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

Defects in pancreatic β-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) -1α, -3β, -4α, and Pdx-1 contribute in the complex transcriptional circuits within the pancreas that are involved in β-cell development and function. In mice, a heterozygous mutation in Pdx-1 alone, but not Hnf-1α(+/−), Hnf-3β(+/−), or Hnf-4α(+/−), causes impaired glucose-stimulated insulin secretion in mice. To investigate the possible functional relationships between these transcription factors on β-cell activity in vivo, we generated mice with the following combined heterozygous mutations: Pdx-1(+/−)/Hnf-1α(+/−), Pdx-1(+/−)/Hnf-3β(+/−), Pdx-1(+/−)/Hnf-4α(+/−), Hnf-1α(+/−)/Hnf-4α(+/−), and Hnf-3β(+/−)/Hnf-4α(+/−). The greatest loss in function was in combined heterozygous null alleles of Pdx-1 and Hnf-1α (Pdx-1(+/−)/Hnf-1α(+/−)), or Pdx-1 and Hnf-3β (Pdx-1(+/−)/Hnf-3β(+/−)). 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(+/−) mice alone. The loss in β-cell function in Pdx-1(+/−)/Hnf-3β(+/−) 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-1α(+/−) mice. The islet cell architecture was also abnormal in Pdx-1(+/−)/Hnf-3β(+/−) and Pdx-1(+/−)/Hnf-1α(+/−) 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 β-cell function. These studies also established polygenic mouse models for investigating the mechanisms contributing to β-cell dysfunction in diabetes.