Natural blood sugar level lowering compound could lead to new drugs to treat type 2 diabetes

A carbohydrate isolated from the liver lowers blood sugar levels after it is injected into diabetic rats, according to research carried out by a team of experts at the University of Virginia Health System (UVHS).

The UVHS team believes this compound, called D-chiro-Inositol-Galactosamine, or INS2, acts as a messenger inside cells to switch on enzymes that regulate blood sugar, taking glucose from the bloodstream into the liver and muscles where it is stored. INS2 is naturally occurring in the body and is found in human blood.

Their findings are published in the Oct. 4, 2005 issue of the journal Biochemistry and could lead to new drugs to treat type 2 diabetes, the most common form of the disease. In type 2, the blood has normal or high levels of the insulin, but the liver and muscles don't respond well to the hormone. As a result, blood sugar stays high, causing health problems. Diabetes is a known risk factor for nerve and kidney damage, stroke, heart disease and blindness, among other complications. Some scientists think that the complications are due to modifications in certain proteins and in how genes respond to insulin.

"We believe this molecule works by sending a message inside the cell to respond to insulin, which helps cells dispose of excess glucose," said Joseph Larner, MD, PhD, professor emeritus at UVHS and former chairman of the department of pharmacology, who has been studying the molecule for nearly two decades. Larner and his colleagues isolated INS2 from cow livers, determined its chemical structure, synthesized it, then injected the compound into diabetic rats, with blood sugar levels at or above 500 milligrams per deciliter. The rats were then injected with insulin. Diabetes researchers at UVHS were pleased that the more compound they injected, the more blood sugar decreased in the animals. "This compound is dose dependent and active. It potentiates the action of insulin," explained David Brautigan, PhD, director of the Center for Cell Signaling at UVHS.

Larner and Brautigan are part of a multi-disciplinary team at UVHS that includes chemist Milton Brown and structural biologist John Bushweller. Using computer modeling, they docked the INS2 compound onto an enzyme in cells called PP2C. If INS2 could activate PP2C, it would trigger other events in cells activated by insulin.

"INS2 was added and the purified PP2C enzyme was activated," Brautigan said. "When we changed one amino acid in PP2C that the modeling predicted was the site for INS2, then the activation by INS2 was absent. In that way the enzyme assay confirmed the model." The UVHS group has been working to define the action of INS2 in hopes that it will potentially help millions of diabetics worldwide. A 3D image of the molecule graces the cover of Biochemistry's Oct. 4th issue.