Diazoxide-Responsive KATP Hyperinsulinism

What is diazoxide-responsive KATP HI?

Congenital hyperinsulinism (HI) is a genetic disorder in which the insulin cells of the pancreas, called beta cells, secrete too much insulin. Excess insulin causes low blood sugar (hypoglycemia).

Ordinarily, beta cells secrete just enough insulin to keep the blood sugar in the normal range. In children with HI, the secretion of insulin is not properly regulated, causing excess insulin secretion and low blood sugar.

In diazoxide-responsive KATP hyperinsulinism, potassium channels in the beta cell (named KATP channels), which regulate insulin secretion, do not work properly.

All beta cells in the pancreas are affected; therefore the disorder is diffuse across the whole pancreas. This form of congenital HI is usually medically managed.

Causes

Diazoxide-responsive KATP HI is caused by a defect in the SUR1 (sulfonylurea receptor; also known by its gene name, ABCC8) component of the KATP channel.

The same type of disease can be caused by a defect in the other component of the potassium channel, Kir6.2 (potassium ion channel; also known by its gene name, KCNJ11).

Inheritance of the genetic defect is dominant, meaning only one parent must have a mutation of one of the genes in question to cause disease in the child.

Symptoms

Diazoxide-responsive KATP hyperinsulinism often causes extremely high birth weight and severe low blood glucose in the first days of life.

This disease also cause low blood sugar (hypoglycemia). The symptoms of hypoglycemia in infants are often difficult to identify, as they can be similar to normal infant activities.

Common symptoms of hypoglycemia include:

  • irritability
  • sleepiness
  • lethargy
  • excessive hunger
  • rapid heart rate

More severe symptoms, such as seizures and coma, can occur with a prolonged low blood sugar or an extremely low blood sugar. Common symptoms of hypoglycemia in older children include feelings of shakiness, weakness, tiredness, confusion, and rapid heart rate.

We consider a normal blood sugar to be >70 mg/dL. Anything less than 60 mg/dL is low, although severe symptoms due to hypoglycemia are not likely unless the blood sugar is less than 50 mg/dL. Prolonged or severe low blood sugar can cause seizures and permanent brain damage.

Diagnosis

The diagnosis of congenital hyperinsulinism is based on history, laboratory findings, and genetic testing. Prompt diagnosis and establishment of effective treatment are essential to avoid neurologic damage. The diagnosis is made by evaluating the child's medical history, and the result of laboratory and genetic tests.

History

The history of the child is an important piece of the puzzle. This includes information such as when the low blood sugars started, the timing of the low blood sugars, whether the baby was born large for gestational age (LGA), any family history of low blood sugar or unexplained infant deaths.

Laboratory findings

Blood tests drawn when the blood sugar is less than 50 mg/dL are essential to the diagnosis of HI. In congenital HI, with a blood sugar <50, you will see suppressed ketones and free fatty acids, an elevated insulin level (although this may not always be captured), and a glycemic response to glucagon, with the blood sugar rising more than 30 mg/dL when glucagon is administered.

It is important that these samples at the time of a critically low blood sugar be obtained in an experienced, controlled environment, as we do not want a child to be kept with a critically low blood sugar longer than is absolutely necessary to make the diagnosis.

Genetic testing

The DNA from a blood sample from the child with congenital HI and each parent can be analyzed to screen for the mutations that cause the most common types of HI. This can be done at commercial laboratories and should be considered in any child suspected to have congenital HI. Contact us for more information on where to have this testing performed.

Protein tolerance test

An oral protein tolerance test can also be useful in diagnosing GDH-HI, as a protein load can trigger high insulin levels and low blood glucose. The Children’s Hospital of Philadelphia has special expertise in protein tolerance testing.

Treatment

Diazoxide-responsive KATP hyperinsulinism is very well controlled with a medicine called diazoxide (Proglycem).

Long-term outcomes

We are now tracking and compiling data on the long-term outlook for children with Congenital HI. We know that with rapid diagnosis and appropriate treatment, keeping blood sugars >70 mg/dL, it is less likely that children with congenital HI will have long-term effects of hypoglycemia. With focal hyperinsulinism, 94 percent of children are cured with surgery.

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