Best of the best: DeFronzo’s work included in 100th anniversary of Journal of Clinical Investigation

Shared by

The work of diabetes-research pioneer Ralph A. DeFronzo, MD, diabetes division, University of Texas Health Science Center at San Antonio’s Joe R. and Teresa Lozano Long School of Medicine, is featured as part of the 100th anniversary of the Journal of Clinical Investigation. The journal is showcasing a series of viewpoint articles highlighting what the publication calls “some of the most important work related to human health.”

In his article for the JCI anniversary series, DeFronzo discusses the transformative discovery of utilizing the SGLT2/SGLT1 inhibitor phlorizin as a treatment for Type 2 diabetes.

DeFronzo

Research began in the late 1980s with three papers about phlorizin treatment in diabetic rats.

In a non-diabetic person, glucose rises to a certain threshold and any glucose beyond that spills into the urine.

In a diabetic person, the threshold for spilling glucose into the urine is much higher, meaning the body hangs onto more glucose.

“We don’t want that glucose hanging around because that can cause damage to your eyes, your nerves. This was a brand-new observation,” DeFronzo said.

DeFronzo knew lowering the glucose threshold was possible through the drug phlorizin, which comes from the bark of apple trees when they bloom in the spring.

Perhaps an apple a day could keep the doctors away, DeFronzo deduced. But not quite yet.

Phlorizin showed promise as a potential diabetes treatment. But in its pure form, the drug caused gastrointestinal distress and was poorly absorbed in humans.

The beginning of SGLT2 inhibitors

DeFronzo and his team approached the pharmaceutical company Bristol Myers Squibb to develop a phlorizin-like drug for glucose reabsorption that could be tolerated in humans.

The company produced a chemical synthesis of a more specific SGLT2 inhibitor, similar to phlorizin without the negative side effects.

Two things happened in succession after that, DeFronzo recalls.

Bristol Myers Squibb became AstraZeneca, which then called in kidney consultants to see what they thought of this potential treatment.

The consultants believed the interaction of the drug would worsen kidney disease, so the project was put on hold.

DeFronzo said a while later when he was working with Samuel Thier, a nephrologist known for his work on inherited renal tubular disorders, he observed patients with lifelong glucosuria who did not have kidney damage.

“I said, ‘Look, this is crazy that you would think this [drug] can damage the kidney. These people are 40, 50, 67 years old. They were born with this genetic defect and they’ve been spilling glucose in their urine all their life and they have normal kidney function,’” DeFronzo explained.

This finally convinced AstraZeneca to take another look at the treatment. After a delay of more than a decade, new studies were conducted and the treatment was proven safe and effective.

Further studies showed the drug not only lowers glucose without damaging the kidneys, it provides some protection to them as well.

Dramatic results with multi-protective features

“The endpoints were pretty dramatic. Fewer people receiving kidney transplants ended up on dialysis. And of course, the drugs then got approval for protection of the kidneys,” DeFronzo said.

While DeFronzo strongly believed this treatment would help lower glucose in Type 2 diabetics and protect kidney function, a serendipitous twist was that the treatment also lessened or prevented damage to the heart.

Stemming from that initial investigation into phlorizin, there are now four Food and Drug Administration-approved SGLT2 inhibitor drugs available in the United States for the treatment of type 2 diabetes with one in five diabetic patients is prescribed one of these drugs.

“The drugs, not surprisingly, became very popular with cardiologists, kidney specialists and endocrinologists. … It appeals to virtually everybody. And so, this was a pretty exciting breakthrough,” DeFronzo said.

New physiologic mechanism discovered

Along with this advance, DeFronzo said the studies uncovered a previously unrecognized physiologic mechanism.

DeFronzo said with SGLT2 inhibitors, within minutes of the body discharging glucose into the urine, the renal nerves are activated and signal the liver to produce glucose at the exact same rate as what was expelled.

“This is a miraculous discovery. … So as a side effect of these drugs, we discovered this whole new mechanism that when glucose appears in the urine, your liver produces glucose and prevents you from becoming hypoglycemic,” DeFronzo said.

Additionally, since these drugs work on the kidneys as opposed to the liver like most other diabetes treatments, SGLT2 inhibitors can be used safely in collaboration with these other drugs.

This pivotal work published in 2020, DeFronzo said, was the first proof in human studies showing the exact mechanism of glucose toxicity and why it is harmful. While high glucose is damaging on its own, it also leads to tissues becoming unresponsive to insulin, called insulin resistance. This can cause beta cell failure, a characteristic in diabetics.

“There was so much science and clinical application that came out of that. This is why they wanted to feature this in the 100th anniversary of the JCI,” he said.

DeFronzo said the work was an observation, that turned into translational science, that ended up helping people with diabetes, along with protecting against kidney failure and heart failure.

“It’s a major contribution. It’s helped save lives. If you don’t end up on dialysis or requiring a kidney transplant. That’s, I think, pretty important. And all from an apple tree, can you imagine? The simplest things,” he said.

­­­­­­­­­­­­­­­­­­____________________________________________________________________________

SGLT2 inhibitors: cardiorenal metabolic drugs for the ages

Ralph A. DeFronzo

First Published: March 1, 2024, Journal of Clinical Investigation

https://www.jci.org/articles/view/177625

 

The University of Texas Health Science Center at San Antonio (UT Health San Antonio) is one of the

country’s leading health science universities and is designated as a Hispanic-Serving Institution by the

U.S. Department of Education. With missions of teaching, research, patient care and community

engagement, its schools of medicine, nursing, dentistry, health professions, graduate biomedical

sciences and public health have graduated more than 42,550 alumni who are leading change, advancing their fields and renewing hope for patients and their families throughout South Texas and the world.

To learn about the many ways “We make lives better®,” visit UTHealthSA.org.

Stay connected with The University of Texas Health Science at San Antonio on Facebook, Twitter, LinkedIn, Instagram and YouTube.

 

Burial of Ashes Ceremony honors body donors for student education and research

Shared by

Omid B. Rahimi, PhD, director of the Human Anatomy Program and professor in the Department of Cell Systems & Anatomy, welcomed the attendees, expressed his gratitude and respect for all the participants in the Body Donation Program and conveyed appreciation for the compassion and support of their family and friends.

UT Health San Antonio recently held an Interment Ceremony, also called the Burial of Ashes, an annual gathering to inter the cremated remains of those who gave their bodies for health professional student education and research, and to honor the donors.

More than 120 donor family members joined students, faculty and staff at the ceremony held at the Pestana Lecture Hall in the Medical School Building, Wednesday, May 1.

The event began with a beautiful rendition of “Amazing Grace” by bagpiper Robert Chalk.

The event began with a beautiful rendition of “Amazing Grace” by bagpiper Robert Chalk.

Omid B. Rahimi, PhD, director of the Human Anatomy Program and professor in the Department of Cell Systems & Anatomy, welcomed the attendees, expressed his gratitude and respect for all the participants in the Body Donation Program and conveyed appreciation for the compassion and support of their family and friends.

“Irrespective of occupation, social standing, age, health, or ailment, each donor’s invaluable gift equally contributes in shaping the well-being of future generations,” Rahimi said. “This ceremony is dedicated to those who, in death, have served the living through their generosity and kindness. We honor their memory and recognize their contribution today.”

More than 120 donor family members joined students, faculty and staff at the ceremony held at the Pestana Lecture Hall in the Medical School Building, Wednesday, May 1.

“This ceremony exists to commemorate those who gifted their bodies to education and research,” Rahimi said. “Through their act, hundreds of students each year are able to learn the complex details of the human body, but more importantly, because of this gift, students are able to experience the spirit of love and giving that is the basis of their future practice of caring for their patients.”

Following Dr. Rahimi’s introduction, Deborah L. Conway, MD, professor of obstetrics and gynecology and vice dean for Undergraduate Medical Education at the Joe R. and Teresa Lozano Long School of Medicine, provided remarks, followed by seven student representatives including: Alyssa Nail, a first-year Doctor of Physical Therapy student at the School Health of Professions; Nhat Pham, a first-year Doctor of Medicine student at the Long School of Medicine; Roshan Patel, a first-year Doctor of Dentistry student at the School of Dentistry;  Belinda Bernal, a Master of Science student in Cell Systems & Anatomy at the Graduate School of Biomedical Sciences; Erin Kraus, a second-year Doctor of Medicine student at the University of Incarnate Word School of Osteopathic Medicine; Grace McGuire, a first-year Doctor of Occupational Therapy student at the School of Health Professions; and Stephen Thurgood, a first-year Physician Assistant Studies student at the School of Health Professions.

Click here to view additional photos from the event.

To learn more about the university’s Body Donation Program, visit https://lsom.uthscsa.edu/dcsa/body-donation-program/.

 

 

$11 million NIH grant awarded for five-year investigation of novel oral chlamydia vaccine

Shared by

The study of a novel oral vaccine that could protect against chlamydia infection received more than $11 million in National Institutes of Health funding through a five-year U01 grant in April 2024.

“We are excited about receiving the U01 award because it will enable us to move our basic microbiology and immunology bench research work closer to developing a medically significant reagent for making human lives better, our institution’s overall mission,” said Guangming Zhong, MD, PhD, professor of Microbiology, Immunology and Molecular Genetics with the Joe R. and Teresa Lozano Long School of Medicine at The University of Texas Health Science Center at San Antonio.

Zhong said this vaccine, called intrOv, came about after several years of persistent effort studying chlamydial pathogenic mechanisms in mice.

While investigating mouse-adapted chlamydia, the team accidentally

Guangming Zhong, MD, PhD

found that genital chlamydia that spread to the gastrointestinal tract established long-standing colonization.

From there, they tried an oral inoculation of chlamydia to the GI system and found that it became not only non-pathogenic, but also offered protective immunity against subsequent infection in other tissues including the genital tract and airways.

This surprising finding, Zhong said, led them to conclude that an oral delivery of chlamydia could serve as a vaccination against the infection.

The team then created mutant versions of the infection that could no longer cause disease but could induce transmucosal protection.

One of these attenuated mutants, intrOv, included unique qualities viable for cross-species translation to the human pathogen of chlamydia.

“Since the human pathogen chlamydia has more than 15 serotypes, developing a vaccine against all 15 serotypes is challenging. Using the mouse-adapted, chlamydia-based vaccine intrOv to cover all 15 serotypes is a nice surprise,” Zhong said.

This grant supports the production of investigative new drug-enabling data for moving the oral chlamydia vaccine to phase 1 trials.

“We will optimize the immunization regimens, identify protection immune correlates in mouse models and validate the vaccine efficacy in pigs and non-human primates,” Zhong said.

If all goes well at that stage, the team will file an investigational new drug application with the Food and Drug Administration to advance the vaccine to clinical trials by the end of the grant’s timeframe.

In 2022, the health science center was granted an exclusive global license to allow Ohio biopharmaceutical company Blue Water Vaccines Inc. to develop Zhong’s findings into an oral vaccine for chlamydia.

Other study collaborators from the Long School of Medicine’s microbiology, immunology and molecular genetics department include Zhenming “Jack” Xu, PhD, and Nu Zhang, PhD, who will provide B cell and T cell expertise.

Collaborators for the study include Pat Frost, DVM, and Marie-Claire Gauduin, PhD, primate genital-tract infection experts with Texas Biomedical Research Institute; Yufeng Wang, PhD, bioinformatics expert with The University of Texas at San Antonio; Luis M de la Maza, MD, PhD, with the University of California at Irvine; Huizhou Fan, MD, PhD, with Rutgers University; Harlan Caldwell, PhD, chief of chlamydial diseases section at the National Institute of Allergy and Infectious  Diseases; Robert Brunham, MD, with the University of British Columbia; and William Geisler, MD, MPH, from the University of Alabama.

According to the Centers for Disease Control and Prevention, chlamydia is the most reported sexually transmitted infection and affects about 4 million people in the United States each year. The infection is often left untreated due to the lack of specific symptoms. Untreated chlamydial infections can lead to severe complications including pelvic inflammatory disease, infertility and ectopic pregnancy.

There is no vaccine available presently to prevent chlamydia. Vaccines are currently available only for three STIs – HPV, Hepatitis A and Hepatitis B.

 

 

The University of Texas Health Science Center at San Antonio (UT Health San Antonio), a primary driver of San Antonio’s $44.1 billion health care and biosciences sector, is the largest academic research institution in South Texas with an annual research portfolio of $360 million. Driving substantial economic impact with its six professional schools, a diverse workforce of 7,900, an annual operating budget of $1.08 billion and clinical practices that provide 2.6 million patient visits each year, UT Health San Antonio plans to add more than 1,500 higher-wage jobs over the next five years to serve San Antonio, Bexar County and South Texas. To learn about the many ways “We make lives better®,” visit UTHealthSA.org.

Stay connected with The University of Texas Health Science Center at San Antonio on Facebook, Twitter, LinkedIn, Instagram and YouTube.