Type 2 diabetes accounts for 90 percent to 95 percent of the estimated 16 million Americans with diabetes. Patients with the disorder develop resistance to insulin, a hormone that helps the body control blood sugar levels. In many cases, their beta cells also make less insulin. Physicians typically treat the condition with a sulfonylurea and metformin, a drug that increases insulin sensitivity.
Sulfonylureas bind to potassium channels on the surfaces of beta cells. These channels normally control electrical activity and hence the levels of calcium in the cell; when the drug blocks the channels, calcium levels rise in the beta cell, causing release of insulin.
Nichols and Remedi saw an important opportunity to learn about the long-term failure of sulfonylureas with the availability of an implantable time-release capsule form of one of the drugs, glibenclamide. They implanted the capsules in the necks of mice. As expected, the drugs initially caused mouse beta cells to release more insulin and blood sugar levels dropped rapidly. Within a few days, though, the response to the drug reversed: Insulin secretion levels dropped, and blood sugar levels rose dramatically.
Examination of the pancreas showed that the animals' beta cells were still alive and contained normal levels of insulin.
"The problem seems to lie somewhere between the trigger for secreting insulin, which was hyperactivated while they were on the medication, and the actual mechanisms that release insulin," Nichols says. "The insulin is there, it's just not ready to release."
Nichols and Remedi are currently seeking further insight into the causes of this breakdown.
|Contact: Michael Purdy|
Washington University School of Medicine