Glucose intolerance in a xenotransplantation model: studies in alpha-gal knockout mice.
Xenotransplantation holds the promise of replacing failing human organs with organs of animal origin. Transplantation of pancreatic islets from pigs to humans might restore glucose homeostasis and offer diabetic patients considerable improvement in their quality of life. The alpha-gal epitope, present in all mammals except humans, apes and Old World monkeys, is a decisive obstruction to successful xenotransplantation of vascularized organs as the reaction of alpha-gal-bearing endothelia with natural alpha-gal antibodies in the human blood mediates hyperacute rejection of the xenograft. Alpha-galactosyl transferase knockout mice (alpha-GT KO) develop cataract, but no other lesions have been established in these mice. Here we report for the first time that alpha-GT KO mice have impaired glucose tolerance (p<0.001) and decreased insulin sensitivity (p<0.0001). Homeostasis model assessment shows impaired beta-cell function (p<0.05). Similar physiological changes have not been examined in the alpha-galactosyl transferase pig. However, an association between alpha-galactosyl transferase knockout and impaired beta-cell function could have critical importance for islet xenotransplantation.
Dahl
Kirsten
K
The Royal Veterinary and Agricultural University, Department of Veterinary Pathobiology, Division of Laboratory Animal Science and Welfare, Frederiksberg, Denmark. kdhl@novonordisk.com
Buschard
Karsten
K
Gram
Dorte X
DX
d'Apice
Anthony J F
AJ
Hansen
Axel K
AK
D000818:Animals; D001774:Blood Chemical Analysis; D001835:Body Weight; D005700:Galactosyltransferases / Q000235:genetics*; D018149:Glucose Intolerance / Q000235:genetics / Q000276:immunology*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D010179:Pancreas / Q000166:cytology; D014183:Transplantation, Heterologous; D014312:Trisaccharides / Q000235:genetics / Q000276:immunology*
D007328:Insulin; D014312:Trisaccharides; C076569:alpha-galactosyl epitope; D005700:Galactosyltransferases; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase