IPF1/PDX1 deficiency and beta-cell dysfunction in Psammomys obesus, an animal with type 2 diabetes

The homeodomain transcription factor IPF1/PDX1 is required in beta -cells f or efficient expression of insulin, glucose transporter 2, and prohormone c onvertases 1/3 and 2. Psammomys obesus, a model of diet-responsive type 2 d iabetes, shows markedly depleted insulin stores when given a high-energy (H E) diet. Despite hyperglycemia, insulin mRNA levels initially remained unch anged and then decreased gradually to 15% of the basal level by 3 weeks. Mo reover, insulin gene expression was not increased when isolated P. obesus i slets were exposed to elevated glucose concentrations. Consistent with thes e observations, no functional Ipf1/Pdx1 gene product was detected in islets of newborn or adult P. obesus using immunostaining, Western blot, DNA bind ing, and reverse transcriptase-polymerase chain reaction analyses. Other be ta -cell. transcription factors (e.g., ISL-1, Nkx2.2, and Nkx6.1) were expr essed in P. obesus islets, and the DNA binding activity of the insulin tran scription factors RIPE3b1-Act and IEF1 was intact. lpf1/Pdx1 gene transfer to isolated P. obesus islets normalized the defect in glucose-stimulated in sulin gene expression and prevented the rapid depletion of insulin content after exposure to high glucose. Taken together, these results suggest that the inability of P. obesus islets to adapt to dietary overload, with deplet ion of insulin content as a consequence, results from IPF1/PDX1 deficiency. However, because not all animals become hyperglycemic on HE diet, addition al factors may be important for the development of diabetes in this animal model.