When Dr. Fran Cogen, diabetes program director at Children's National Medical Center in Washington, read last year that patients with neonatal diabetes caused by particular genetic mutations could be successfully switched from insulin therapy to oral sulfonylureas, her mind raced.
“We realized we probably had several children with diabetes who were diagnosed under a year of age,” she said. The news about the mutations and treatment “was very interesting to me.”
She called Dr. Louis Philipson, the endocrinologist at the University of Chicago who—according to the article—had just treated a 6-year-old girl found to have a mutation in the KCNJ11 gene with high-dose sulfonylurea therapy, weaning her off her insulin pump.
After hearing about the treatment firsthand, she called one of the patients at Children's, an 18-year-old male whose diabetes had been diagnosed when he was a young infant. Genetic testing revealed that he too had the KCNJ11 mutation, and the family is now gearing up for treatment and a future that, at least in the short term, may well not involve insulin therapy.
Researchers who have spent the last several years trying to demonstrate that diabetes diagnosed before 6 months of age is almost never autoimmune hope that recent developments and reports in the literature will prompt more endocrinologists to take note of their patients' histories and order genetic tests when appropriate.
Neonatal diabetes, which is estimated to occur in 1 of every 100,000 newborns, is one of several clinical presentations in children for which a diagnosis of monogenic diabetes should be considered, experts say. A variety of genetic causes has been identified, but experts now believe that between 30% and 50% of children diagnosed with diabetes under 6 months of age have one of two mutations that affect the ATP-sensitive potassium channel of the beta cell.
The most common cause of permanent neonatal diabetes mellitus—the type of neonatal diabetes that has required continual insulin treatment from diagnosis onward—is a mutation in the KCNJ11 gene, which encodes a subunit of this channel called Kir6.2.
The mutation makes Kir6.2 less sensitive to the build-up of ATP and the channel thus fails to close in the presence of glucose (and increased intracellular ATP), leading to drastic reductions in insulin secretion.
Another less common cause is associated with mutations in the ABCC8 gene, which encodes the sulfonylurea receptor (SUR1)–another subunit of the beta cell's ATP-sensitive potassium channel.
Research on the mutations—and the notion that sulfonylureas can close this channel through an ATP-independent route—culminated last August when Dr. Andrew Hattersley of Peninsula Medical School in Exeter, England, and colleagues from several countries reported in the New England Journal of Medicine that 44 of 49 (90%) patients with kir6.2 mutations—aged 2 months to 36 years—successfully discontinued insulin after receiving high doses of sulfonylureas.
Glycosylated hemoglobin levels improved in all the patients, from a mean of 8.1% before sulfonylurea treatment to 6.4% at 12 weeks after cessation of insulin.
At 1 year, as the patients continued with much lower doses of sulfonylureas, the improved glycemic control was sustained—without any reports of severe hypoglycemia or any significant change in the frequency of hypoglycemia episodes (N. Engl. J. Med. 2006;355:467–77). As of last month, the patients' responses have been maintained past 2 years, Dr. Hattersley said in an interview.
Investigators of a second study published in the same issue of the journal reported that five out of nine patients with the ABCC8 mutation were also successfully switched from insulin therapy to oral sulfonylurea therapy (N. Engl. J. Med. 2006;355:456–65).
The long-term outlook for these patients, however, is uncertain. “We don't know, will they start having hypoglycemia? Will they start having inappropriate weight gain? Does the effectiveness (of sulfonylureas) wear out?” said Dr. Jay Cohen, medical director of the Endocrine Clinic in Memphis, Tenn.
Formation of a registry to assess long-term safety and efficacy would be helpful, he said, since “it's likely that no one institution will have more than one or two or three kids [with neonatal diabetes].”
Dr. Naomi Neufeld, professor of pediatrics at the University of California, Los Angeles, said she agrees that all children with neonatal diabetes should now be screened for the mutations, but she said she would approach treatment with some words of caution.
“It's intriguing to me to wonder, what happens 10 years from now? Will these children be different from those who burn out their pancreas?” she said.
Dr. Philipson said that while no one knows for sure, he suspects that they will indeed be different. “We know in type 2 diabetes, there's a significant failure of sulfonylureas over time. But these are [often] patients who are obese, insulin resistant, maybe hyperlipidemic, or [who] have other aspects of the metabolic syndrome that could impact negatively on their beta-cell function,” he said in an interview.