Reduction in pancreatic transcription factor PDX-1 impairs glucose-stimulated insulin secretion

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 glucagonlike 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.