Profound defects in pancreatic -cell function in mice with combined heterozygous mutations in Pdx-1, Hnf-1 , and Hnf-3

Defects in pancreatic -cell function contribute to the development of type 2 diabetes, a polygenic disease that is characterized by insulin resistance and compromised insulin secretion. Hepatocyte nuclear factors (HNFs) -1 , -3 , -4 , and Pdx-1 contribute in the complex transcriptional circuits within the pancreas that are involved in -cell development and function. In mice, a heterozygous mutation in Pdx-1 alone, but not Hnf-1 / , Hnf-3 / , or Hnf4 / , causes impaired glucose-stimulated insulin secretion in mice. To investigate the possible functional relationships between these transcription factors on -cell activity in vivo, we generated mice with the following combined heterozygous mutations: Pdx1 / Hnf-1 / , Pdx-1 / Hnf-3 / , Pdx-1 / Hnf-4 / , Hnf1 / Hnf-4 / , and Hnf-3 / Hnf-4 / . The greatest loss in function was in combined heterozygous null alleles of Pdx-1 and Hnf-1 (Pdx-1 / Hnf-1 / ), or Pdx-1 and Hnf-3 (Pdx-1 / Hnf3 / ). Both double mutants develop progressively impaired glucose tolerance and acquire a compromised firstand second-phase insulin secretion profile in response to glucose compared with Pdx-1 / mice alone. The loss in -cell function in Pdx-1 / Hnf3 / mice was associated with decreased expression of Nkx-6.1, glucokinase (Gck), aldolase B (aldo-B), and insulin, whereas Nkx2.2, Nkx-6.1, Glut-2, Gck, aldo-B, the liver isoform of pyruvate kinase, and insulin expression was reduced in Pdx-1 / Hnf-1 / mice. The islet cell architecture was also abnormal in Pdx-1 / Hnf3 / and Pdx-1 / Hnf-1 / mice, with glucagon-expressing cells scattered throughout the islet, a defect that may be connected to decreased E-cadherin expression. Our data suggest that functional interactions between key islet regulatory factors play an important role in maintaining islet architecture and -cell function. These studies also established polygenic mouse models for investigating the mechanisms contributing to -cell dysfunction in diabetes.