The yin and yang of beta cell genetics
The opposite phenotypes of diabetes and hyperinsulinism can be caused by different types of mutations within the same genes. For example, rare activating GCK gene mutations cause hyperinsulinism whereas the more common loss-of function mutations result in mild fasting hyperglycaemia in the heterozygous state or recessively inherited permanent neonatal diabetes.
The knowledge that inactivating mutations in the KCNJ11 and ABCC8 genes encoding the beta-cell ATP sensitive potassium (KATP) channel subunits Kir6.2 and SUR1 are the most common cause of congenital hyperinsulinaemic hypoglycaemia led to the identification of gain-of-function mutations as a common cause of neonatal diabetes. Most patients with KATP neonatal diabetes achieve improved glycaemic control and quality of life with sulphonylurea tablets.
Some patients experience both hyperinsulinism and diabetes as a consequence of a single gene mutation, but at different stages of their life. Both dominant KATP channel missense mutations and mutations in the HNF4A transcription factor gene can cause increased birth weight, presumably due to increased insulin secretion in utero, neonatal hyperinsulinaemic hypoglycaemia but with an increased risk of diabetes in later life.