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.
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.
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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
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