2.1. Congenital Hyperinsulinism

More than 30 mutations in the KCNJ11 gene have been found to cause congenital hyperinsulinism. This condition causes frequent episodes of low blood sugar (hypoglycemia), decreased energy, and irritability. Most of these mutations change single protein building blocks (amino acids) in the protein sequence, reducing or preventing activity of the K-ATP channels. Loss of K-ATP channel function leads to the constant release of insulin from beta cells. As a result, glucose is rapidly removed from the bloodstream. Without treatment, the hypoglycemia caused by congenital hyperinsulinism may result in serious complications such as intellectual disability and seizures.

2.2. Permanent Neonatal Diabetes Mellitus

At least 30 mutations in the KCNJ11 gene have been identified in people with permanent neonatal diabetes mellitus. Individuals with this condition often have a low birth weight and develop increased blood sugar (hyperglycemia) within the first 6 months of life.

KCNJ11 gene mutations that cause permanent neonatal diabetes mellitus change single amino acids in the protein sequence. These mutations result in K-ATP channels that do not close, leading to reduced insulin secretion from beta cells and impaired blood sugar control.

2.3. Other Disorders

Other KCNJ11 gene mutations that have a relatively mild effect on K-ATP channel function as compared to that seen in permanent neonatal diabetes mellitus (see above) cause a condition called transient neonatal diabetes mellitus. Infants with this condition have hyperglycemia during the first 6 months of life, but their blood sugar returns to normal by age 18 months. However, affected individuals usually develop hyperglycemia again during adolescence or early adulthood. As in permanent neonatal diabetes mellitus, KCNJ11 gene mutations that cause transient neonatal diabetes mellitus also interfere with K-ATP channel closure and lead to a reduction in insulin secretion.

A normal variation (polymorphism) in the KCNJ11 gene is associated with an increased risk of type 2 diabetes, the most common form of diabetes. This variant leads to a change in the K-ATP channel, replacing the amino acid glutamic acid with the amino acid lysine at position 23, written as Glu23Lys or E23K. People with type 2 diabetes have hyperglycemia because the body does not respond correctly to the insulin secreted from beta cells. The same variant has also been associated with changes in the heart's response to stress, leading to an increased risk of heart failure. Although changes in the KCNJ11 gene can be associated with type 2 diabetes and heart failure, a combination of lifestyle, genetic, and environmental factors all play a part in determining the risk of these complex disorders.