Nesidioblastosis No Longer! It's All about Genetics

The past two decades have witnessed rapid advances in elucidating genetic forms of hyperinsulinemic hypoglycemia that have dramatically eclipsed our previous concepts about congenital hyperinsulinism in infants and children. Before this time, persistent hypoglycemia in infants, a disorder first described as “idiopathic hypoglycemia of infancy” in the mid-1950s (1), was attributed to nesidioblastosis, a supposed disturbance in embryonic morphogenesis in which insulin cells continued to bud off pancreatic ducts beyond the time of birth (2). This increase in -cell mass was presumed to explain hypoglycemia in infants affected with nesidioblastosis. By the mid1980s, however, studies by Rahier et al. (3) and other pathologists had convincingly proven that nesidioblastosis is merely a normal feature of the pancreas in early infancy. In pediatrics, use of the term has fortunately been abandoned. Interestingly, nesidioblastosis continues to be mentioned in adults as if it were still a specific entity. For example, patients with hypoglycemia post gastric bypass surgery have recently been labeled as having nesidioblastosis (4). The recognition of a genetic, as opposed to an embryological, basis for congenital hyperinsulinism evolved from the recognition of familial cases with either dominant or recessive patterns of inheritance (5). Currently, thanks to work by many investigators, eight different loci have been associated with hyperinsulinism: ABCC8, KCNJ11, HADH1, GCK, GLUD1, SLC16A1, UCP2, and HNF4a (Table 1). Mutations of these loci have significant differences in phenotype and inheritance pattern that can be helpful in differentiation and management. The first defects to be discovered, and still the most common genes associated with hyperinsulinism, involve the ABCC8 and KCNJ11 genes that are located together on the short arm of chromosome 11 and encode the two subunits of the -cell ATP-dependent potassium channel: SUR1 and Kir6.2. Recessive mutations of these genes cause a severe form of neonatal hypoglycemia that frequently requires near-total pancreatectomy. In addition, these mutations are responsible for the focal form of congenital hyperinsulinism, caused by isodisomy for a paternally transmitted ABCC8 or KCNJ11 mutation. Dominant missense mutations of these genes have also been discovered that can be associated with either medically controllable or medically unresponsive hyperinsulinism (6, 7). Mutations in HADH1, which encodes SCHAD, a fatty acid oxidation enzyme, cause the only other recessive form of hyperinsulinism (8). Dominant, activating mutations of GCK, which encodes glucokinase, can cause hyperinsulinism that responds poorly to medical therapy. Other dominant forms of hyperinsulinism include activating mutations of GLUD1, which encodes glutamate dehydrogenase, a key step in amino acidstimulated insulin secretion; inactivating mutations of UCP2, a mitochondrial uncoupling protein; activating mutations of SLC16A1 (encodes MCT1), a plasma membrane pyruvate transporter; and inactivating mutations of HNF4a, a nuclear transcription factor also associated with maturity-onset diabetes of the young 1, a form of monogenic diabetes of youth. Phenotypic features that distinguish some of these disorders can be helpful in suggesting the likely gene involved. Large birth weight is common in ABCC8, KCNJ11, GCK, and HNF4a defects. Hyperammonemia is a distinctive feature of GLUD1 mutations [“hyperinsulinism/hyperammonemia (HI/HA) syndrome”]. Protein-sensitive hypoglycemia occurs in HI/HA and SCHAD hyperinsulinism, due to hypersensitivity to leucine stimulation of insulin release. Protein sensitivity also occurs with mutations of ABCC8 and KCNJ11, but it is not due to leucine sensitivity. Hypoglycemia after ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2011 by The Endocrine Society doi: 10.1210/jc.2011-0164 Received January 19, 2011. Accepted January 28, 2011.