Episode 117
From Gila Monster to GLP-1 Revolution
Meanwhile, in a Laboratory
In 1990, researchers isolated a peptide from Gila monster venom. Two years later, work from the Bronx VA Medical Center described exendin-4, a molecule that resembled human GLP-1 but lasted far longer in circulation.
Human GLP-1 survives only minutes before the body breaks it down. Exendin-4 resisted that breakdown. That difference changed everything.
Soon afterward, the first GLP-1 receptor agonist reached patients under the brand name Byetta. At the time, physicians used it to treat diabetes. No one called it a weight-loss drug. No one predicted it would reshape obesity medicine.
And yet, the foundation was already in place.
While I Was Operating
At the Phoenix Indian Medical Center, I performed weight loss surgery in a population with some of the highest rates of type 2 diabetes in the world. Researchers there studied metabolism intensely. The “thrifty gene” hypothesis gained traction in that environment. Scientists asked whether efficient energy storage, once protective in scarcity, became harmful in abundance.
At the same time, I watched something remarkable in the operating room. After gastric bypass, patients’ blood sugars often improved within days, before meaningful weight loss occurred. Hormones were shifting. Physiology was driving outcomes.
Meanwhile, GLP-1 drugs evolved.
Researchers lengthened their half-lives. Chemists modified their structures so they bound albumin and stayed active for days rather than minutes. Clinical trials expanded. Safety data accumulated.
Eventually, semaglutide showed average weight loss approaching fifteen percent of body weight in obesity trials. Then tirzepatide, now marketed as Zepbound for obesity, exceeded 20 percent weight reduction in higher-dose studies. In addition, cardiovascular outcome trials demonstrated reductions in major adverse cardiac events in high-risk patients.
These were not cosmetic results. These were metabolic and cardiovascular outcomes.
Food Noise
Patients rarely talk about receptors. They talk about noise.
Food noise.
The constant internal dialogue about eating. The mental pull toward the pantry. The background chatter that never quite stops.
GLP-1 receptors exist in appetite-regulating areas of the brain, including the hypothalamus and brainstem. These medications act through vagal signaling and through regions where the blood-brain barrier is more permissive. As a result, they modulate satiety and reward pathways.
Consequently, many patients report something simple but profound: the noise quiets.
Not disappears. Quiet.
That distinction matters.
Diet Culture Pushback
Predictably, not everyone celebrates this shift.
Diet culture thrives on the belief that weight reflects character. Some coaches insist the solution is fewer calories. Others argue for more beef, more butter, more fiber, or stricter discipline. Entire industries depend on the idea that trying harder solves everything.
However, biology does not negotiate with virtue.
Obesity is a chronic, relapsing, neurohormonal disease. No one worked harder at weight loss than many of my surgical patients. Likewise, I do not lack willpower. And I practice culinary medicine. Preaching and eating a Mediterranean diet.
Nevertheless, effort alone does not silence dysregulated signaling.
Calling GLP-1 therapy “cheating” misunderstands the science. These medications restore signaling. They amplify satiety. They reduce excess reward drive. They support physiology.
That is treatment, not moral compromise.
My Parallel Universe
When I began my career, I weighed about 185 pounds. Years later, hospital cafeterias, exhaustion, and irregular meals pushed me to 225. I understood obesity clinically. Then I understood it personally.
In one version of my career, revision surgery remains the answer for weight regain. In this version, I reached for GLP-1 therapy instead.
Today, I weigh what I weighed when Nixon was president.
I am both surgeon and patient.
And your reporter.
A Necessary Caution
GLP-1 medications carry risks as well as benefits. Nausea can occur. Gastric emptying slows. Gallbladder disease risk may increase, although obesity itself already raises that risk substantially. Physicians must monitor dosing carefully.
Therefore, if you consider GLP-1 therapy, work with a trained physician who understands obesity medicine. Avoid quick online scripts. Seek supervision. Demand follow-up.
Metabolic medicine deserves serious care.
The Desert Was the Beginning
I once thought Phoenix was punishment. The heat felt relentless. Even Satan might choose a cooler vacation. Only Canadians brave July—and who can blame them?
However, what felt like exile turned out to be preparation.
In that same desert, I learned surgery. Researchers debated the thrifty gene. A venomous lizard carried a peptide that would become the basis of modern metabolic therapy.
I thought I had been sent to hell. But I found beauty in the desert, and by the time I left Arizona, I missed it terribly.
Little did I know I was sent to the future in Arizona.
Transcript
>> Dr. Terry Simpson: M In 1991, I finished my residency and surgery in
Speaker:Seattle, Washington. Hiking in Seattle meant pine
Speaker:needles, damp earth, a good rain show. You packed
Speaker:Gore Tex, you expected mist or rain, and the
Speaker:forest smelled alive. And then I landed in Phoenix
Speaker:in July. Now, this wasn't a choice. I owed the
Speaker:federal government because they paid for my
Speaker:medical school and when given a choice of places
Speaker:to go to fill that billet. While I wanted to be in
Speaker:Anchorage, Phoenix was the only one that was open
Speaker:that actually involved the city. Well, hiking
Speaker:there meant bottled water and lots of it. And you
Speaker:didn't pack a shell, you packed survival. The day
Speaker:I went to Phoenix, it was 113 degrees at 6 o'
Speaker:clock in the evening. The hills had fires from
Speaker:small wildfires all over. And when you stepped out
Speaker:of the car, the air felt like someone opened the
Speaker:oven door and left it there. I didn't see beauty.
Speaker:I saw brown rocks, no pine trees, no water. And I
Speaker:remember thinking quite seriously, this must be
Speaker:the only place in the world where even the lizards
Speaker:carry venom. I was fairly certain I'd been sent
Speaker:there because I was going to hell and this was
Speaker:orientation and it was really hotter than hell.
Speaker:And frankly, I suspect even Satan didn't vacation
Speaker:there. Only Canadians. And who could blame them?
Speaker:February in Toronto. But the desert waits you out.
Speaker:And eventually I fell in love with it. The rocks
Speaker:were copper at dusk. The saguaros now look like
Speaker:cathedral columns to me. And if you're patient,
Speaker:very patient, you might see one of the most
Speaker:beautiful and dangerous creatures in North
Speaker:America. The Gila monster. Beaded orange and
Speaker:black, skin like mosaic tile. Heavy bodied,
Speaker:deliberate. It doesn't rush, it doesn't need to.
Speaker:It has venom in its bite. Gila Bend is named after
Speaker:it, Gila river bears its name, and the desert
Speaker:itself named after this creature. And little did I
Speaker:know that this slow, venomous lizard would one day
Speaker:give me the medication I inject. Today, Zepbound.
Speaker:Today on Forku, we will be making sense of the
Speaker:madness of GLP1 and the lizards who gave them to
Speaker:us. I am your Chief Medical Explanationist, Dr.
Speaker:Terry Simpson, and this is Fork U Fork University,
Speaker:where we make sense of the madness, bust a few
Speaker:myths and teach you a little bit about food and
Speaker:medicine. A year before I left Seattle in 1990, an
Speaker:endocrinologist named John Ng isolated a peptide
Speaker:from the saliva or the venom of the Gila monster.
Speaker:Now, he wasn't hunting reptiles, he was studying
Speaker:glucose regulation. Because think of this, the
Speaker:Gila monster doesn't eat that often. So how do
Speaker:they regulate their glucose? We regulated second
Speaker:by second. They didn't. And from the venom, he
Speaker:isolated a molecule called extendin 4. Two years
Speaker:later, while I was now at Phoenix, at the Bronx VA
Speaker:Medical center, he purified it and published the
Speaker:results. And here was the key. It resembled human
Speaker:GLP1 or glucagon, like peptide 1, but it lasted
Speaker:longer. Native GLP1, the kind that you and I
Speaker:build, survives in circulation about two minutes.
Speaker:Two minutes? Minutes. And that's before your own
Speaker:body has an enzyme which is called DPP4. It
Speaker:destroys it. Now, extendin4 resisted that
Speaker:breakdown. It had staying power. And the discovery
Speaker:eventually became the medication known as Byeda,
Speaker:which was first released for the United States in
Speaker:2005. It was the first GLP1 receptor agonist. It
Speaker:was a drug for diabetes, not a weight loss drug,
Speaker:not a cultural phenomenon, just careful
Speaker:endocrinology. All of this happened while I was in
Speaker:Phoenix. One of the things that they noticed about
Speaker:this drug was that the patients who were on it
Speaker:lost weight. And so when I would be dealing with
Speaker:my friends who were in internal medicine and they
Speaker:would have a patient who had both diabetes and
Speaker:excess weight, they would start putting them on
Speaker:Vieta, um, on the hopes that they would lose 2-4
Speaker:kg. Everything intersected for me in Phoenix. I
Speaker:had begun my career at the Phoenix Indian Medical
Speaker:center, and that's where I cut my teeth doing
Speaker:weight loss surgery. Type 2 diabetes among Pima
Speaker:Indians in Arizona is among the highest prevalence
Speaker:recorded anywhere in the world. Obesity rates were
Speaker:also high. Metabolic disease was everywhere. But
Speaker:in Phoenix, and especially at the medical center,
Speaker:it wasn't just clinical, it was also scientific.
Speaker:There's a metabolic ward there, which is basically
Speaker:a hospital ward dedicated to doing research about
Speaker:diet and fat mass. And it's from the National
Speaker:Institutes of Health. It was in Phoenix that the
Speaker:thrifty gene hypothesis was articulated. In that
Speaker:ecosystem, which means something like efficiency
Speaker:and scarcity becomes liability in abundance,
Speaker:meaning if you're in an area where you can't eat
Speaker:much, when you can eat much, you tend to store
Speaker:more. Now, there's more than one thrifty gene, as
Speaker:we found out. There's multiple ones, but at that
Speaker:time, we only thought about one. Here's a funny
Speaker:thing. The person who actually invented the
Speaker:thrifty gene hypothesis offered me a job at the
Speaker:nih. And sometimes I think, what a fascinating
Speaker:ride that would have been. But we can't go back
Speaker:except in history. So anyway, as I became known in
Speaker:the weight loss surgery world, these drugs were
Speaker:being studied Modified, lengthened, refined. And I
Speaker:remember this friend of mine, she was actually
Speaker:involved in some of the early trials. And I
Speaker:remember this conversation vividly. She said, we
Speaker:have drugs that are going to replace surgery
Speaker:someday. I kind of scoffed at her. Replace
Speaker:surgery. Nothing replaces surgery. But guess what?
Speaker:She was right. Because during the 1990s, the late
Speaker:1990s were the fen phen revolution. And you may
Speaker:remember hearing about that. Two drugs put
Speaker:together led to weight loss, lack of interest in
Speaker:weight, until we discovered that there were issues
Speaker:with the tricuspid valve of the heart. And some
Speaker:patients actually had to have heart surgery
Speaker:because of this combination of drugs, which is no
Speaker:longer available thanks to FDA monitoring. So
Speaker:Byetta was the first drug that showed this
Speaker:promise. And then they began to refine the drug
Speaker:not only for the GLP1 effects on diabetes, but
Speaker:also for weight loss. The next medications were
Speaker:ligutride, semaglutide and tirzepatide, or
Speaker:zeppbound. Scientists continue to engineer longer
Speaker:half lives by attaching fatty acid side chains. So
Speaker:the molecules bind to the albumin in your body and
Speaker:they circulate longer. Now, you make GLP1, your
Speaker:body makes it, but it lasts about two minutes,
Speaker:whereas Ozempic or semaglutide lasts about a week.
Speaker:Tirzepatide lasts about five days. There are
Speaker:stable levels, steady receptor activation, not
Speaker:spikes and crashes. And in obesity trials, Ozempic
Speaker:produced weight loss approaching 15% of body
Speaker:weight. And the pills about the same. Tirzepatide
Speaker:or Tirzepbound exceeded 20% in the higher doses.
Speaker:And those approaches kind of began to match
Speaker:surgical outcomes. Even more importantly,
Speaker:cardiovascular outcome trials showed that
Speaker:reduction in major adverse cardiac events. So this
Speaker:wasn't just beach season medicine. This is heart
Speaker:attack and, um, stroke medicine. Now let's talk
Speaker:about what patients describe and have described to
Speaker:me from every one of them that I've operated on
Speaker:food noise, not hunger noise. A, uh, constant loop
Speaker:saying, what's next? What's in the fridge? Maybe
Speaker:I'll have a little more. Now, GLP RET1 receptors
Speaker:are expressed in your brain in a place called the
Speaker:hypothalamus and the brain stem. These drugs act
Speaker:by vagal signaling, meaning the vagus nerve, which
Speaker:goes down to your stomach and bowels in areas
Speaker:where the blood brain barrier is more permissive.
Speaker:They modulate appetite circuits, they dampen
Speaker:reward signally, they amplify satiety. And for
Speaker:many people, the noise quiets, not disappears,
Speaker:quiets. And that difference matters. When I had my
Speaker:first injection of Zepbound back in October, of
Speaker:2024. About 12 hours later, I noticed it was quiet
Speaker:in my brain. I didn't realize I had food noise. I
Speaker:don't think I understood what food noise was. I
Speaker:thought it was just this relentless desire that my
Speaker:patients had, but it was something deeper. And all
Speaker:of a sudden I could turn away from the plate and
Speaker:walk away and not think about it again. I could
Speaker:plan my vacations around historical objects
Speaker:instead of the next Michelin star restaurant. I
Speaker:wasn't interested in what we were going to have
Speaker:for dinner that night. I was interested in what we
Speaker:were going to do. But you know who isn't thrilled
Speaker:with GLP1 therapy? Diet culture, the low carb
Speaker:absolutist, the just eat fewer calories. Coaches,
Speaker:the ones selling books, meal plans because obesity
Speaker:is purely willpower in their minds and their
Speaker:answer is always try harder. Or that obesity is a
Speaker:moral failure, then shame for its treatment. But
Speaker:if obesity is neurohormonal dysregulation, the
Speaker:story changes and so does their business model. So
Speaker:no one worked harder at weight loss than my
Speaker:patients. No one. And I don't lack willpower
Speaker:either. I know food. I practice culinary medicine.
Speaker:I live and eat the Mediterranean diet. And you
Speaker:should too. But biology does not negotiate with
Speaker:virtue. When people told my surgery patients that
Speaker:surgery was the easy way out, they revealed how
Speaker:little they understood. Because surgery is not
Speaker:easy. And injecting myself once a week is not
Speaker:easy. I know it's hard to believe, but this
Speaker:surgeon has a phobia of needles. And yet I do it.
Speaker:Calling a doctor and asking for help. That takes
Speaker:courage. There are parallel universes in this
Speaker:story. In one, my career remained purely surgical.
Speaker:Revision, surgery when weight returns. And in this
Speaker:one, when revision loomed, I began to reach for
Speaker:GLP1 therapies instead. Less incision, more
Speaker:physiology. In the one universe, I actually
Speaker:considered surgery for myself. In this universe, I
Speaker:made a phone call to a physician. And now I weigh
Speaker:what I weighed when Nixon was president. I am both
Speaker:a surgeon and a patient. And your reporter. Now
Speaker:let me give you the caution. GLP1 drugs have risks
Speaker:and benefits. They can cause nausea. They can slow
Speaker:gastric emptying. You can become dehydrated. Some
Speaker:people talk about gallbladder risk, but remember,
Speaker:obesity itself carries a much higher gallbladder
Speaker:risk than GLP1s dollars. These drugs need
Speaker:monitoring. And if you're going to use one, you
Speaker:deserve a physician. Who is yours. Someone trained
Speaker:in obesity medicine. Not a pop up website, not a
Speaker:quick script mill. This is serious metabolic
Speaker:therapy and it deserves serious medical
Speaker:supervision. And no, I am not your doctor, nor
Speaker:will I be. I once believed that I had been sent to
Speaker:Phoenix as punishment. It was hotter than hell.
Speaker:Even Satan, I suspect vacations elsewhere and only
Speaker:Canadians brave July. But what I thought was exile
Speaker:was preparation. In the same desert where I
Speaker:learned to operate on metabolic disease. In that
Speaker:same ecosystem where the thrifty gene hypothesis
Speaker:was debated, a slow, beautiful venomous lizard
Speaker:carried the molecular key to a revolution. I
Speaker:thought I'd been sent to hell. It turns out I had
Speaker:been sent to the future. Please check the blog
Speaker:associated with this@your dr's orders.com
Speaker:and4q.com and uh, please check out my
Speaker:substack@drsimpson.com this was written and
Speaker:researched by me, Dr. Terry Simpson. And while I
Speaker:am a board certified physician, I am not your
Speaker:physician. If you're considering GLP1 therapy or
Speaker:changing your diet, you deserve a board certified
Speaker:physician trained in obesity medicine and a
Speaker:registered dietitian, not a quick online script
Speaker:mill. Please consult your own physician before
Speaker:making medical decision. All things audio are done
Speaker:by our friends at Simpler media. And the pod got
Speaker:himself Mr. Evotera producer. Girl productions
Speaker:make me sound more interesting than I am. Have a
Speaker:good week everybody. Hey Evo. If there are
Speaker:parallel universes, I'd like to think that in one
Speaker:of them I stayed in Seattle and never met the
Speaker:lizard. But in this universe, evolution
Speaker:outperformed diet culture. It turns out the future
Speaker:was crawling across a desert rock the whole time.
Speaker:One of the best things about Phoenix was meeting
Speaker:you. Uh, hey Ally, Terry finally said something
Speaker:nice about me. So cancel that rate increase I had
Speaker:planned. Thanks.
