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

Defects in pancreatic [beta]-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[alpha], -3[beta], -4[alpha], and Pdx-1 contribute in the complex transcriptional circuits within the pancreas that are involved in [beta]-cell development and function. In mice, a heterozygous mutation in Pdx-1 alone, but not Hnf-1[[alpha].sup.+/-], Hnf-3[[beta].sup.+/-], or Hnf-4[[alpha].sup.+/-], causes impaired glucose-stimulated insulin secretion in mice. To investigate the possible functional relationships between these transcription factors on [beta]-cell activity in vivo, we generated mice with the following combined heterozygous mutations: Pdx-[1.sup.+/-]/Hnf-1[[alpha].sup.+/-], Pdx-[1.sup.+/-]/Hnf-3[[beta].sup.+/-], Pdx-[1.sup.+/-]/Hnf-4[[alpha].sup.+/-, Hnf-1[[alpha].sup.+/-]/Hnf-4[[alpha].sup.+/-], and Hnf-3[[beta].sup.+/-]/Hnf-4[[alpha].sup.+/-]. The greatest loss in function was in combined heterozygous null alleles of Pdx-1 and Hnf-1[alpha](Pdx-[1.sup.+/-]/Hnf-1[[alpha].sup.+/-]), or Pdx-1 and Hnf-3[beta](Pdx-[1.sup.+/-]/Hnf-3[[beta].sup.+/-]). Both double mutants develop progressively impaired glucose tolerance and acquire a compromised first- and second-phase insulin secretion profile in response to glucose compared with Pdx-[1.sup.+/-] mice alone. The loss in [beta]-cell function in Pdx-[1.sup.+/-]/Hnf-3[[beta].sup.+/-] 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.sup.+/-]/Hnf-1[[alpha].sup.+/-] mice. The islet cell architecture was also abnormal in Pdx-[1.sup.+/-]/Hnf-3[[beta].sup.+/-] and Pdx-[1.sup.+/-]/Hnf-1[[alpha].sup.+/-] 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 [beta]-cell function. These studies also established polygenic mouse models for investigating the mechanisms contributing to [beta]-cell dysfunction in diabetes. hepatocyte nuclear factors | diabetes mellitus | insulin secretion | pancreatic islets