GLP-101

Insulin secretion happens pretty quickly after a meal, in part, due to nutrients and gut-derived incretins like GLP-1.  GLP-1 secretion only happens with a meal, so the insulinemic response to oral glucose is greater than that to i.v. glucose:

 

 

Part 2. The liver sees WAY more insulin than peripheral tissues when this happens.  And it’s probably that way for a reason; ie, perhaps you need more insulin to shut down hepatic glucose output than to stimulate muscle glucose uptake and shut down lipolysis, etc.

 

 




 

The opposite occurs in diabetics injecting insulin: skeletal muscle and adipose see disproportionately more insulin.  Maybe even too much insulin, as this can cause lipohypertrophy and insulin resistance.  I don’t know the difference in liver/periphery exposure with endo vs. exo insulin, but I believe Petro does.

Big Pharma got keen to this and started working on an injectable insulin that preferentially targeted liver, “insulin peglispro” (Russel-Jones 2016).  However, they found a somewhat predictable side effect, elevated liver fat compared to other insulin preparations.

 




 

Enter: GLP-1

GLP-1 stimulates insulin secretion, shuts down glucagon, and slows gastric emptying.  All of these things contribute to GLP-1’s anti-hyperglycemic effect.

 

 

GLP-1’s half-life is dismally short, so some longer-lasting mimetics were developed – the “-tides,” eg, exanatide (Byetta) and liraglutide (Victoza).  DPP-IV inhibitors prolong the half-life of endogenous GLP-1 (and probably a lot of other things) – the “-gliptins,” eg, sitagliptin (Januvia), vildagliptin (Galvus), and saxagliptin (Onglyza).

They all basically work, but dulaglutide (Trulicity) is all the rage because it causes weight loss… in all fairness, this is basically true for most of the –tides, but more so for Trulicity.

 




 

Uh-oh, these drugs enhance insulin secretion but cause weight loss…  maybe via appetite suppression or CICO or something (eg, Jones et al., 2012).

 

Part 3. Rumor has it that DPP-4 inhibitors were first discovered in Gila Monster venom (ok, not really a rumor).  Why are DPP-4 inhibitors in Gila Monster venom?  I don’t know.  Ha!  DPP-4 is an anti-hyperglycemic agent, not a hypoglycemic agent… and anything trying to hunt a Gila Monster is probably hungry, not in a fed state, so there wouldn’t be any GLP-1 around anyway.  Turns out Gila Monster venom has a wide variety of toxins, so presence of DPP-4 inhibitors may be a coincidence, accident, or interact with something else.  Whatevs.

 

calories proper

 

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  • Lisa Greer

    Hi Bill. I really like your blog and enjoyed your book! I have about 100 pounds left to lose. I’ve lost 30 over the past 2 years of trying and getting diagnosed with ADHD-PI and PCOS (I’ve know that for many years but wasn’t properly treated until after 2011) which I definitely have. I made no progress until I went on meds. I could never seem to NOT eat more than I expended. I have always had a huge appetite, and my NEAT is low from what I can tell, even though I used to exercise a lot and dance to keep weight off when I was younger (I had to do a lot of it for it to work, too).

    As for ADHD, apparently, neurotransmitter levels not being right go hand in hand with obesity. Who knew? 😉 I was born hungry, I’m told. My point is, I’m on the low dose of Trulicity to help with weight and insulin resistance, and I find that it does little or nothing for me weight loss wise. I prefer metformin, but I have to stay on 1000 mg (a low dose for someone with PCOS) due to a dodgy stomach, prone to bleeding and severe anemia. I have tried topiramate, too, but the side effect of it making me very very tired and depressed after a couple of days of taking it make it a no go for every day use, though it does work for weight loss for me at a low dose, even. I just can’t take it consistently. But my main meds are Vyvanse, trulicity, and metformin for now.

    I am at the point of considering gastric sleeve. I’m 40, and I’m tired of fighting my ravenous appetite. It makes CICO very hard…in any form I undertake it. I am stuck in a range of 5 pounds and can’t seem to get below it. Do you have any thoughts for people like me that my endocrinologist doesn’t have? I haven’t found my docs to be much help in this department at all, and I’ve been heavy like this for over 10 years. Do you think the sleeve is worth pursuing? I need something that will take my appetite down more than it is now without horrible med side effects and also help with high blood pressure, etc. that I have. Weight loss should help…and that’s what I’m aiming for. Sorry for the book.

  • Dr.Dan

    A component of Gila Monster venom is “exendin-4”, a GLP-1 analogue that was eventually marketed as “exenatide” (Byetta). It’s a potent GLP-1 receptor agonist but has better pharmacokinetics due to having DPP-IV resistance.

    It is not a DPP-IV inhibitor …. but it is a DPP-IV resistant analogue of GLP-1.

    • any idea why it’s in the venom?

      • Dr.Dan

        No – it’s a question that often came up at the end of talks I have given in the past (I used to use exendin-4 and truncated versions as pharmacological tools, so would throw in a pic of a Gila monster etc). I did once track down a Gila expert – the answers were a bit vague. Things may be clearer now, but the hypothesis at the time was it was related to the long periods that the lizard can go between meals (I think they can eat huge amounts and then nothing … like snakes). They also store their fat in their tails, which is kind of weird.

        And it’s not really in the venom – it’s in the saliva… unlike snakes, these guys don’t come equipped with hypodermic needles (they clamp on and chew … apparently they are very hard to dislodge once they do this. Ouch!). Strange thing is that they are the top predator in their environment, so don’t need venom as a defence … and they don’t need it to catch prey either (often raid eggs from nest etc. Given that exendin-4 is not toxic, it could just be in the saliva as an artefact, while the more noxious stuff is there by design.