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Why Rats Do Not Get Islet Amyloid: The Amylin Story and the Design of Pramlintide
Some peptides are easy to make and impossible to keep dissolved. Human amylin is one of them. It is a 37-amino-acid hormone made by the same cells as insulin, and it has a nasty habit of clumping into the fibers that damage those cells. A comparison with the rat version of the same peptide showed how to fix it.
Key takeaways
- Amylin, also called islet amyloid polypeptide, was isolated in 1987 by groups in the UK and Sweden.
- It is released with insulin and helps slow gastric emptying and reduce appetite in research models.
- Human amylin forms amyloid fibrils; rat amylin does not.
- The difference is that rat amylin has prolines at positions 25, 28 and 29.
- Pramlintide, approved in 2005, is human amylin with those three prolines.
A hormone found in deposits
In 1987, Garth Cooper and colleagues in Oxford, and Per Westermark and colleagues in Uppsala, separately studied the amyloid deposits found in the islets of the pancreas in people with type 2 diabetes and in some tumors. The deposits were made mostly of a previously unknown peptide of 37 amino acids. It was later shown to be a normal hormone, made and released alongside insulin.
A peptide that sticks to itself
In the stretch of sequence between positions 20 and 29, human amylin has an arrangement that favors forming beta-sheet structures. Those sheets stack into long fibrils. Fibrils are insoluble and can damage cells, which is why human amylin is also a notorious headache in the lab: solutions turn cloudy and activity falls. Our posts on aggregation and how to detect it explain the process.
The rat clue
Rats and mice make amylin too, but they do not develop islet amyloid. When researchers compared the sequences, the answer was striking. The rodent peptide has proline at three positions in the amyloid-prone stretch, 25, 28 and 29. Proline is a rigid amino acid that breaks beta-sheet structure like a kink in a chain.
Designing pramlintide
Amylin Pharmaceuticals took the human sequence and substituted proline at positions 25, 28 and 29. The result keeps the biological activity of amylin while dissolving cleanly and resisting fibril formation. Named pramlintide, it was approved in 2005. It is a good example of designing against aggregation, a different goal from the half-life work in our half-life post.
Lessons for researchers
- Comparing sequences between species can reveal which positions matter.
- A single amino acid type, proline, can break a structure.
- Aggregation-prone peptides need care with pH, concentration and storage; see isoelectric point.
- A clear solution is the starting point for reliable data.
The bottom line
The amylin story is a lesson in reading sequences. A few small differences between species held the key to a better molecule. Read about related metabolic peptides in our appetite hormone map and the incretin story.
Related reading
- Why peptides aggregate
- The appetite hormone map
- Half-life engineering
- Browse the full Research Library
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For laboratory research use only. Not for human or veterinary use, and not intended to diagnose, treat, cure or prevent any condition. This article is educational and is not medical advice.