Neonatal Diabetes Mellitus

Abstract

An explosion of work over the last decade has produced insight into the multiple hereditary causes of a nonimmunological form of diabetes diagnosed most frequently within the first 6 months of life.These studies are providing increased understanding of genes involved in the entire chain of steps that control glucose homeostasis.Neonatal diabetes is now understood to arise from mutations in genes that play critical roles in the development of the pancreas, of ␤-cell apoptosis and insulin processing, as well as the regulation of insulin release.For the basic researcher, this work is providing novel tools to explore fundamental molecular and cellular processes.For the clinician, these studies underscore the need to identify the genetic cause underlying each case.It is increasingly clear that the prognosis, therapeutic approach, and genetic counseling a physician provides must be tailored to a specific gene in order to provide the best medical care.(Endocrine Reviews 29: 265-291, 2008) I. Introduction II.Diagnosis of Neonatal Diabetes Mellitus III.Frequency of TNDM vs. PNDM IV.Etiology of Transient Neonatal Diabetes Mellitus (OMIM 601410, 600937, 600509) V. Chromosome 6q Anomalies (OMIM 601410) Are the Main Cause of TNDM VI.Hepatic Nuclear Factor 1␤ (OMIM 189907) VII.Permanent Neonatal Diabetes Mellitus VIII.Abnormal Pancreatic Development A. Pancreas transcription factor 1, ␣ subunit (PTF1a) (OMIM 607194, 609069) B. Pancreatic and duodenal homeobox 1/insulinpromoter-factor 1 (PDX1/IPF-1) (OMIM 600733) C. GLIS subfamily of Kruppel-like zinc finger proteins -3 (GLIS3) (OMIM 610199) IX.PNDM Attributable to Increased ␤-Cell Apoptosis or Necrosis: Pancreatic Eukaryotic Initiation Factor 2␣ Kinase (EIF2AK3); Wolcott-Rallison Syndrome (OMIM 226980) X. Insulin XI.Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-Linked (IPEX), FOXP3 (OMIM 304790/304930) XII.PNDM Attributable to ␤-Cell Dysfunction and Impaired Glucose-Stimulated Insulin Secretion XIII.Glucokinase (GCK) (OMIM 606176) XIV.TNDM and PNDM Attributable to Reduced Insulin Secretion Secondary to Overactivity of ATP-Sensitive Potassium Channels, KCNJ11 and ABCC8 (OMIM 600509, 600937, 610374) A. Clinical aspects B. Channel aspects XV.Location of KCNJ11 and ABCC8 Mutations XVI.Sulfonylureas Are an Effective Therapy for NDM Caused by Overactive K ATP Channels XVII.Summary "With few exceptions, diabetes in childhood knows no cure, no matter how mild it may appear in the beginning, nor how gradual its development in the first months or even years."Carl von Noorden, great European authority, 1913 "All cases which have come to my attention of youthful patients with diabetes living for many long periods of time have been hereditary."E. P. Joslin,