Diabetic phenotype of transgenic pigs introduced by dominant-negative mutant hepatocyte nuclear factor 1α

The present study aimed to identify the characteristics of genetically modified pigs carrying a mutant human gene as a research model for diabetes and its complications.

We developed a transgenic cloned pig (founder, male) carrying a mutant gene, i.e., human HNF-1α (P291fsinsC), which is responsible for maturity-onset diabetes of the young type 3. Transgenic progeny obtained via the artificial insemination of wild type (WT) sows with the cryopreserved sperm derived from the founder pig was pathologically examined.

The transgenic progeny maintained a high blood glucose level (>200mg/dL). Additionally, the oral glucose tolerance test results showed that the recovery of blood glucose levels in the transgenic progeny was significantly delayed compared with that in the WT semi-siblings. Hypoplasia of the islets of Langerhans was confirmed by the histopathological image of the pancreas, based on the hyperglycemia noted in the progeny being ascribed to decreased insulin secretion. Retinal hemorrhage and cotton-wool spots, i.e., findings consistent with non-proliferative diabetic retinopathy, were detected, and these progressed over time. The histopathological image of the renal glomeruli showed a nodular lesion that is characteristic of diabetic nephropathy in humans.

These data demonstrated that the genetically modified pig that we developed is a promising model for research on diabetes and its complications.