by Ed Bryant
In Voice of the Diabetic Vol 14, No 2, April 1999,
I reviewed research into the action of the human hormone amylin, and its relationship
to good diabetes control. Here is a quick review of what we have learned since.
For decades, diabetes researchers thought type 1 diabetes was simply about lack
of insulin. Their model of euglycemia, normal blood glucose, was a balancing
act between two hormones, insulin and glucagon. All diabetes medication either
stimulated, replaced, or augmented the action of one of these two, and that
there might be another hormone at work, a third piece of the puzzle, was not
considered.
We may now have the missing piece. Amylin Pharmaceuticals, Inc., a San Diego,
California based company, has been researching the human hormone Amylin, and
their findings, while still under investigation, are fascinating. Their product,
pramlintide (trade name Simlyn), is now in Phase III clinicals.
Amyloid, the parent compound, was first noted about a century
ago, by pathologists performing autopsies. In the 1980s, the chemical was analyzed,
and the peptide amylin sequenced from it. Because naturally-occurring human
amylin is too thick and viscous to inject, Amylin Pharmaceuticals developed
its injectable analog, pramlintide (Simlyn).
There is a lot of research interest in amyloid compounds, and the role they
may play in other diseases, most notably Alzheimers disease. One company, Neurochem,
from Quebec, Canada, is even exploring the role of "rogue" amyloids
in the destruction of normal amylin response in type 2 diabetes -- but our focus
is on the relationship between amylin and insulin.
These two hormones are both produced in the Beta cells of the human pancreas.
A type 1 diabetic, deficient in insulin, is equally deficient in amylin. A type
2 diabetic may exhibit a lesser amylin deficit (or dysfunction, Neurochem, above,
is researching this issue). But what does amylin do?
Amylin appears to have a moderating effect on blood glucose absorption, from
the gut into the blood. It acts as a set of brakes, slowing and managing meal-derived
glucose inflow, controlling pancreatic glucagon secretion, and thus regulating
hepatic (liver) glucose production. It smoothes the "peaks and valleys"
of blood sugar fluctuation, improving overall glycemic control.
In studies where Hemoglobin A1C test results were compared between those who
used both insulin and Simlyn, and those who used only insulin, the A1C test
results of those who used the injectable amylin analog were significantly lower
than those who did not.
Clinical trials also revealed that most overweight diabetics who received Simlyn
lost weight, while most lean diabetics, given the same medications, did not
lose weight. Although the mechanism that produced these pleasant, unexpected
findings is not yet clear, I find it exciting, as achieving and maintaining
ideal weight contributes to good health, a sense of well-being, and for some,
a reduction in the amount of insulin needed to maintain good control.
Many diabetics have experienced episodes of severe hypoglycemia, dangerously
low blood sugars. "Tight control," multiple-test, multiple injection
therapy to keep the blood sugars as close to a non-diabetic "normal"
as possible, increases the risk of "hypos." Animal studies have shown
that pramlintide, which normally retards release of glucose stored in the liver,
suspends its action in the presence of hypoglycemia. This suggests a healthy
supply of Simlyn might help lower the blood glucose without increasing the risk
of hypoglycemia. Some test data suggest a reduction in hypoglycemic episodes
for the duration of amylin therapy.
Amylin Pharmaceuticals conducted a series of clinical tests several years ago, Phase IIIs involving a graduated series of dosages. Most of the results from this research were well within acceptable standards; but the group receiving the highest dosages encountered unexpected difficulties, and the U.S. Food and Drug Administration, which rules on the safety and suitability of every new drug to be sold in the United States, understandably ordered more tests before approval would be considered. This second round of Phase III clinicals is now under way.
These are not small tests. In the first set of Phase IIIs, over 1700 people received Simlyn. Both type 1 and insulin-using type 2 diabetics took it, in different strengths, and with minimal side effects in all but the highest dosages. In most cases, significant reductions in hemoglobin A1C numbers were noted -- and it has been proven lower A1Cs significantly cut the risk of diabetes complications.
Much work is still under way to determine amylin's exact role in the management of diabetes. If Simlyn's retests are successful, if the company can answer the questions its high-dosage results exposed (and deal with the tremendous expense of retesting the drug), we may well see FDA approval. If they cannot, it will go into the books as one more idea that didn't quite make it. For the sake of all diabetics, I hope we see this one happen. Stay tuned.