Latest / Fork U with Dr. Terry Simpson / From Gila Monster to GLP-1 Revolution

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From Gila Monster to GLP-1 Revolution · Fork U with Dr. Terry Simpson

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  >> Dr. Terry Simpson: M In 1991, I finished my residency and surgery in
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  Seattle, Washington. Hiking in Seattle meant pine
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  needles, damp earth, a good rain show. You packed
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  Gore Tex, you expected mist or rain, and the
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  forest smelled alive. And then I landed in Phoenix
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  in July. Now, this wasn't a choice. I owed the
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  federal government because they paid for my
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  medical school and when given a choice of places
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  to go to fill that billet. While I wanted to be in
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  Anchorage, Phoenix was the only one that was open
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  that actually involved the city. Well, hiking
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  there meant bottled water and lots of it. And you
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  didn't pack a shell, you packed survival. The day
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  I went to Phoenix, it was 113 degrees at 6 o'
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  clock in the evening. The hills had fires from
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  small wildfires all over. And when you stepped out
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  of the car, the air felt like someone opened the
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  oven door and left it there. I didn't see beauty.
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  I saw brown rocks, no pine trees, no water. And I
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  remember thinking quite seriously, this must be
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  the only place in the world where even the lizards
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  carry venom. I was fairly certain I'd been sent
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  there because I was going to hell and this was
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  orientation and it was really hotter than hell.
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  And frankly, I suspect even Satan didn't vacation
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  there. Only Canadians. And who could blame them?
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  February in Toronto. But the desert waits you out.
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  And eventually I fell in love with it. The rocks
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  were copper at dusk. The saguaros now look like
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  cathedral columns to me. And if you're patient,
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  very patient, you might see one of the most
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  beautiful and dangerous creatures in North
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  America. The Gila monster. Beaded orange and
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  black, skin like mosaic tile. Heavy bodied,
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  deliberate. It doesn't rush, it doesn't need to.
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  It has venom in its bite. Gila Bend is named after
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  it, Gila river bears its name, and the desert
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  itself named after this creature. And little did I
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  know that this slow, venomous lizard would one day
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  give me the medication I inject. Today, Zepbound.
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  Today on Forku, we will be making sense of the
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  madness of GLP1 and the lizards who gave them to
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  us. I am your Chief Medical Explanationist, Dr.
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  Terry Simpson, and this is Fork U Fork University,
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  where we make sense of the madness, bust a few
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  myths and teach you a little bit about food and
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  medicine. A year before I left Seattle in 1990, an
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  endocrinologist named John Ng isolated a peptide
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  from the saliva or the venom of the Gila monster.
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  Now, he wasn't hunting reptiles, he was studying
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  glucose regulation. Because think of this, the
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  Gila monster doesn't eat that often. So how do
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  they regulate their glucose? We regulated second
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  by second. They didn't. And from the venom, he
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  isolated a molecule called extendin 4. Two years
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  later, while I was now at Phoenix, at the Bronx VA
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  Medical center, he purified it and published the
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  results. And here was the key. It resembled human
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  GLP1 or glucagon, like peptide 1, but it lasted
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  longer. Native GLP1, the kind that you and I
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  build, survives in circulation about two minutes.
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  Two minutes? Minutes. And that's before your own
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  body has an enzyme which is called DPP4. It
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  destroys it. Now, extendin4 resisted that
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  breakdown. It had staying power. And the discovery
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  eventually became the medication known as Byeda,
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  which was first released for the United States in
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  2005. It was the first GLP1 receptor agonist. It
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  was a drug for diabetes, not a weight loss drug,
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  not a cultural phenomenon, just careful
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  endocrinology. All of this happened while I was in
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  Phoenix. One of the things that they noticed about
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  this drug was that the patients who were on it
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  lost weight. And so when I would be dealing with
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  my friends who were in internal medicine and they
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  would have a patient who had both diabetes and
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  excess weight, they would start putting them on
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  Vieta, um, on the hopes that they would lose 2-4
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  kg. Everything intersected for me in Phoenix. I
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  had begun my career at the Phoenix Indian Medical
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  center, and that's where I cut my teeth doing
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  weight loss surgery. Type 2 diabetes among Pima
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  Indians in Arizona is among the highest prevalence
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  recorded anywhere in the world. Obesity rates were
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  also high. Metabolic disease was everywhere. But
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  in Phoenix, and especially at the medical center,
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  it wasn't just clinical, it was also scientific.
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  There's a metabolic ward there, which is basically
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  a hospital ward dedicated to doing research about
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  diet and fat mass. And it's from the National
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  Institutes of Health. It was in Phoenix that the
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  thrifty gene hypothesis was articulated. In that
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  ecosystem, which means something like efficiency
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  and scarcity becomes liability in abundance,
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  meaning if you're in an area where you can't eat
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  much, when you can eat much, you tend to store
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  more. Now, there's more than one thrifty gene, as
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  we found out. There's multiple ones, but at that
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  time, we only thought about one. Here's a funny
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  thing. The person who actually invented the
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  thrifty gene hypothesis offered me a job at the
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  nih. And sometimes I think, what a fascinating
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  ride that would have been. But we can't go back
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  except in history. So anyway, as I became known in
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  the weight loss surgery world, these drugs were
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  being studied Modified, lengthened, refined. And I
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  remember this friend of mine, she was actually
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  involved in some of the early trials. And I
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  remember this conversation vividly. She said, we
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  have drugs that are going to replace surgery
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  someday. I kind of scoffed at her. Replace
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  surgery. Nothing replaces surgery. But guess what?
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  She was right. Because during the 1990s, the late
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  1990s were the fen phen revolution. And you may
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  remember hearing about that. Two drugs put
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  together led to weight loss, lack of interest in
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  weight, until we discovered that there were issues
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  with the tricuspid valve of the heart. And some
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  patients actually had to have heart surgery
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  because of this combination of drugs, which is no
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  longer available thanks to FDA monitoring. So
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  Byetta was the first drug that showed this
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  promise. And then they began to refine the drug
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  not only for the GLP1 effects on diabetes, but
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  also for weight loss. The next medications were
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  ligutride, semaglutide and tirzepatide, or
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  zeppbound. Scientists continue to engineer longer
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  half lives by attaching fatty acid side chains. So
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  the molecules bind to the albumin in your body and
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  they circulate longer. Now, you make GLP1, your
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  body makes it, but it lasts about two minutes,
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  whereas Ozempic or semaglutide lasts about a week.
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  Tirzepatide lasts about five days. There are
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  stable levels, steady receptor activation, not
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  spikes and crashes. And in obesity trials, Ozempic
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  produced weight loss approaching 15% of body
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  weight. And the pills about the same. Tirzepatide
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  or Tirzepbound exceeded 20% in the higher doses.
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  And those approaches kind of began to match
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  surgical outcomes. Even more importantly,
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  cardiovascular outcome trials showed that
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  reduction in major adverse cardiac events. So this
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  wasn't just beach season medicine. This is heart
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  attack and, um, stroke medicine. Now let's talk
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  about what patients describe and have described to
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  me from every one of them that I've operated on
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  food noise, not hunger noise. A, uh, constant loop
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  saying, what's next? What's in the fridge? Maybe
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  I'll have a little more. Now, GLP RET1 receptors
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  are expressed in your brain in a place called the
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  hypothalamus and the brain stem. These drugs act
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  by vagal signaling, meaning the vagus nerve, which
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  goes down to your stomach and bowels in areas
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  where the blood brain barrier is more permissive.
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  They modulate appetite circuits, they dampen
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  reward signally, they amplify satiety. And for
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  many people, the noise quiets, not disappears,
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  quiets. And that difference matters. When I had my
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  first injection of Zepbound back in October, of
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  2024. About 12 hours later, I noticed it was quiet
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  in my brain. I didn't realize I had food noise. I
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  don't think I understood what food noise was. I
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  thought it was just this relentless desire that my
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  patients had, but it was something deeper. And all
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  of a sudden I could turn away from the plate and
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  walk away and not think about it again. I could
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  plan my vacations around historical objects
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  instead of the next Michelin star restaurant. I
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  wasn't interested in what we were going to have
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  for dinner that night. I was interested in what we
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  were going to do. But you know who isn't thrilled
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  with GLP1 therapy? Diet culture, the low carb
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  absolutist, the just eat fewer calories. Coaches,
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  the ones selling books, meal plans because obesity
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  is purely willpower in their minds and their
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  answer is always try harder. Or that obesity is a
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  moral failure, then shame for its treatment. But
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  if obesity is neurohormonal dysregulation, the
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  story changes and so does their business model. So
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  no one worked harder at weight loss than my
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  patients. No one. And I don't lack willpower
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  either. I know food. I practice culinary medicine.
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  I live and eat the Mediterranean diet. And you
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  should too. But biology does not negotiate with
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  virtue. When people told my surgery patients that
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  surgery was the easy way out, they revealed how
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  little they understood. Because surgery is not
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  easy. And injecting myself once a week is not
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  easy. I know it's hard to believe, but this
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  surgeon has a phobia of needles. And yet I do it.
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  Calling a doctor and asking for help. That takes
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  courage. There are parallel universes in this
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  story. In one, my career remained purely surgical.
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  Revision, surgery when weight returns. And in this
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  one, when revision loomed, I began to reach for
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  GLP1 therapies instead. Less incision, more
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  physiology. In the one universe, I actually
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  considered surgery for myself. In this universe, I
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  made a phone call to a physician. And now I weigh
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  what I weighed when Nixon was president. I am both
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  a surgeon and a patient. And your reporter. Now
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  let me give you the caution. GLP1 drugs have risks
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  and benefits. They can cause nausea. They can slow
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  gastric emptying. You can become dehydrated. Some
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  people talk about gallbladder risk, but remember,
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  obesity itself carries a much higher gallbladder
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  risk than GLP1s dollars. These drugs need
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  monitoring. And if you're going to use one, you
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  deserve a physician. Who is yours. Someone trained
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  in obesity medicine. Not a pop up website, not a
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  quick script mill. This is serious metabolic
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  therapy and it deserves serious medical
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  supervision. And no, I am not your doctor, nor
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  will I be. I once believed that I had been sent to
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  Phoenix as punishment. It was hotter than hell.
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  Even Satan, I suspect vacations elsewhere and only
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  Canadians brave July. But what I thought was exile
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  was preparation. In the same desert where I
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  learned to operate on metabolic disease. In that
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  same ecosystem where the thrifty gene hypothesis
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  was debated, a slow, beautiful venomous lizard
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  carried the molecular key to a revolution. I
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  thought I'd been sent to hell. It turns out I had
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  been sent to the future. Please check the blog
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  associated with this@your dr's orders.com
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  and4q.com and uh, please check out my
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  substack@drsimpson.com this was written and
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  researched by me, Dr. Terry Simpson. And while I
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  am a board certified physician, I am not your
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  physician. If you're considering GLP1 therapy or
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  changing your diet, you deserve a board certified
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  physician trained in obesity medicine and a
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  registered dietitian, not a quick online script
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  mill. Please consult your own physician before
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  making medical decision. All things audio are done
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  by our friends at Simpler media. And the pod got
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  himself Mr. Evotera producer. Girl productions
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  make me sound more interesting than I am. Have a
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  good week everybody. Hey Evo. If there are
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  parallel universes, I'd like to think that in one
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  of them I stayed in Seattle and never met the
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  lizard. But in this universe, evolution
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  outperformed diet culture. It turns out the future
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  was crawling across a desert rock the whole time.
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  One of the best things about Phoenix was meeting
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  you. Uh, hey Ally, Terry finally said something
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  nice about me. So cancel that rate increase I had
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  planned. Thanks.