When Hyperinsulinism is a Family Affair

Inactivating mutations in the beta cell K_ATP channels are the most common cause of congenital hyperinsulinism (HI), accounting for approximately 60% of all cases with known genotype. The beta cell K_ATP channels play a very important role in the regulation of insulin secretion by coupling the metabolic state of the cell to membrane potential. When plasma glucose is high, glucose metabolism in the beta cell results in higher ATP/ADP ratio triggering closure of the K_ATP channels, which depolarizes the plasma membrane opening voltage-dependent calcium channels. The increase in cytosolic calcium then triggers insulin release. The K_ATP channels stay opened when plasma glucose is low, turning off insulin secretion.

The importance of the K_ATP channels in glucose metabolism is demonstrated by the fact that activating mutations in the two genes encoding the channel — ABCC8, which encodes for the SUR1 subunit, and KCNJ11, encoding Kir6.2 — are the most common cause of permanent neonatal diabetes; and inactivating mutations cause congenital hyperinsulinism.

None of this was known when Brad was diagnosed with hyperinsulinism in the early 1960s. He presented with persistent hypoglycemia and was evaluated at Children’s Hospital of Philadelphia (CHOP) by Dr. Lester Baker, who first described the clinical features of hyperinsulinism. Because there were no treatments available back then, Brad underwent a pancreatectomy, which controlled the hypoglycemia but resulted in diabetes later. His brother, diagnosed after diazoxide was first introduced as a treatment for hyperinsulinism in 1964, avoided pancreatectomy and was successfully treated with diazoxide.

By the time Brad’s daughter, Kristen, was born in 1993 and exhibited symptoms of hypoglycemia shortly after birth, it was understood that in some families hyperinsulinism was inherited in an autosomal dominant pattern. She was promptly diagnosed by Dr. Charles Stanley, founder of the Congenital Hyperinsulinism Center at CHOP and started on therapy with diazoxide. She required treatment until she was 9 years old.

Two years after Kristen was born, recessive mutations in ABCC8 were described as the first known genetic cause of congenital hyperinsulinism. Years later, Brad’s family participated in a research study that identified a genetic variant in ABCC8 (delS1387) as the cause of their hyperinsulinism. Their family’s hyperinsulinism phenotype was clearly milder and responsive to diazoxide, in contrast to the severe phenotype of children with recessive mutations in the same gene who require pancreatectomy because of severe, diazoxide-unresponsive hyperinsulinism. The study of these families, including Brad’s, as well as laboratory studies expressing the different mutations in cell-based models, led to the understanding of the different genotype-phenotype subtypes of K_ATP hyperinsulinism.

Recessive mutations result in channels that do not traffic to the cell surface and thus, the hyperinsulinism is diazoxide-unresponsive. When both copies of the genes harbor a recessive mutation, the hyperinsulinism is diffuse, while a paternally inherited recessive mutation in combination with somatic loss of the maternal gene result in focal hyperinsulinism. Dominant mutations produce channels that traffic normally to the plasma membrane and can be responsive or unresponsive to diazoxide, depending on the degree of channel activity. The mutation found in Brad and his family was classified as dominant diazoxide-responsive.

When Kristen found out she was pregnant in January 2022, one of her first calls was to Dr. Diva De León-Crutchlow, Chief of the Division of Endocrinology and Diabetes and Director of the Congenital Hyperinsulinism Center at CHOP. Kristen and her husband met with Dr. De León-Crutchlow and Vicki Sanders, MS, LCGC, CHOP Congenital Hyperinsulinism Center genetic counselor, to receive genetic counseling and to prepare a plan for Kristen’s pregnancy and delivery.

Kristen has managed her HI with diet and exercise since she was able to stop taking diazoxide during childhood. Dr. De León-Crutchlow advised against Kristen having the typical test for gestational diabetes. The dysfunctional K_ATP channels, result in beta-cell “glucose blindness,” thus, insulin secretion does not turn-off when plasma glucose is low, and conversely, insulin secretion does not increase in response to a glucose load, which may lead her obstetrician to misdiagnose her with diabetes. Instead, Kristen wore a continuous glucose monitor for a month, which reassured her OB she didn’t have gestational diabetes.

Following the recommendations of the Pediatric Endocrine Society guidelines for evaluation and management of persistent hypoglycemia in neonates, infants and children, a plan was put in place to monitor Kristen’s baby for hypoglycemia, since there was 50% chance that the baby would inherit the family mutation.

When Rian was born at Bryn Mawr Hospital, an affiliate hospital in the CHOP Care Network, the medical team checked her glucose levels immediately and they came back in the 40s mg/dL — a bit low, but within the normal range for a newborn in the first few hours of life. When her glucose didn’t rise after a couple of hours, Rian was moved to the NICU for closer monitoring and given dextrose through an umbilical catheter to boost her glucose levels.

On her third day of life, Rian was transferred to CHOP. While waiting for the genetic test results, under the care of CHOP’s HI Center, Rian underwent a diagnostic fasting test that confirmed she had hyperinsulinism. She was started on diazoxide, and the intravenous dextrose was discontinued. The genetic testing results confirmed that she had inherited the family mutation. She has been thriving and developing normally. Her parents monitor her glucoses twice daily, and she is followed by the CHOP multidisciplinary team, just as her mother and her grandfather did before her.