title: Reduction in pancreatic transcription factor PDX-1 impairs glucose-stimulated insulin secretion.
abstract: Complete lack of transcription factor PDX-1 leads to pancreatic agenesis, whereas heterozygosity for PDX-1 mutations has been recently noted in some individuals with maturity-onset diabetes of the young (MODY) and in some individuals with type 2 diabetes. To determine how alterations in PDX-1 affect islet function, we examined insulin secretion and islet physiology in mice with one PDX-1 allele inactivated. PDX-1(+/-) mice had a normal fasting blood glucose and pancreatic insulin content but had impaired glucose tolerance and secreted less insulin during glucose tolerance testing. The expression of PDX-1 and glucose transporter 2 in islets from PDX-1(+/-) mice was reduced to 68 and 55%, respectively, whereas glucokinase expression was not significantly altered. NAD(P)H generation in response to glucose was reduced by 30% in PDX-1(+/-) mice. The in situ perfused pancreas of PDX-1(+/-) mice secreted about 45% less insulin when stimulated with 16.7 mm glucose. The K(m) for insulin release was similar in wild type and PDX-1(+/-) mice. Insulin secretion in response to 20 mm arginine was unchanged; the response to 10 nm glucagon-like peptide-1 was slightly increased. However, insulin secretory responses to 10 mm 2-ketoisocaproate and 20 mm KCl were significantly reduced (by 61 and 66%, respectively). These results indicate that a modest reduction in PDX-1 impairs several events in glucose-stimulated insulin secretion (such as NAD(P)H generation, mitochondrial function, and/or mobilization of intracellular Ca(2+)) and that PDX-1 is important for normal function of adult pancreatic islets.
authors.affiliation: Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee 37212, USA.
authors.forename: Marcela
authors.initials: M
authors.lastname: Brissova
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shiota
authors.forename: Wendell E
authors.initials: WE
authors.lastname: Nicholson
authors.forename: Maureen
authors.initials: M
authors.lastname: Gannon
authors.forename: Susan M
authors.initials: SM
authors.lastname: Knobel
authors.forename: David W
authors.initials: DW
authors.lastname: Piston
authors.forename: Christopher V E
authors.initials: CV
authors.lastname: Wright
authors.forename: Alvin C
authors.initials: AC
authors.lastname: Powers
mesh_terms: D000818:Animals; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D006579:Heterozygote; D018398:Homeodomain Proteins; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D005947:Glucose