Pramlintide
(Symlin)

The Discovery

The Insulin Story (Incomplete)

What Nobody Realized Was Missing

In 1922, Frederick Banting and Charles Best discovered insulin, and it was revolutionary. Suddenly, Type 1 diabetics — people whose pancreases had stopped producing any insulin — could be treated. The insulin shots saved millions of lives. For over 60 years, insulin was the only diabetes treatment available, and it worked amazingly well compared to doing nothing.

But insulin didn't solve the whole problem. Even with perfect insulin control, Type 1 diabetics struggled. Their blood sugar would spike after meals, crash too low at night, and stay unpredictable despite careful dosing. Doctors and patients just accepted this as normal. 'You'll always struggle with control,' they'd say. 'That's what diabetes means.'

What nobody realized was that your pancreas makes TWO crucial hormones, not one. Insulin controls how much sugar gets taken up by cells. But it has a partner — another hormone released at the exact same time from the exact same cells. Nobody knew what that second hormone did or how important it was, because it had never been properly studied. It was just... missing, with no name, no recognition, and definitely no replacement therapy.

The Breakthrough

The Sticky Problem Revealed

Why Is Human Amylin Such a Mess?

In 1987, the mystery hormone finally got a name: amylin. When Garth Cooper and Per Westermark published their discoveries, they revealed something shocking — amylin wasn't just hiding in pancreases. It was hiding in TOXIC CLUMPS. The deposits Cooper found in diabetic pancreases were made of amylin fibrils — twisted, stuck-together protein tangles that looked like the plaques in Alzheimer's disease.

This raised an urgent question: if amylin normally works alongside insulin, why does it clump up and become toxic? Scientists studying the structure realized the terrifying answer: human amylin naturally wants to aggregate. The amino acids in its sequence contain 'sticky' regions that make the molecules grab onto each other and form fibrils. When beta cells die in Type 1 diabetes, amylin sits around in the tissue, clumps together, and becomes poison. In Type 2 diabetes, amylin fibrils actually help kill the beta cells in the first place.

This meant that making a drug from human amylin was nearly impossible. How do you inject something that clumps up into toxic fibrils? The molecule would aggregate in the syringe, in the bloodstream, maybe in the tissues. It seemed like Nature had made an unsolvable problem: a hormone that your body desperately needs, wrapped in a chemical structure that refuses to stay soluble.

The Trials

The Rat Solution

Borrowing Nature's Chemistry Hack

Here's where the story takes an unexpected turn. Scientists looked at rat amylin — the version that rats naturally produce — and found something remarkable: rats don't get the same amylin aggregation problem that humans do. Why? Because rat amylin has proline amino acids at three specific positions (25, 28, and 29) that act like 'kinks' in the chain, preventing the molecules from sticking together.

An idea emerged: what if you took human amylin — the version patients actually needed — and swapped in just three amino acids at those exact positions, replacing them with prolines from the rat version? You'd get something with human amylin's effects, but rat amylin's solubility. It was elegant: borrow one specific trick from a completely different species and solve the whole aggregation problem.

This modified version was called pramlintide. It had the same 37-amino-acid length as native amylin. It had 34 amino acids identical to human amylin. But those three proline substitutions made all the difference — pramlintide stayed soluble in the bloodstream, didn't clump into toxic fibrils, and could actually be injected safely. The chemists had done what seemed impossible: turned a toxic hormone into a usable medicine by learning from a rat.

The Crisis

The FDA's Skepticism

When the FDA Says No (Twice)

Even with a brilliant solution, getting pramlintide approved wasn't easy. When Amylin Pharmaceuticals submitted pramlintide to the FDA in the late 1990s, the agency was skeptical. Amylin replacement? For diabetes? It seemed unnecessary when insulin already worked. The FDA rejected the application. Amylin went back to the drawing board and gathered more data. A second submission came back with another rejection.

Meanwhile, Amylin Pharmaceuticals faced financial ruin. The company had bet everything on pramlintide, spent millions on development, and had nothing to show for it except rejections. The stock price plummeted. Investors questioned whether amylin biology was real. Inside the company, people debated whether they should give up entirely on the amylin strategy.

But the clinical trial data kept coming in, and it was undeniable: patients taking insulin plus pramlintide had better blood sugar control and lost weight compared to insulin alone. The benefit wasn't huge — pramlintide wasn't going to replace insulin — but it was real and meaningful. Finally, on March 16, 2005, the FDA approved pramlintide (Symlin) for use with insulin in both Type 1 and Type 2 diabetes. It was the first and only amylin analog ever approved. The journey from toxic hormone to usable medicine had taken 18 years.

The Legacy

The Complicated Legacy

A Proven Drug That Never Became a Blockbuster

Pramlintide proved something important: Type 1 diabetics needed more than just insulin. The hormone works, the science is real, and patients benefit from amylin replacement. Yet despite FDA approval, Symlin never became a blockbuster drug. The main reason was inconvenient: you had to inject it separately from insulin, three times a day before meals. Most Type 1 patients were already managing multiple insulin injections. Adding a fourth medication was a burden. Some patients developed nausea at first. The market uptake never matched the scientific achievement.

But Amylin Pharmaceuticals' bigger success was waiting in the wings. The same company that developed pramlintide also created exenatide (Byetta), a different gut hormone drug that became hugely popular. In 2012, Bristol-Myers Squibb and AstraZeneca acquired Amylin for $7 billion — not primarily for pramlintide, but for the amylin research strategy and exenatide franchise that proved gut hormones were important for diabetes treatment.

Today, pramlintide sits in a strange position: scientifically proven, FDA-approved, with real benefits, but overshadowed by newer GLP-1 drugs like semaglutide that came later and have simpler dosing. Yet for certain Type 1 diabetics, Symlin remains the only medication that replaces the hormone their body is actually missing. The quest that started with toxins in diabetic pancreases, moved through rat amylin chemistry, survived FDA skepticism, and proved amylin replacement works — it didn't change the world. But it changed the understanding of what Type 1 diabetes actually is.