Why do people with obesity often develop more severe forms of asthma? Could the answer lie in methylglyoxal, a small molecule that is both produced by our bodies and found in certain foods? In this interview, Prof. Edson Antunes explains how a sequence of discoveries led his laboratory to investigate the role of methylglyoxal, opening new perspectives for the development of future therapies.
Small Contributions Across Different Fields
Throughout more than four decades dedicated to experimental pharmacology, Prof. Edson Antunes has built a career focused on understanding the mechanisms underlying diseases and identifying new therapeutic approaches.
Prof. Edson holds a degree in Biology from UNICAMP, a master’s degree in Physiology (UNICAMP), and a Ph.D. in Pharmacology (USP). He is currently a Full Professor at the School of Medical Sciences at UNICAMP, where he leads a laboratory in the Department of Pharmacology, conducting research on inflammation, pulmonary diseases, and lower urinary tract disorders.
His scientific journey, however, has encompassed an even broader range of research areas. Reflecting on his career, he explains that his scientific legacy has been built through “small contributions across different fields.”
Before focusing on lower urinary tract disorders and pulmonary diseases, Prof. Edson investigated inflammation in the context of animal venoms. During this period, he developed much of the expertise in inflammatory responses that would later guide his work on asthma and lung inflammation.
He also recalls another major milestone in his career: the development of drugs for erectile dysfunction. In collaboration with other researchers, including Prof. Gilberto De Nucci, his group carried out the entire preclinical experimental phase in animal models for compounds belonging to the phosphodiesterase type 5 (PDE5) inhibitor class, including Helleva. The laboratory findings provided the experimental foundation for advancing these compounds into subsequent clinical studies.
In recent years, however, Prof. Edson has become primarily recognized for his research on bladder dysfunction.
“I think I’m now better known internationally for my work on the bladder than for my other research areas. Not necessarily because these are my most important studies, but because there are relatively few groups working on this topic,” he says.
When Obesity Entered the Story
It was precisely the knowledge accumulated over years of studying inflammatory processes that paved the way for one of the laboratory’s main research lines: understanding why obesity worsens asthma and what role metabolic disorders, such as diabetes, play in this process.
Asthma is a chronic inflammatory disease affecting the airways (the tubes that carry air to the lungs). During asthma attacks, these airways become inflamed, narrow, and produce excess mucus, making it difficult for air to pass through. This results in symptoms such as shortness of breath, wheezing, coughing, and chest tightness, which vary in severity and frequency among patients.
Obesity has increasingly become both a major public health concern and an important risk factor for asthma. Clinicians have long observed that patients with obesity tend to develop more severe asthma and respond less effectively to conventional treatments.
According to Prof. Edson, however, there was still no convincing explanation for this phenomenon. “Many physicians say, ‘It’s because lung mechanics are impaired.’ But that explanation always seemed rather weak to me. What exactly gets worse? Why?” he reflects.
Lung mechanics refers to the ability of the lungs and chest wall to expand and contract in order to move air. Although excess body weight can indeed restrict these movements, this explanation alone does not fully account for why asthma becomes more severe or why patients with obesity respond poorly to treatment. The underlying biological mechanisms remained unclear.
“That question was always in the back of my mind: we need to study this,” he recalls.
The investigation began when nutritionist Dr. Marina Calixto joined the laboratory. Drawing on her expertise, the team developed a high-fat diet to induce obesity in laboratory animals. At the time, the researchers prepared the diet themselves, mixing fat with other ingredients in a homemade recipe. “It was basically like making a giant candy,” he jokes. “The animals loved it.”
Using this model, the researchers successfully reproduced not only obesity but also its associated metabolic alterations, including diabetes. The experiments showed that, just as observed in humans, obese animals developed more intense lung inflammation and more severe asthma than lean animals.
These findings demonstrated that obesity does not aggravate asthma solely by impairing respiratory mechanics. Inflammatory and metabolic changes also play an essential role.
This discovery paved the way for a new line of investigation that would eventually lead the group to study a molecule produced in excess during diabetes: methylglyoxal.
From Diabetes to Methylglyoxal
Prof. Edson wondered: what exactly connects diabetes to worsening asthma? The answer might lie in methylglyoxal, a small molecule produced in excess when blood glucose levels remain elevated.
We previously introduced methylglyoxal in our article “Glycated Collagen: What Diabetes Leaves Behind in Blood Vessels Even After Treatment.” In brief, methylglyoxal is a byproduct of glucose metabolism. Under normal conditions, the body rapidly detoxifies and eliminates it. However, in individuals with diabetes, its concentration can rise dramatically, promoting protein damage and contributing to inflammatory processes associated with numerous diseases.
The investigation into the relationship between methylglyoxal and asthma originated from an earlier publication by the group, with Dr. Marina Calixto as first author. That study showed that metformin, a drug widely used to treat type 2 diabetes, could also improve asthma in obese mice.
The prevailing explanation at the time was that, by controlling diabetes and reducing insulin resistance, metformin also decreased pulmonary inflammation.
Later, however, Prof. Edson came across a different hypothesis. Several studies had shown that metformin can also bind directly to methylglyoxal, forming an inactive compound and lowering its concentration in the body.
“When I read those papers, I thought: maybe, in Marina’s study, metformin was actually neutralizing methylglyoxal,” he recalls.
This observation shifted the direction of the research. Rather than viewing elevated glucose itself as the main driver of asthma worsening, the group began investigating whether methylglyoxal might actually be the critical culprit.
One of methylglyoxal’s defining characteristics is its extreme chemical reactivity. It readily interacts with important proteins in the body, altering their structure and generating compounds known as Advanced Glycation End Products (AGEs).
Imagine that proteins are like carefully engineered tools designed to perform highly specific functions. Methylglyoxal behaves like an extremely sticky caramel: it coats the surface of these tools, changing their shape and preventing them from functioning properly.
These modified proteins (the AGEs) are then recognized by the body as danger signals. When they bind to a receptor called RAGE (Receptor for Advanced Glycation End Products), it is as if they press an alarm button, triggering an inflammatory response.
This sequence (methylglyoxal accumulation, AGE formation, and activation of the RAGE receptor) has become the central focus of the laboratory’s current research, particularly the work of postdoctoral researcher Dr. Matheus Leite de Medeiros and master’s student Mateus Costa Leutz. Their hypothesis is that this molecular axis is one of the key mechanisms intensifying the pulmonary inflammation observed in obese and diabetic individuals with asthma.
Although methylglyoxal has been known to science for decades, its role in asthma remains largely unexplored. “If you search for ‘asthma,’ ‘airways,’ and ‘methylglyoxal,’ you’ll mostly find our publications,” says Prof. Edson.
“We’re trying to establish the idea that activation of this pathway, initiated by methylglyoxal, plays an important role in asthma. If we can block it, we may be able to improve the treatment of the disease.”
Today, this research line is being pursued by postdoctoral researcher Dr. Matheus and master’s student Mateus. In addition to investigating the biological consequences of the methylglyoxal–AGE–RAGE pathway, they are also evaluating strategies capable of interrupting it. These approaches include compounds that remove methylglyoxal, degrade already-formed AGEs, or prevent activation of the RAGE receptor.
Searching for New Treatments
If methylglyoxal truly contributes to the worsening of asthma and other diabetes-related complications, an important question emerges: could blocking this pathway become a new therapeutic strategy?
This question now guides part of the laboratory’s current research. Dr. Matheus is investigating several experimental compounds capable of interfering with different steps of the pathway, either by reducing methylglyoxal levels, preventing AGE formation, or blocking activation of the RAGE receptor.
One of the most extensively studied compounds is alagebrium (ALT-711), which was developed to break the molecular cross-links formed during the glycation process. In essence, it disrupts the bonds between methylglyoxal-derived products and proteins, effectively breaking apart the AGEs that have already formed.
Alagebrium progressed to relatively advanced stages of clinical testing before its development was discontinued prior to commercialization. Nevertheless, it remains an important research tool.
In addition to alagebrium, the group is also investigating compounds such as azeliragon, which blocks the RAGE receptor. Although still under development, azeliragon has also been studied in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, reinforcing the idea that this molecular pathway may contribute to a wide range of pathological conditions.
According to Prof. Edson, it is still too early to determine whether these strategies will ultimately lead to new therapies. However, the growing body of evidence highlights the importance of better understanding methylglyoxal’s role. “In my view, whenever there is hyperglycemia, there is excess methylglyoxal. And methylglyoxal is an extremely reactive molecule,” he says.
If future studies continue to support this hypothesis, blocking methylglyoxal or preventing its downstream effects could represent a novel therapeutic approach not only for asthma associated with obesity and diabetes, but also for other complications driven by chronic hyperglycemia.
From the Lungs to the Bladder
While the laboratory’s work on methylglyoxal was advancing in the context of pulmonary inflammation, the researchers realized that the same hypothesis might also explain another common, but far less recognized, complication of diabetes: diabetic bladder dysfunction.
In fact, Prof. Edson’s interest in the lower urinary tract began long before the discovery of methylglyoxal’s role. After years of studying vascular smooth muscle, he decided to focus on another smooth muscle organ: the urinary bladder.
“Cardiovascular research using blood vessels is extremely competitive. There are many outstanding groups working in that area. So I thought, ‘I need to find another smooth muscle tissue to study.’ That’s how I started working on the bladder,” he recalls.
The group’s first studies were carried out during the Ph.D. of Dr. Fabiola Mónica, now also a faculty member in the Graduate Program in Pharmacology at UNICAMP. At that time, the researchers investigated the role of nitric oxide in bladder function during urine storage and voiding. Very few laboratories were studying this question.
Years later, however, the experience gained from obesity and diabetes models led Prof. Edson to ask a new question: how do these metabolic disorders affect the lower urinary tract?
The question was particularly important because diabetic bladder dysfunction is among the most common complications of diabetes. It is estimated that more than half of people with diabetes develop some degree of urinary dysfunction during their lifetime.
Initially, many patients experience urinary urgency, increased urinary frequency, or an overactive bladder. As the disease progresses, however, the bladder may gradually lose its contractile strength and become unable to empty completely, increasing the risk of urinary retention, infections, and, in some cases, urinary incontinence.
Despite its high prevalence, diabetic bladder dysfunction remains relatively overlooked. Moreover, current treatment options are limited. Available medications help relieve symptoms but do not address the underlying cause of the disease, and some have been associated with significant adverse effects following long-term use.
We discussed diabetic bladder dysfunction in greater detail in our article “Diabetes: New Faculty Member Investigates a Silent Complication.” That story highlights the research of Prof. Mariana de Oliveira, who completed her Ph.D. under Prof. Edson’s supervision and was the first author of the group’s pioneering study investigating the effects of methylglyoxal on the urinary bladder.
Within this context, the researchers proposed that methylglyoxal might also play an important role in bladder dysfunction. If diabetes increases circulating methylglyoxal levels, it would be reasonable to expect the molecule to accumulate in bladder tissue as well, triggering the same inflammatory axis observed in the lungs.
The group’s findings supported this hypothesis. They identified elevated levels of methylglyoxal, increased AGE formation, and enhanced activation of the RAGE receptor in the bladders of experimental models of diabetes.
Furthermore, they demonstrated that prolonged exposure to methylglyoxal alone is sufficient to reproduce characteristic features of diabetic bladder dysfunction, including changes in bladder storage capacity and impaired contraction of the detrusor muscle, the smooth muscle responsible for expelling urine during urination.
Today, this research line encompasses several ongoing projects. Postdoctoral researcher Dr. Ákila Lara de Oliveira and master’s student Tiago Marinho Barbalho are investigating potential therapeutic targets within the methylglyoxal–AGE–RAGE axis, including the specific role of the RAGE receptor and whether blocking it can prevent or reverse diabetic bladder dysfunction.
Meanwhile, Clarissa Paiva Horioka‘s master’s research explores a particularly intriguing question: could dietary methylglyoxal, present in ultra-processed foods, further aggravate bladder dysfunction in diabetic animals?
Methylglyoxal May Also Come from the Diet
Clarissa’s work originated from a question that emerged almost by chance during the development of this research program. Until then, the group had primarily associated methylglyoxal with diabetes, since the molecule is produced in greater amounts when blood glucose remains chronically elevated.
But could its biological effects be studied independently of hyperglycemia?
To answer this question, the laboratory developed a different experimental model. Instead of inducing diabetes, the researchers administered methylglyoxal directly in the drinking water of healthy animals. These animals maintained normal blood glucose levels while exhibiting elevated circulating concentrations of methylglyoxal.
The results were striking. After approximately twelve weeks, the animals developed alterations remarkably similar to those observed in diabetic models: they exhibited more severe pulmonary inflammation and bladder dysfunction resembling diabetic bladder disease.
“That’s when we started discussing a different possibility,” says Prof. Edson. “Could this model actually represent chronic dietary exposure to methylglyoxal rather than the methylglyoxal produced by the body’s own metabolism?“
The hypothesis is plausible because methylglyoxal is not produced exclusively by our metabolism. It can also be generated during food preparation. When foods rich in sugars and proteins are heated at high temperatures (for example, during bread baking) the Maillard reaction takes place.
The Maillard reaction is a series of chemical reactions responsible for the characteristic aroma, flavor, and golden-brown color of foods such as bread, roasted coffee, chocolate, and many ultra-processed products. During this process, small amounts of methylglyoxal and other highly reactive compounds are also formed.
This does not necessarily mean that these foods are harmful or should be avoided. Prof. Edson himself emphasizes this point.
“I believe healthy individuals can cope much better with this type of exposure. The main concern remains patients with diabetes, particularly those who already have persistent hyperglycemia. In that case, you combine the methylglyoxal produced by the body with potentially high dietary intake.”
This is precisely the question Clarissa’s master’s project seeks to answer: can chronic consumption of dietary methylglyoxal worsen the urinary dysfunction already caused by diabetes?
If confirmed, these findings could broaden our understanding of how diet and metabolism interact in the development of diabetic complications, opening new perspectives for both prevention and treatment.
The Questions That Remain Unanswered
Although the laboratory’s research has significantly advanced our understanding of methylglyoxal’s role in several diabetes-related complications, many questions remain unanswered. For Prof. Edson, it is precisely these unanswered questions that make scientific research so fascinating.
One of the questions that intrigues him the most concerns an apparent contradiction that has puzzled clinicians and researchers for decades. It is well established that type 2 diabetes, which is frequently associated with obesity, increases both the risk of developing asthma and the severity of the disease. Surprisingly, the same does not seem to hold true for type 1 diabetes.
“There’s a very interesting observation. Individuals with type 1 diabetes rarely develop asthma. This clinical observation has attracted researchers’ attention for many years,” he explains.
The same phenomenon has also been observed in experimental models. Despite exhibiting elevated blood glucose levels, animals with type 1 diabetes do not develop the same degree of pulmonary inflammation seen in models of type 2 diabetes.
What makes this finding particularly intriguing is that both forms of diabetes involve hyperglycemia, a condition that promotes the formation of methylglyoxal. If methylglyoxal truly contributes to asthma severity, why do the two diseases behave so differently?
“That’s a question we still don’t have an answer to,” admits Prof. Edson. One possible explanation involves insulin itself. While type 2 diabetes is characterized primarily by insulin resistance, type 1 diabetes results from the body’s inability to produce sufficient insulin. However, exactly how these differences influence pulmonary inflammation remains unknown.
Perhaps understanding why type 1 diabetes appears to protect against asthma will uncover previously unrecognized biological mechanisms and, ultimately, reveal new strategies for preventing or treating the disease.
The Curiosity That Drives Science
For Prof. Edson, research is about much more than answering questions, it is a continuous process of generating new ones. That is what continues to motivate him to walk into the laboratory every day after decades of scientific work.
“Every day brings a surprise. Every experimental result has the potential to reveal something completely unexpected. And when that happens, a new question immediately arises. You want to understand what’s behind that biological phenomenon.”
According to him, that curiosity has never faded. If anything, it has only grown stronger. “I’m genuinely addicted to asking questions,” he says with a smile. “I still walk into the lab and ask my students, ‘Have you finished the experiment yet?’ If they say yes, I immediately want a spoiler of the results. Waiting for the graph to be ready takes too long.”
Perhaps that relentless curiosity is precisely what explains his career. In a scientific journey marked by “small contributions across different fields,” every answer seems to serve less as a conclusion than as the starting point for the next investigation.
Funding
The research featured in this article was supported by the São Paulo Research Foundation (FAPESP) under grant numbers 23/09353-5, 24/03508-0, 24/10306-4, and 25/10412-1.
This article was also produced with the support of the São Paulo Research Foundation (FAPESP), Brazil, under grant 25/17158-3. The opinions, hypotheses, conclusions, and recommendations expressed herein are those of the authors and do not necessarily reflect the views of FAPESP.
Further Reading
Initial study demonstrating the effects of metformin on obesity-associated asthma (DOI: 10.1371/journal.pone.0076786)
First publication from the group on methylglyoxal in the airways (DOI: 10.1016/j.intimp.2020.106254)
First publication from the group on methylglyoxal in the urinary bladder (DOI: 10.3389/fphys.2020.00290)
Methylglyoxal in Allergic and Non-Allergic Pulmonary Inflammatory Responses (Ph.D. thesis, Dr. Matheus Leite de Medeiros)
Methylglyoxal and Micturition Function (Ph.D. thesis, Dr. Ákila Lara de Oliveira)
The methylglyoxal–AGE–RAGE pathway in the airways (DOI: 10.2147/JIR.S337115)
The methylglyoxal–AGE–RAGE pathway in obesity-associated bladder dysfunction (DOI: 10.1152/ajprenal.00089.2023)
Metformin against methylglyoxal-induced bladder dysfunction (DOI: 10.1016/j.ejphar.2021.174502)
Metformin against methylglyoxal-induced airway dysfunction (DOI: 10.3390/ijms24119549)
Azeliragon against methylglyoxal-induced bladder dysfunction (DOI: 10.3390/antiox14070793)
Empagliflozin against methylglyoxal-induced airway dysfunction (DOI: 10.3390/ijms26125753)
Written by:
Mia Schezaro Ramos
Pharmacist. Ph.D. in Pharmacology. Science journalist, illustrator, trans, Nintendo enthusiast, K-pop fan, and dependent on physical exercise to stay sane.