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: Marcela Brissova, Masakazu Shiota, Wendell E Nicholson, Maureen Gannon, Susan M Knobel, David W Piston, Christopher V E Wright, Alvin C Powers
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 277 Issue 13 Pg. 11225-32 (Mar 29 2002) ISSN: 0021-9258 [Print] United States
• PMID: 11781323 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Homeodomain Proteins
• Insulin
• Trans-Activators
• pancreatic and duodenal homeobox 1 protein
• Glucose

Topics

• Animals
• Female
• Glucose (pharmacology)
• Heterozygote
• Homeodomain Proteins
• Immunohistochemistry
• Insulin (blood, metabolism)
• Insulin Secretion
• Islets of Langerhans (drug effects, metabolism)
• Male
• Mice
• Mice, Knockout
• Trans-Activators (genetics, metabolism, physiology)