Premium
Glucose metabolism in pigs expressing human genes under an insulin promoter
Author(s) -
Wijkstrom Martin,
Bottino Rita,
Iwase Hayoto,
Hara Hidetaka,
Ekser Burcin,
Windt Dirk,
Long Cassandra,
Toledo Frederico G. S.,
Phelps Carol J.,
Trucco Massimo,
Cooper David K. C.,
Ayares David
Publication year - 2014
Publication title -
xenotransplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.052
H-Index - 61
eISSN - 1399-3089
pISSN - 0908-665X
DOI - 10.1111/xen.12145
Subject(s) - xenotransplantation , islet , biology , insulin , transgene , glucagon , transplantation , endocrinology , medicine , immunosuppression , genetically modified mouse , immune system , gene , immunology , genetics
Background Xenotransplantation of porcine islets can reverse diabetes in non‐human primates. The remaining hurdles for clinical application include safe and effective T‐cell‐directed immunosuppression, but protection against the innate immune system and coagulation dysfunction may be more difficult to achieve. Islet‐targeted genetic manipulation of islet‐source pigs represents a powerful tool to protect against graft loss. However, whether these genetic alterations would impair islet function is unknown. Methods On a background of α1,3‐galactosyltransferase gene‐knockout (GTKO)/human (h)CD46, additional genes ( hCD 39, human tissue factor pathway inhibitor, porcine CTLA4‐Ig) were inserted in different combinations under an insulin promoter to promote expression in islets (confirmed by immunofluorescence). Seven pigs were tested for baseline and glucose/arginine‐challenged levels of glucose, insulin, C‐peptide, and glucagon. Results This preliminary study did not show definite evidence of β‐cell deficiencies, even when three transgenes were expressed under the insulin promoter. Of seven animals, all were normoglycemic at fasting, and five of seven had normal glucose disposal rates after challenge. All animals exhibited insulin, C‐peptide, and glucagon responses to both glucose and arginine challenge; however, significant interindividual variation was observed. Conclusions Multiple islet‐targeted transgenic expression was not associated with an overtly detrimental effect on islet function, suggesting that complex genetic constructs designed for islet protection warrants further testing in islet xenotransplantation models.