Swine as an Animal Model for Diabetes - part 4

While mainstream models of diabetes research remain rodents, there has been an increasing need for translational research in large animal models of the disease. Swine have many similarities to humans that make them a good choice for modeling diabetes including an omnivorous diet, gastrointestinal tract anatomy and physiology, general metabolic status, and pancreatic size, shape, and position (particular in minipigs). Further, the fact that swine are closer to humans phylogenetically, as evidenced by swine and human insulin polypeptides differing by only one amino acid, is important when interpreting data or translating results to clinical applications. Another advantage of the swine model is their similar pharmacokinetics with respect to subcutaneously administered drugs. [2,9]

Swine models of type 1 diabetes (T1D), type 2 diabetes (T2D), and maturity-onset diabetes of the young type 3 (MODY3) have been developed. The swine T1D model is created by administering streptozotocin (STZ) to intact animals. STZ is preferentially lethal to the insulin-secreting β-cells in pancreatic islets of Langerhans and STZ-treated swine display a human-like diabetic phenotype as evidenced by their significantly increased blood glucose levels after both intravenous and oral glucose delivery. This model has been used for a variety of investigations into T1D pathology including recent proteomics studies that implicate several proteins as potential target candidates for further analysis. [9] Models of T2D include a new transgenic swine line in which pancreatic β-cells express a dominant negative mutant human gipr transgene. Discovery studies in mice have implicated glucose-dependent insulinotropic polypeptide (GIP) and its receptor (GIPR) in T2D pathogenesis. Normally, lipid- or glucose-induced GIP secretion from enteroendocrine cells promotes glucose-mediated insulin release. However, in T2D patients, GIP and/or GIPR are functionally impaired resulting in poor insulin response to oral glucose. Transgenic GIPR^dn swine display deficits in oral, but not intravenous, glucose tolerance resulting from poor insulin secretion at 11 weeks of age. By 5 months, these animals additionally displayed a marked reduction in total β-cell volume and by 11 months, intravenous glucose tolerance is also significantly impaired. These results confirm that GIP/GIPR are critically involved in the maintenance of β-cell health in vivo and thus further promote their status as potential T2D therapeutic targets. [2] A transgenic swine model of MODY3 has been developed in which a dominant negative mutation in the human hepatocyte nuclear factor 1α (HNF1A) transgene is expressed. Like GIPR, HNF1A was first identified as a candidate target in mouse. While most transgenic HNF1A^dn piglets died shortly after birth, those that survived displayed elevated non-fasting blood glucose levels and transgenic protein expression in the pancreas and kidney. Upon closer examination, malformation of pancreatic islet structures and glomerular hypertrophy and sclerosis of the kidneys is evident. [2]

References

1.      Swindle, M.M. et al. (2011) Swine as models in biomedical research and toxicology testing. Vet. Pathol. [Epub ahead of print, Mar 25].

2.      Aigner, B. et al. (2010) Transgenic pigs as models for translational biomedical research. J. Mol. Med. 88:653-664.

3.       Lunney, J.K. (2007) Advances in swine biomedical model genomics. Int. J. Biol. Sci. 3:179-184.

4.      Dixon, J.A. and Spinale, F.G. (2009) Large animal models of heart failure: a critical link in the translation of basic science to clinical practice. Circ. Heart Fail. 2(3):262-271.

5.      Heusch, G. et al. (2011) The in-situ pig heart with regional ischemia/reperfusion – ready for translation. J. Mol. Cell. Cardiol. [Epub ahead of print, Mar 5].

6.       hu, K.Q. et al. (2007) Review of the female Duroc/Yorkshire pig model of human fibroproliferative scarring. Wound Repair Regen. 15(Suppl. 1):S32-S39.

7.      Gomez-Raya, L. et al. (2007) Modeling inheritance of malignant melanoma with DNA markers in Sinclair swine. Genetics 176(1):585-597.

8.      Rambow, F. et al. (2008) Gene expression signature for spontaneous cancer regression in melanoma pigs. Neoplasia 10(7):714-726.

9.      Lee, P.Y. et al. (2010) Proteomic analysis of pancreata from mini-pigs treated with straptozotocin as type I diabetes models. J. Microbiol. Biotechnol. 20(4):817-820.

10.  Rogers, C.S. et al. (2008) The porcine lung as a potential model for cystic fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 295:L240-L263.

11.  Naim, M.Y. et al. (2010) Folic acid enhances early functional recovery in a piglet model of pediatric head injury. Dev. Neurosci. 32:466-479.

12.  Kuluz, J.W. et al. (2007) New pediatric model of ischemic stroke in infant piglets by photothrombosis – acute changes in cerebral blood flow, microvasculature, and early histopathology. Stroke 38:1932-1937.

13.   Wakeman, D.R. (2006) Large animal models are critical for rationally advancing regenerative therapies. Regen. Med. 1(4):405-413.