Complex Biology of Hyperinsulinism May Offer Clues to Better Treatment

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Analyzing insulin-producing pancreatic cells from children with congenital hyperinsulinism (HI), CHOP endocrinology experts have discovered patterns of metabolic function and gene expression that may lay the groundwork for potential new treatments for this rare disease.

Diva Deleon, MD “This study shows that the pathophysiology of hyperinsulinism is far more complex than commonly understood,” said co-study leader Diva D. De Leon, MD, an Endocrinologist and Director of CHOP’s Congenital Hyperinsulinism Center. “We expect that this improved understanding of events at the cellular level will allow us to identify opportunities for improved treatments.”

De Leon and co-study leader Changhong Li, MD, PhD, also a CHOP scientist, published the study online April 25 in the journal Diabetes. Both study leaders, along with multiple co-authors, are also members of the Institute for Diabetes, Obesity and Metabolism in the Perelman School of Medicine at the University of Pennsylvania.

In congenital HI, gene mutations disrupt the insulin-secreting beta cells in the pancreas and cause insulin levels to become excessive, leading to dangerously low concentrations of glucose (blood sugar). The most severe form of congenital HI results from mutations that inactivate potassium channels in the beta cells. This type of HI does not respond to current drugs, and may result in brain damage or death. When the defective cells are concentrated in a small area of the pancreas (focal HI), surgery can produce a cure, but when all the beta cells are defective (diffuse HI), surgery improves but does not cure the hyperinsulinism and can leave a patient vulnerable to diabetes.

The conventional understanding is that the defective potassium channels in this type of HI simply allow uncontrolled insulin secretion. The current study offers a more comprehensive view, revealing secondary changes in gene expression and metabolic patterns that lead to broader biological effects. “Our goal is to use this knowledge to identify new targets for more effective treatments for this devastating condition,” said De Leon.

The National Institutes of Health supported this research (grants DK098517, DK056268, and DK19525).

Changhong Li et al, “Functional and metabolic consequences of ATP-dependent potassium channel inactivation in human islets,” Diabetes, published online April 25, 2017.

Contact: The Children’s Hospital of Philadelphia,