Glucose intolerance in a xenotransplantation model: Studies in alpha-gal knockout mice

The Royal Veterinary and Agricultural University, Department of Veterinary Pathobiology, Division of Laboratory Animal Science and Welfare, Frederiksberg, Denmark.
Apmis (Impact Factor: 2.04). 11/2006; 114(11):805-11. DOI: 10.1111/j.1600-0463.2006.apm_393.x
Source: PubMed


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.

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    • "An oral glucose tolerance test was performed in Experiment  1 prior to the initiation of the experimental diets and again at termination of the experimental period. The mice were fasted overnight, blood was collected from the tail vein as previously described [24] at time points −30, 0, 30, 60, 120, and 180 minutes, and glucose was monitored immediately on a FreeStyle Mini glucometer (Hermedico, Denmark) as previously described [25]. After the first two blood samples at t = 0, each mouse was dosed p.o. with 2 g/kg glucose (500 g/L Glucose SAD infusion solution, Veterinary Pharmacy, University of Copenhagen, Denmark). "
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    • "Rapid progression to full opacities occurred, on average, within seven to eight days. Early nuclear and posterior cortical changes as well as fibre folds and swollen sutures have been observed (Dahl et al. 2006, and references therein). Another mouse model for congenital cataracts was characterized by targeting the gene coding for perlecan (Hspg2, mapped to chromosome 4). "
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    ABSTRACT: Im Rahmen einer Invitro-Studie mit porcinene Aortenendothelzellen wurde der Einfluss von Hypothermie und den Kardioplegielösungen UW-Lösung und Bretschneider-Lösung auf die alpha-gal-Epitope untersucht. Zur Bestimmung des Einflusses von Hypothermie auf die alpha-gal-Epitope wurden die Zellen der Versuchsgruppen über 1h,4h und 6h bei 4°C gekühlt, die Zellen der Kontrollgruppen wurden über den entsprechenden Zeitraum bei 38°C inkubiert. Zur Bestimmung des Einflusses der Kardioplegielösungen wurden die Zellen der Versuchsgruppen über 4h bei 4°C unter Zusatz von Bretschneider- oder UW-Lösung gekühlt, während die Zellen der Kontrollgruppen über 4h bei 4°C ohne Zusatz der entsprechenden Lösung gekühlt wurden. Es zeigte sich kein signifikanter Einfluss der Hypothermie von 4°C auf die alpha-Gal-Epitope. Die Kardioplegielösungen aber führten zu einer signifikanten Reduktion der Epitope pro Zelle (UW-Lösung 50%, Bretschneider-Lösung 32%). Der hier nachgewiesene alpha-gal-Epitop reduzierende Effekt der Kardioplegielösungen könnte eine therapeutische Option zur Verhinderung der Abstoßungsreaktionen in der Xenotransplantation darstellen.
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