The Genetics of Hyperinsulinemic Hypoglycemia

Abstract

Hyperinsulinemic hypoglycemia (HH) is characterized by failure to suppress insulin secretion from pancreatic β-cell in the presence of hypoglycemia. Severe persistent hypoglycemia in infants can lead to permanent brain damage resulting in developmental delay. Early identification and careful management of these patients who have HH is therefore vital to prevent permanent neurological insult. Congenital forms of HH are a clinically and genetically heterogeneous group of conditions caused by mutations in nine different genes (ABCC8, KCNJ11, GLUD1, CGK, HADH, SLC16A1, HNF4A, HNF1A, and UCP2). The most severe forms are due to mutations in ABCC8 and KCJN11, which encode the two components of pancreatic β-cell adenosine triphosphate sensitive potassium channel. The clinical heterogeneity is manifested in varying severity ranging from extremely severe life-threatening disease to very subtle symptoms of hypoglycemia. Furthermore, clinical response to medical and surgical management is extremely variable. Histologically, two subtypes (diffuse and focal) of congenital hyperinsulinism have been described. Recent advancement in understanding the genetic etiology, histological characterization into focal and diffuse forms combined with improved imaging (such as fluorine 18 L-3, 4-dihydroxyphenylalanine positron emission tomography 18F-DOPA-PET scanning) and surgical techniques have greatly improved management leading to a complete cure in focal forms of congenital hyperinsulinism by focal lesionectomy. This review outlines the genetic mechanisms of hyperinsulinemic hypoglycemia.