1/ Over a century ago, scientists uncovered a curious link between the gut & the pancreas. This sparked decades of research, culminating in one of the greatest medical breakthroughs. This is the story of GLP-1 that I would like to share. 𧡠x.com
2/ I'll draw from a couple key papers:
Daniel J. Drucker (2024): jci.org
Knudsen & Lau (2019): ncbi.nlm.nih.gov
Daniel J. Drucker (2024): jci.org
Knudsen & Lau (2019): ncbi.nlm.nih.gov
3/ The story starts in the early 1900s. Researchers observed that oral glucose triggered a stronger insulin response than intravenous glucose. Why would this be? It seemed to indicate a gut signal to the pancreas, suggesting the existence of a hormone, later named βincretin.β
4/ In the 1980s, the incretin GLP-1 was discovered by Habener, Holst, & @DanielJDrucker π¨π¦ π. GLP1, a gut hormone sends a message to the pancreas to stimulate insulin secretion... but only when blood glucose is high. Could this be a potential game-changer for type 2 diabetes?
5/ Further research found that GLP-1 slows gastric emptying, suppresses glucagon, and reducing body weight by modulating key circuits in the non-conscious brain. With each revelation it became clearer that they may be on the brink of a transformative breakthrough in medicine.
6/ An issue though was that GLP-1 had a very short half-life. It lasted just 2 minutes due to rapid degradation by the enzyme DPP-4. This posed a major challenge because any therapy based on it would not succeed if the body quickly chewed it up and spit it out.
7/ Then in the 1990's there was a fortunate discovery of exendin-4 in Gila monster venom. This hormone had similar effects & structure to human GLP1. It was also resistant to DPP4 breakdown. This led to the drug exenatide & a resource to figure out how to escape the savage DPP4.
8/ Nobel Prize winning advances in protein engineering allowed scientists to synthesize proteins one amino acid at a time. They could now build GLP1a w/ precise modifications:
πamino acid substitutions to resist DPP-4.
πadd fatty acid to bind albumin, enabling slow release
πamino acid substitutions to resist DPP-4.
πadd fatty acid to bind albumin, enabling slow release
9/ The innovations eventually led to semaglutide & a large portfolio of clinical trials showing broad benefit across multiple diseases: diabetes, obesity, heart disesae, kidney disease, liver disease, OSA, and arthritis, and many more to come.
10/ The arrival of GLP1a is a transformative moment in medicine. GLP1a, by treating obesity, treats the root cause of a broad swath of chronic diseases that were previously thought of as separate. This will eventually impact health systems into a more integrated approach.
11/ GLP-1 unlocked the potential of other hormones, like GIP, glucagon, and amylin which had limited effects on their own but are synergistic together. New combination therapies like tirzepatide are setting the stage for even more effective treatments for metabolic disease.
12/ Science & medicine is π. All the arduous bench work now directly impacts my patient's lives. GLP1 directly treats the underlying neurobiology of obesity, where the disease is "seated" in the interplay between gut hormones and the non-conscious brain.
13/ GLP1a is effective treatment for the real & chronic disease of obesity & all of its manifestations - the most important disease of our time. And I'm excited to be here. A huge bonus!? Effective treatment also gives us an opportunity to release all the unnecessary blame & shame. So let it go!
And hereβs the beginning if you wanted to like or share. Feel free to follow me along as well! My hope is to share information that can make the π a better place. I practice obesity medicine and hope to see a society arise that no longer needs my services!
Loading suggestions...