Reduction in Pancreatic Transcription Factor PDX-1 Impairs Glucose-stimulated Insulin Secretion

• Published in: The Journal of biological chemistry 2002-03, Vol.277 (13), p.11225-11232
• Main Authors: Brissova, Marcela, Shiota, Masakazu, Nicholson, Wendell E., Gannon, Maureen, Knobel, Susan M., Piston, David W., Wright, Christopher V.E., Powers, Alvin C.
• Format: Article
• Language: English
• Subjects: Animals; Female; glucagon-like peptide 1; Glucose - pharmacology; glucose transporter 2; Heterozygote; Homeodomain Proteins; Immunohistochemistry; Insulin - blood; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Male; Mice; Mice, Knockout; NADPH; PDX-1 protein; Trans-Activators - genetics; Trans-Activators - metabolism; Trans-Activators - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111272200

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 Km 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 Ca2+) and that PDX-1 is important for normal function of adult pancreatic islets.