beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes.
To study the late beta-cell-specific function of the homeodomain protein IPF1/PDX1 we have generated mice in which the Ipf1/Pdx1 gene has been disrupted specifically in beta cells. These mice develop diabetes with age, and we show that IPF1/PDX1 is required for maintaining the beta cell identity by positively regulating insulin and islet amyloid polypeptide expression and by repressing glucagon expression. We also provide evidence that IPF1/PDX1 regulates the expression of Glut2 in a dosage-dependent manner suggesting that lowered IPF1/PDX1 activity may contribute to the development of type II diabetes by causing impaired expression of both Glut2 and insulin.
Ahlgren
U
U
Department of Microbiology, University of Umeâ, S-901 87 Umeâ, Sweden.
Jonsson
J
J
Jonsson
L
L
Simu
K
K
Edlund
H
H
D000682:Amyloid / Q000032:analysis; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D005796:Genes / Q000235:genetics*; D005934:Glucagon / Q000032:analysis; D018149:Glucose Intolerance; D005951:Glucose Tolerance Test; D051273:Glucose Transporter Type 2; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000032:analysis; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000737:chemistry / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D009004:Monosaccharide Transport Proteins / Q000032:analysis; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics
D000682:Amyloid; D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D009004:Monosaccharide Transport Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D005934:Glucagon