ABCC8

The ABCC8 gene provides instructions for making the sulfonylurea receptor 1 (SUR1) protein. The SUR1 protein is one part (subunit) of the ATP-sensitive potassium (K-ATP) channel that is found across cell membranes in the beta cells of the pancreas. Beta cells secrete insulin, which is a hormone that helps control blood sugar levels. Insulin controls how much sugar (in the form of glucose) is passed from the bloodstream into cells to be used as energy. The K-ATP channel controls the secretion of insulin out of beta cells and into the bloodstream. These channels open and close in response to the amount of glucose in the bloodstream, which helps regulate insulin secretion and control blood sugar levels. The closing of the channels results in a process that triggers insulin secretion by beta cells.

familial hyperinsulinism - caused by mutations in the ABCC8 gene

More than 150 mutations in the ABCC8 gene have been found to cause familial hyperinsulinism. Most of these mutations change single protein building blocks (amino acids) in the SUR1 protein. One mutation has been found in many affected individuals in central Finland. This mutation replaces the amino acid valine with the amino acid aspartic acid at position 187 in the SUR1 protein (written as Val187Asp or V187D).

Some ABCC8 mutations prevent the SUR1 protein from reaching the cell membrane, interfering with the proper formation of the K-ATP channel. Other mutations interfere with the K-ATP channel's function or its responses to outside molecules. Defective K-ATP channels lead to the constant release of insulin from beta cells. As a result, glucose is rapidly removed from the bloodstream. 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 ABCC8 gene

At least 14 mutations in the ABCC8 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.

ABCC8 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 ABCC8 gene

Other ABCC8 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, ABCC8 gene mutations that cause transient neonatal diabetes mellitus interfere with K-ATP channel closure and lead to a reduction in insulin secretion.

Some studies suggest that normal variations (polymorphisms) in the ABCC8 gene are associated with an increased risk of type 2 diabetes mellitus, the most common form of diabetes. Other studies, however, have not found an association between ABCC8 gene variants and type 2 diabetes mellitus. People with this disease have hyperglycemia because the body does not respond correctly to the insulin secreted from beta cells. Although changes in the ABCC8 gene may be associated with type 2 diabetes mellitus, a combination of lifestyle, genetic, and environmental factors all play a part in determining the risk of this complex disorder.