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The work of diabetes research pioneer Ralph A. DeFronzo, M.D., Ph.D., of the Division of Diabetes at the Joe R. and Teresa Lozano Long College of Medicine at the University of Texas at San Antonio, is featured as one of 100 researchers.Number Celebrating the 10th anniversary of the Journal of Clinical Investigation , the magazine is presenting a series of perspective articles highlighting what it calls “some of the most important research in human health.”
In a JCI Anniversary Series article, DeFronzo discusses the groundbreaking discovery of the SGLT2/SGLT1 inhibitor phlorizin for the treatment of type 2 diabetes.
Research began in the late 1980s with three papers on phlorizin treatment of diabetic rats.
In people without diabetes, blood glucose levels rise to a certain threshold, above which blood glucose is excreted in the urine.
In people with diabetes, the threshold for excreting glucose in the urine is so high that the body retains more glucose.
“You don't want glucose to remain in the body because it can cause damage to the eyes and nerves. This is a completely new observation,” DeFronzo said.
DeFronzo knew that it was possible to lower the blood sugar threshold with a drug called phlorizin, extracted from the bark of apple trees that flower in the spring.
Maybe eating an apple a day will keep the doctor away, DeFronzo speculated. But not yet.
Phlorizin was seen as a promising antidiabetic drug, but in its pure form it caused gastrointestinal problems and was poorly absorbed by the human body.
The beginning of SGLT2 inhibitors
DeFronzo and his team approached the pharmaceutical company Bristol-Myers Squibb to develop a glucose reabsorption drug similar to phlorizin that could be tolerated by humans.
The company has chemically synthesized a more specific SGLT2 inhibitor that is similar to phlorizin but without the side effects.
Then, two things happened in quick succession, DeFronzo recalled.
Bristol-Myers Squibb, now AstraZeneca, invited nephrologists to weigh in on this potential treatment.
The consultants believed that drug interactions could worsen the kidney disease, and the project was put on hold.
Sometime later, while working with Samuel Tear, a nephrologist known for his research into inherited renal tubular diseases, DeFronzo said he observed patients who had lifelong diabetes despite no kidney damage.
“I said, 'Look, this is a crazy thing to think. [drug] “It can damage the kidneys. These people are 40, 50, 67 years old. They were born with this genetic defect and have been excreting glucose in their urine their whole life, but their kidney function is normal,” DeFronzo explained.
This prompted AstraZeneca to finally revisit the treatment: after more than a decade of delay, new studies have been conducted and the treatment has been proven to be safe and effective.
Further research has shown that the drug not only lowers blood sugar levels without damaging the kidneys, but also provides some kidney protection.
Multi-Protection Features for Dramatic Results
“The results were really dramatic. Fewer kidney transplant recipients were on dialysis. And, of course, the drug was approved as a kidney-protective drug,” DeFronzo said.
DeFronzo firmly believed the treatment would lower blood sugar levels and protect kidney function in people with type 2 diabetes, but in an unexpected twist, the treatment also reduced or prevented damage to the heart.
Since the initial studies on phlorizin, there are now four SGLT2 inhibitors approved by the Food and Drug Administration for the treatment of type 2 diabetes in the United States. 1 in 5 people with diabetes One of these medications will be prescribed.
“As expected, this drug has become very popular among cardiologists, nephrologists, endocrinologists. … It has appeal to just about everyone. So this was a very exciting breakthrough,” DeFronzo said.
Discovery of new physiological mechanisms
Along with this advance, DeFronzo said the research has revealed previously unrecognized physiological mechanisms.
DeFronzo said that with SGLT2 inhibitors, renal nerves become activated within minutes of the body excreting glucose in the urine, signaling the liver to produce glucose at the exact same rate as the glucose that was excreted.
“This is a miraculous discovery. … We've discovered a completely new mechanism by which the liver produces glucose when glucose appears in the urine as a side effect of these drugs, preventing hypoglycemia,” DeFronzo said.
Additionally, because these drugs act on the kidneys rather than the liver like most other diabetes medications, SGLT2 inhibitors can be used safely in combination with other medications.
This important work DeFronzo said the study, published in 2020, was the first evidence in a human study showing the exact mechanism of glucose toxicity and why it's harmful. High blood sugar is harmful in itself, but it also causes tissues to fail to respond to insulin, a condition called insulin resistance. This can lead to the beta-cell failure that characterizes people with diabetes.
“A lot of scientific and clinical applications have come out of that, which is why we wanted to highlight this in JCI's 100th anniversary celebrations,” he said.
DeFronzo said the research started as observational and progressed into translational science, ultimately helping people with diabetes as well as preventing kidney and heart failure.
“It's a huge contribution. It helps save lives. If they don't need dialysis or a kidney transplant. I think that's pretty significant. And all of this comes from an apple tree. Can you imagine? It's the simplest thing,” he said.
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SGLT2 inhibitors: a long-standing cardiorenal metabolic drug
Ralph A. DeFronzo
First edition publication date: March 1, 2024 Clinical Research Journal
https://www.jci.org/articles/view/177625
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