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.

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