1. Neu5Gc and α1-3 GAL Xenoantigen Knockout Does Not Affect Glycemia Homeostasis and Insulin Secretion in Pigs.
- Author
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Salama A, Mosser M, Lévêque X, Perota A, Judor JP, Danna C, Pogu S, Mouré A, Jégou D, Gaide N, Abadie J, Gauthier O, Concordet JP, Le Bas-Bernardet S, Riochet D, Le Berre L, Hervouet J, Minault D, Weiss P, Guicheux J, Brouard S, Bosch S, Lagutina I, Duchi R, Lazzari G, Cozzi E, Blancho G, Conchon S, Galli C, Soulillou JP, and Bach JM
- Subjects
- Animals, Antigens, Heterophile, Blood Glucose drug effects, Blood Glucose metabolism, C-Peptide drug effects, C-Peptide metabolism, Diabetes Mellitus, Type 1 surgery, Galactose immunology, Gene Knockout Techniques, Glucagon drug effects, Glucagon metabolism, Homeostasis, Insulin Secretion, Islets of Langerhans metabolism, Islets of Langerhans pathology, Islets of Langerhans Transplantation, Male, Neuraminic Acids immunology, Pancreas metabolism, Swine, Transplantation, Heterologous, Galactose genetics, Glucose pharmacology, Insulin metabolism, Islets of Langerhans drug effects, Neuraminic Acids metabolism, Purinergic P1 Receptor Antagonists pharmacology, Theophylline pharmacology
- Abstract
Xenocell therapy from neonate or adult pig pancreatic islets is one of the most promising alternatives to allograft in type 1 diabetes for addressing organ shortage. In humans, however, natural and elicited antibodies specific for pig xenoantigens, α-(1,3)-galactose (GAL) and N -glycolylneuraminic acid (Neu5Gc), are likely to significantly contribute to xenoislet rejection. We obtained double-knockout (DKO) pigs lacking GAL and Neu5Gc. Because Neu5Gc
-/- mice exhibit glycemic dysregulations and pancreatic β-cell dysfunctions, we evaluated islet function and glucose metabolism regulation in DKO pigs. Isolation of islets from neonate piglets yielded identical islet equivalent quantities to quantities obtained from control wild-type pigs. In contrast to wild-type islets, DKO islets did not induce anti-Neu5Gc antibody when grafted in cytidine monophosphate- N -acetylneuraminic acid hydroxylase KO mice and exhibited in vitro normal insulin secretion stimulated by glucose and theophylline. Adult DKO pancreata showed no histological abnormalities, and immunostaining of insulin and glucagon was similar to that from wild-type pancreata. Blood glucose, insulin, C-peptide, the insulin-to-glucagon ratio, and HOMA-insulin resistance in fasted adult DKO pigs and blood glucose and C-peptide changes after intravenous glucose or insulin administration were similar to wild-type pigs. This first evaluation of glucose homeostasis in DKO pigs for two major xenoantigens paves the way to their use in (pre)clinical studies., (© 2017 by the American Diabetes Association.)- Published
- 2017
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