Genetic disorders of the pancreatic beta cell and diabetes (permanent neonatal diabetes and maturity-onset diabetes of the young)

Abstract

Mutations in critical beta-cell genes can result in monogenic diabetes. This clinically heterogeneous group of disorders usually presents soon after birth as neonatal diabetes, or during childhood or early adulthood as maturity-onset diabetes of the young (MODY). Most defects arise in genes involved in pancreatic beta-cell development or the maintenance of beta-cell function. Studying the phenotype of patients with mutations and the mechanisms by which these mutations result in diabetes gives new insights into normal and pathological functioning of the beta cell. The most common genetic etiology in patients with MODY are mutations in the genes that encode the transcription factors hepatocyte nuclear factor (HNF)-1 alpha (TCF1), HNF-4 alpha (HNF4A) and HNF-1 beta (TCF2), and the glycolytic enzyme glycokinase (GCK). Mutations in each of these genes result in different clinical phenotypes and cause beta-cell dysfunction through different mechanisms. The commonest causes of neonatal diabetes are defects in betacell function, arising from mutations in genes encoding the subunits which form the KATP channel, Kir6.2 (KCNJ11) and SUR1 (ABCC8). Defining the genetic subtypes of monogenic diabetes not only helps understanding of the beta cell, it also has considerable implications for patient care. A genetic diagnosis provides accurate information regarding inheritance, prognosis, can explain clinical features and may guide patient treatment. The best example of pharmacogenetics is that patients with KCNJ11 mutations, despite being insulin dependent, can have excellent glycemic control on high-dose sulfonylureas. Defining the genetic etiology of monogenic diabetes has therefore contributed both to science and patient care. © 2008 Springer.