Drug Restores Insulin Secretion for Rare Type 1 Cases

EXETER, England, Aug. 3 -- Children who need insulin injections because of a rare type of diabetes may be able to do well instead with an oral sulfonylurea, according to researchers here.

An estimated 30% to 58% of those children, diagnosed younger than six months old, have a form of diabetes caused by a genetic mutation that prevents closure of the ATP-sensitive potassium channel in beta-islet cells, resulting in impaired insulin secretion. These children are normally treated with exogenous insulin.

But as members of the Neonatal Diabetes International Collaborative Group reported in the Aug. 3 issue of the New England Journal of Medicine, 44 of 49 patients with diabetes caused by the mutation were able to successfully discontinue insulin therapy with the use of oral sulfonylureas, agents that induce insulin secretion.

"We found that most patients with diabetes caused by KCNJ11 mutations can successfully switch from treatment by insulin injection to oral sulfonylurea therapy," wrote Andrew T. Hattersley, M.D., of the Peninsula Medical School here, and colleagues.

"This finding is in contrast to that for most patients with diabetes and undetectable insulin secretion, who need lifelong insulin therapy," they wrote. "This is an example of pharmacogenetics, since the genetic cause of the insulin deficiency determines the response to treatment."

Patients with heterozygous activating mutations in the gene KCNJ11, which encodes the Kir6.2 subunit of the adenosine triphosphate (ATP)-sensitive potassium channel in beta cells, first present with ketoacidosis or severe hypoglycemia, and are given insulin to stabilize glucose metabolism.

The reported occurrence rate of type of diabetes is about one in 500,000 newborns, but the actual occurrence rate may be five times that high, according to Mark A. Sperling, M.D., of the University of Pittsburgh, who wrote an accompanying editorial.

The investigators speculated that because sulfonylureas such as glyburide (Diabeta, Glynase, Micronase) close the beta-cell ATP-sensitive potassium channel by a route independent of ATP, these agents might be able to improve insulin secretion in patients with the KCNJ11 mutation.

To test this idea, they evaluated glycemic control in 49 patients with Kir6.2 mutations who were given oral sulfonylureas, either glyburide, glipazide, gliclazide, tolbutamide, or glimerpiride. Most of the patients (43) were treated with glyburide.

The investigators also looked at smaller subgroups of patients to assess how they secrete insulin in response to intravenous and oral glucose, a mixed meal, and glucagon, and they conducted in vitro studies looking at the response of ATP-sensitive potassium channels in frog oocytes.

They found that 44 of the 49 patients (90%) could successfully discontinue insulin after receiving a sulfonylurea. In addition, the in vitro studies showed that the sulfonylurea tolbutamide blocked the ATP-sensitive potassium channels in a manner similar to that seen in the patients.

Glycosylated hemoglobin (HbA1c) levels improved in all patients who switched to sulfonylurea therapy, from 8.1% before treatment to 6.4% after 12 weeks of treatment, (P<0.001). The improved glycemic control was sustained for at least one year.

The investigators also found that the drug-stimulated insulin secretion was more highly stimulated by oral glucose or a mixed meal than by intravenous glucose, and that exogenous glucagon increased insulin secretion only in the presence of sulfonylureas.

"Sulfonylurea therapy is safe in the short term for patients with diabetes caused by KCNJ11 mutations and is probably more effective than insulin therapy," the authors wrote.

In his editorial, Dr. Sperling wrote that all children with permanent diabetes developing within six months of birth should be tested for the Kir6.2 mutation, and if that test is negative, for a related mutation in the sulfonylurea receptor, labeled SUR1.

Because neonatal diabetes "has severe consequences if left untreated, and in many cases can be treated by a pill, a test for it should be included as part of routine newborn screening programs," he wrote.

He also suggested that Kir6.2 mutations may play a role in some familial forms of type 2 diabetes.

The authors of the study also addressed the issue of genetic diagnosis. "We recommend early molecular genetic diagnosis in all patients with diabetes whose disease was diagnosed before the age of six months, whatever their current age, since the identification of patients with Kir6.2 mutations has important therapeutic implications," they wrote.