Scientists discover signal KO's cause diabetes
signals in liver cells causes diabetes. These findings pave the way
for drug strategies to boost these two different signals and treat
the different metabolic components in sufferers.
An estimated 18 million Americans have type 2 diabetes, and about one-third are unaware they have the disease. In this disorder, the body does not make enough insulin or resists its effect, a phenomenon called insulin resistance. Without effective insulin, cells throughout the body are unable to convert sugar in the bloodstream to energy, resulting in chronic fatigue, thirst and other symptoms of high blood sugar.
People with diabetes also have abnormalities in lipid metabolism and are two to four times more likely to have cardiovascular disease, and they run a higher risk of damage to nerve, eye, kidney and other body tissues.
"By lowering the level of two key insulin signalling proteins in liver cells, we began to uncover just how complex type 2 diabetes and the related metabolic syndrome are," said C. Ronald Kahn, president of Joslin Diabetes Centre.
"Both protein signals needed to be knocked out at the same time to create the full diabetic syndrome, while depleting just one or the other caused only either the glucose or the lipid abnormalities associated with diabetes. Thus, these two pathways complement each other, each controlling a part of the metabolism that is disrupted in type 2 diabetes or the metabolic syndrome."
The study is published in the Feb. 10 online edition of the Journal of Clinical Investigation, and aims to shed new light on the question: 'How do cells normally process the hormone insulin and what goes wrong in diabetes?'
It primarily focused on two of the early intracellular signalling proteins, IRS-1 and IRS-2, and especially their role in the liver, which is a key organ for both glucose and lipid metabolism.
Previous studies have shown that mice bred without the genes for either IRS-1 didn't develop diabetes, while those lacking IRS-2 developed diabetes, but this was primarily because of a defect in the beta cell, so evaluating the role of the liver was impossible.
To solve this dilemma, Dr. Kahn's team used a genetic tool, which allowed the researchers to turn off specific signals with a virus that targets specific cell types with a kind of RNA that would interfere with the liver cells' ability to make IRS-1 or IRS-2.
In the study, the effect of the RNA interference lasted one to two weeks, reducing IRS-1 and IRS-2 by up to 80 percent. By designing separate experiments, the researchers found that each substrate acted on a different part of metabolism. Low levels of IRS-1 drive cells to make more glucose, causing blood sugar to rise. Low levels of IRS-2 are linked to higher levels of blood fats such as triglycerides. Acting alone, neither causes diabetes. But when both substrates are low, diabetes results.
"Our findings show what happens when we knock out these two protein signals, causing conditions to worsen," said Dr. Kahn. "The next step is to look for ways to keep their levels up, possibly leading to new ways to prevent and treat diabetes."
According to the European Association for the study of Diabetes (EASD), the DPP IV inhibitors are among the more promising new therapies in the pipeline for the treatment of type 2 diabetes, which currently affects 37 million people in the top seven markets and is expected to grow to 50 million people by 2012.
Physicians have been disappointed by the lack of successful new therapies for type 2 diabetes in the last 20 years, but if Phase III results, which are expected in Q3 2005, mirror the results to date, LAF-237 could become a useful new tool to diabetologists from 2006.
Meanwhile, Merck & Co has also been working on DPP IV inhibitors and was scheduled to start Phase III trials of a lead candidate, MK-0431, in the middle of 2004. Bristol-Myers Squibb has an unnamed candidate in Phase II, while Novo Nordisk is very active in this area. Researchers from the latter company published an article detailing the structure of DPP IV bound to a substrate in the January 2003 issue of Nature Structural & Molecular Biology.
Other companies working on DPP IV inhibitors includes GlaxoSmithKline, with three compounds in Phase I, and Germany's Probiodrug (which sold its DPP IV platform to UK firm Prosidion in June).
