title: Pancreatic Duodenal Homeobox (PDX-1) in health and disease.
abstract: Insulin is expressed exclusively in the adult beta-cells of the islets of Langerhans. Pancreatic Duodenum Homeobox-1 (PDX-1) is a major regulator of transcription in these cells. It transactivates the insulin gene by binding to a specific DNA motif in its promoter region. Glucose, the main physiological regulator of insulin secretion, also regulates insulin gene transcription through PDX-1. While acute exposure to high glucose concentrations causes an increase in PDX-1 binding, and consequently in insulin mRNA levels, chronic hyperglycemia (toxic to the beta-cell) leads to a decrease in PDX-1 and insulin levels. PDX-1 is absolutely required for pancreas development. In view of the selective expression in adult beta-cells, pancreatic agenesis in both the pdx-1 null mouse and a human carrying a homozygous mutation of PDX-1 was an unexpected and remarkable finding. The homozygous clinical phenotype was neonatal diabetes mellitus (DM) and exocrine insufficiency. Heterozygosity for PDX-1 mutations was found in some individuals with a newly characterized subtype of maturity-onset diabetes of the young (MODY4) and in others with type 2 DM. This review underlines the unique role of PDX-1 in maintaining adult beta-cell-specific functions in normal and disease-related states.
authors.affiliation: Department of Endocrinology, Hadassah University Hospital, General Health Services, Jerusalem, Israel. danielle@md.huji.ac.il
authors.forename: Danielle
authors.initials: D
authors.lastname: Melloul
authors.forename: Anat
authors.initials: A
authors.lastname: Tsur
authors.forename: David
authors.initials: D
authors.lastname: Zangen
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics / Q000628:therapy; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology; D018398:Homeodomain Proteins; D006801:Humans; D007328:Insulin / Q000235:genetics; D007515:Islets of Langerhans / Q000378:metabolism; D009154:Mutation; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*
chemical_list: D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D005947:Glucose