KCNJ11

The KCNJ11 gene provides instructions for making parts (subunits) of the ATP-sensitive potassium (K-ATP) channel. Each K-ATP channel consists of eight subunits. Four subunits are produced from the KCNJ11 gene, and four are produced from another gene called ABCC8.

K-ATP channels are found in beta cells, which are cells in the pancreas that secrete the hormone insulin. The K-ATP channels are embedded in cell membranes, where they open and close in response to the amount of glucose in the bloodstream. Glucose is a simple sugar and the primary energy source for most cells in the body. Closure of the K-ATP channels in response to increased glucose triggers the release of insulin out of beta cells and into the bloodstream, which helps control blood sugar levels.

familial hyperinsulinism - caused by mutations in the KCNJ11 gene

At least 12 mutations in the KCNJ11 gene have been found to cause familial hyperinsulinism. Most of these mutations change single protein building blocks (amino acids) in the protein sequence, reducing or preventing the 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 low blood sugar (hypoglycemia) caused by familial hyperinsulinism may result in serious complications such as intellectual disability and seizures.

permanent neonatal diabetes mellitus - caused by mutations in the KCNJ11 gene

At least 21 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.

other disorders - associated with the KCNJ11 gene

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 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.

At least one normal variation (polymorphism) in the KCNJ11 gene is associated with an increased risk of type 2 diabetes mellitus, the most common form of diabetes. This variant replaces the amino acid glutamic acid with the amino acid lysine at position 23 in the protein sequence, written as Glu23Lys or E23K. People with type 2 diabetes mellitus 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 mellitus and heart failure, a combination of lifestyle, genetic, and environmental factors all play a part in determining the risk of these complex disorders.