy of the Division of Nephrology, Endocrinology and Metabolism. “We treat a vast range of diseases here, including cancer. Of course, if we find that a patient has a gastrointestinal disease, we will refer them to a gastroenterologist, and if they have a neurological disease, we will refer them to a neurologist. But our goal is to provide life-long, total care. As physicians, we want to serve as a hub for our patients.”

This level of care involves, for example, noticing even the slightest change in a patient’s condition. “In my everyday interactions with my patients, I'm carefully observing their skin color and facial expressions when I ask them how they're doing. After doing that for years, I can now notice even the slightest changes.” Prof. Itoh says that this means accepting everything about the patient. “Patients will tell us if they’ve gotten a rash on their hands or have been coughing a lot lately—we get all the details. [laughs] But we try to use those comments to paint a picture of everything happening inside their body.”

“It requires extensive knowledge and experience to treat a patient properly, and, to be honest, the workload can be quite heavy. But we have a group of doctors here who are ready and willing to keep company with patients throughout their lives, so I am very hopeful.”

Outside of patient care, Professor Itoh also promotes medicine to the general public by publishing new books and sharing content on YouTube. “I’m from Kansai, so I instinctively want to please people and make them smile. I guess I was born that way. [laughs] It’s almost as if I became a doctor so that I could make my patients smile. But that impulse actually extends beyond my patients. I also want to share my work with the general public in a way that is easy for them to understand.”

Prof. Itoh says he often talks with the young doctors in his department about having a sense of mission and demonstrating negative capability. “Somehow, I have become a doctor and ended up in my current position. Of course, I’ve worked hard, but at the same time, I believe that I am here today thanks to a confluence of circumstances and the good doctors and patients I have met along the way. In that sense, I think those fortunate to be in a position like mine should do all they can for others. It may come across as a bit self-important, but I don't think it's wrong to have the desire to do good for someone else. It is important to have that sense of mission.”

Prof. Itoh also speaks of “negative capability,” or the ability to accept uncertainties. “Negative capability is about accepting ambiguity. We shouldn’t jump to conclusions just because we think we understand something when we actually don't, nor should we trust that everything a great doctor says is right. Don't run away from a challenge when it gets tough or lonely. Never give up on things you don’t understand, and continue to ask questions. I take that approach because I believe that it will eventually lead to a good outcome. If I gave up, I wouldn’t be able to push myself to the next level.”

Prof. Itoh was also kind enough to share a message for students planning to study at the School of Medicine. “You may be unsure about your own potential. But if you are motivated, Keio is most certainly a place full of opportunities. Keio has a culture of working to better society and a learning environment that fosters that culture, which allows you to connect with other passionate peers and professors. I hope that you—the younger generation—will be able to reach your full potential as you enjoy the challenge of exploring the unknown.”

Hiroshi Itoh

Prof. Itoh graduated from the Kyoto University School of Medicine in 1983 and received his doctorate at the Kyoto University Graduate School of Medicine. He then went to the US, working as a postdoctoral fellow at Harvard University and the Stanford University School of Medicine before returning to Japan and serving as Assistant Professor at the Kyoto University Graduate School of Medicine. In 2006, he became a Professor of Internal Medicine (Nephrology, Endocrinology and Metabolism) at the Keio University School of Medicine. Prof. Itoh specializes in endocrinology, hypertension, diabetes, and anti-aging medicine. Prof. Itoh has authored numerous books, including “Good Obesity, Bad Obesity” (Ii himan warui himan), “The Secret of Super-Longevity” (Chōchōju no himitsu), “Happy Life Expectancy” (Kōfuku jumyō), and “The Age of Organs” (Zoki no Jikan).*