A diet rich in donuts, crackers and ice cream has taken its toll on the more than 15 million Americans who suffer from Type 2 diabetes. As well as having to beware the possibility of a sugar-induced coma, they are at increased risk of cardiovascular disease, renal disease, blindness and blood clots.There are several drugs on the market to treat diabetes but they all have serious side effects. A new approach by Auwerx and colleagues described in today's issue of the journal Molecular Cell may offer a way of avoiding some of these.
Most of the current drugs are compounds called glitazones. These bind to a receptor called perixosome proliferator-activated receptors (PPARs) on the surface of cells.
PPARs increase sugar metabolism and fat cell proliferation by turning specific genes in the nucleus on and off, and molecules that bind to the receptor increase insulin's ability to lower blood sugar in the body. This counteracts Type 2 diabetes, which results, not from a lack of insulin, but from a lack of sensitivity to it.
The hunt has been on for molecules that increase insulin sensitivity but don't trigger the creation of fat cells.
Glitazones contain a chemical group called a thiazolidinedione ring, which binds very firmly to PPAR. So Johan Auwerx and colleagues at the University of Strasbourg in France investigated a molecule provided by researchers at GlaxoWellcome R&D in North Carolina, in which the thiazolidinedione ring was replaced by a different chemical group.
The team found their new molecule did alter PPAR activity, but wasn't as efficient as glitazones. When they treated various models of diabetic mice with the molecule, they found the mice were able to clear sugar from their systems with less insulin, indicating an increased sensitivity of insulin, but that they didn't gain weight.
“This serves as a proof of principle that you can modulate PPAR-gamma activity rather than inducing full activation,” says Frederic Picard of INSERM in Strasbourg. Researchers can now be hopeful of developing side-effect free drugs for Type 2 Diabetes.
First, however, they will have to learn exactly how the new molecule works. It could be that a higher level of PPAR activation is required to trigger the fat-cell creating pathway than is required to increase insulin sensitivity. Alternatively, it could be that the novel shape of the binding area makes a difference to which pathway is triggered.
[Contact: Johan Auwerx]
26-Oct-2001
