The Littlest Patients
A Deeper Understanding of Neonatal Diabetes Leads to Better Treatment
Researcher: Colin Nichols, PhD
Occupation: Cell Biologist, Washington University in St. Louis
Focus: Islet Biology
Research Funding: Research Award
For decades, families whose children are born with neonatal diabetes—an extremely rare form of diabetes that appears in the first six months of life—have faced a terrifying puzzle. For the first few weeks after birth, these infants seem fine. But then they stop gaining weight and are dehydrated and inexplicably ill. In some cases, things get so bad they even lose consciousness.
For newborns with diabetes, management of their condition is profoundly difficult. "Diabetics are supposed to monitor their blood sugar with every meal and take insulin to control it," says Bess Marshall, an associate professor of pediatrics at St. Louis Children's Hospital at the Washington University School of Medicine. "But a little bitty baby eats every two to three hours. That's a lot of feeding, and a lot of insulin shots." Making it worse, newborns can't communicate that they're feeling symptoms of hypoglycemia.
Until five years ago, doctors assumed that some babies just developed type 1 diabetes extremely early. Research by Washington University in St. Louis biologist Colin Nichols, funded in part by a grant from the American Diabetes Association, has revealed a different explanation—and a new way to treat these rare cases.
In a healthy pancreas, insulin is produced in the islets of Langerhans, structures filled with specialized beta cells. (The islets are named after Paul Langerhans, the German scientist who discovered them in 1869.) Beta cells don't release insulin in a constant flow, though. Instead, proteins in the cell walls react to the levels of glucose in the bloodstream. Too much, and the proteins generate an electrical signal that causes release of insulin into the blood. Too little, and the proteins stop the signal, storing the insulin for later.
These proteins—which regulate the flow of potassium through channels in the cell wall—are like automated switches for a sprinkler system that helps keep the body's glucose levels just right.
"It's the switch that connects metabolism to insulin secretion," Nichols says. In type 1 diabetes, the beta cells in the pancreas are destroyed by the body's own immune system. But neonatal diabetes is different. The beta cells are all there, but a genetic mutation disrupts the chemical pathways in the cell walls. The sprinkler system, so to speak, is intact, but the switches that control it are frozen in the "off" position. The symptoms are the same as in type 1: No insulin is released into the bloodstream, and the body is unable to properly process glucose. "Up until three or four years ago, neonatal diabetes was seen as very early onset type 1 diabetes, without functioning beta cells in the pancreas," Nichols says.
With no way to look inside a baby's pancreas, scientists had to assume the drop in insulin levels was caused by vanished beta cells. But work by Nichols on mice with a similar form of diabetes raised the possibility that something else was happening. "With mice, we could take out the pancreas and see the islets of Langerhans are still there, and full of insulin," Nichols says. "That's why it's quite different than what's going on in type 1."
Tapping genetic databases, English researchers had been able to pinpoint the genes responsible for disabling the beta cell insu
lin switches. This made possible genetic tests for babies with diabetes, to separate the ones with neonatal diabetes (and functioning beta cells) from the ones with type 1 (and no beta cells).
The next step was treatment. It turned out that sulfonylureas, a class of drugs usually used to treat type 2 diabetes, were remarkably effective with neonatal diabetes as well. Sulfonylureas (such as glyburide) are designed to encourage the surviving beta cells of people with type 2 diabetes to release more insulin by holding open the potassium channel switches in the cell walls. "Sulfonylureas bring beta cells back into physiological control, so now they secrete insulin more closely to their natural function," Nichols says. In much smaller doses, they work on babies with neonatal diabetes. "These drugs are a magic bullet," Nichols says. "They're potentially a perfect treatment." If patients are treated with the right drugs early enough, it means they can keep their blood glucose under control and limit damage to the body's beta cells—meaning that despite having neonatal diabetes, they may always be able to produce their own insulin.
Neonatal diabetes is extremely rare: The odds of a baby being born with the mutation that causes it are 1 in 100,000, compared with, for example, 1 in 150 for autism. But because it's one of the few instances where the cause of diabetes is clear—Nichols knows exactly which genes are responsible for the malfunctioning potassium channels—it's potentially an important window into the workings of other types of diabetes.
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