Compound That Mimics Insulin Might Lead To Pill For Diabetes

Diabetes occurs when the body's cells are unable to absorb enough blood sugar, or glucose, to fuel their activities. To access this energy supply, cells need assistance from the hormone insulin, which kicks off a complex series of steps inside the cells that allows them to store and use glucose. This cascade of events doesn't occur-or occurs poorly-in diabetics, either because their bodies don't produce insulin (type I diabetes), or because they are resistant to its effects (type II). An oral drug that could trigger the same set of reactions in place of insulin could therefore be a boon for people with either form of the disease.

In order to avoid or delay the serious complications their disease can cause, diabetics must carefully control their blood sugar levels-currently a high-maintenance task. People with the early-onset and more severe type I diabetes need as many as four daily injections of insulin. And people with type II diabetes, who are usually over 40 or overweight, must carefully regulate their diet, weight, and physical activity. About 10% of the population in the Western world develops some degree of type II diabetes, so a pill that made the disease easier to manage could have a widespread benefit.

The research team, whose members are from the US, Spain, and Sweden, screened over 50,000 different compounds to see if any of them might perform as a stand-in for insulin. The compound would have to bind to the cell's insulin receptor and activate a certain enzyme as the first step in the cascade of events that would lead to the sequestering of glucose in the cells. In essence, the compound would need to flip the same biochemical switch in the cell that insulin does. To see if any of the thousands of candidate molecules were up to the task, the scientists incubated the various substances with cultured cells engineered to have an abundance of insulin receptors. Then they tested these mixtures to find out whether the enzyme that initiates the insulin "signal" had been activated.

Insulin is a peptide molecule, a chain of amino acids whose bonds are vulnerable to the digestive acids in the stomach. In their screening tests, Bei Zhang of Merck Research Laboratories in Rahway, New Jersey and her colleagues were looking specifically at nonpeptide molecules, which can be absorbed into the bloodstream after being swallowed in a pill form. The most promising candidate was L-783,281, a compound whose prosaic name belies its origins from a fungus on a leaf collected in what is now the Democratic Republic of Congo. Remarkably, in a variety of tests, this tiny compound mimicked the activity of the much larger insulin molecule.

First the scientists experimented with the compound on cultured cells to determine that it docked onto the correct receptor and stimulated the same response as insulin. Then they administered the new compound by mouth to two different strains of mice that are standard animal models for human diabetes and found that it significantly lowered the mice's blood sugar.

The development of a pill that can be used in human diabetics will require much more research. Scientists must now tinker with the molecule to see if they can maximize its effectiveness while keeping it safe. Zhang and her colleagues are optimistic that other yet-unknown compounds besides L-783,281 might also be able to effectively imitate insulin. Further research could then lead to the development of a new suite of anti-diabetic drugs.