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

ArticleinApmis 114(11):805-11 · November 2006with23 Reads
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.
    • "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). "
    [Show abstract] [Hide abstract] ABSTRACT: Consumption of isoflavones may prevent adiposity, hepatic steatosis, and dyslipidaemia. However, studies in the area are few and primarily with genistein. This study investigated the effects of formononetin and its synthetic analogue, 2-heptyl-formononetin (C7F), on lipid and cholesterol metabolism in C57BL/6J mice. The mice were fed a cholesterol-enriched diet for five weeks to induce hypercholesterolemia and were then fed either the cholesterol-enriched diet or the cholesterol-enriched diet-supplemented formononetin or C7F for three weeks. Body weight and composition, glucose homeostasis, and plasma lipids were compared. In another experiment, mice were fed the above diets for five weeks, and hepatic triglyceride accumulation and gene expression and histology of adipose tissue and liver were examined. Supplementation with C7F increased plasma HDL-cholesterol thereby increasing the plasma level of total cholesterol. Supplementation with formononetin did not affect plasma cholesterol but increased plasma triglycerides levels. Supplementation with formononetin and C7F induced hepatic steatosis. However, formononetin decreased markers of inflammation and liver injury. The development of hepatic steatosis was associated with deregulated expression of hepatic genes involved in lipid and lipoprotein metabolism. In conclusion, supplementation with formononetin and C7F to a cholesterol-enriched diet adversely affected lipid and lipoprotein metabolism in C57BL/6J mice.
    Full-text · Article · Apr 2013
    • "Transplantation of GT- KO and WT porcine islets into immunodeficient mice [11] and immunosuppressed monkeys [12,13] has not demonstrated any major differences in terms of functionality. Recently, however, Dahl et al. described impaired glucose metabolism in GT-KO mice [14] . Determination of whether GT- KO pigs have impaired glucose metabolism is critically important for islet xenotransplantation. "
    [Show abstract] [Hide abstract] ABSTRACT: Xenotransplantation of porcine islets could be a valuable alternative to the shortage of human islets for transplantation. To overcome the immunological obstacle of antibody-mediated rejection, pigs homozygous for alpha1,3-galactosyltransferase gene knock-out (GT-KO) have been produced. The effect of this mutation on glucose metabolism is unknown. Glucose, insulin, C-peptide and glucagon levels were studied in eight adult pigs (four wild-type [WT] and four GT-KO) during intravenous glucose tolerance test (IVGTT), arginine stimulation test (AST), and insulin tolerance test (ITT). Morphological analysis of the pancreata was also performed. The in vitro insulin response to a high glucose concentration and theophylline were studied in a dynamic perfusion system with isolated islets. Basal and stimulated blood glucose levels were similar in WT and GT-KO pigs. Basal insulin, C-peptide and glucagon were higher in GT-KO pigs. C-peptide and insulin responses to arginine and glucose were also higher in GT-KO animals. The reduction in blood glucose during ITT and IVGTT was similar in WT and GT-KO pigs. The extent of staining for insulin and glucagon in the pancreata were similar. The basal insulin secretion of isolated islets was higher in GT-KO pigs, while stimulation indexes for glucose and theophylline were similar to WT. GT-KO pigs demonstrated differences in glucose metabolism compared to WT pigs, the cause for which remains uncertain. It is unlikely that these differences would in any way affect the outcome of GT-KO porcine islet xenotransplantation.
    Full-text · Article · Mar 2010
    • "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). "
    [Show abstract] [Hide abstract] ABSTRACT: Much of our knowledge about the function of genes in cataracts has been derived from the molecular analysis of spontaneous or induced mutations in the mouse. Mutations affecting the mouse lens can be identified easily by visual inspection, and a remarkable number of mutant lines have been characterized. In contrast to humans, most of the genetic mouse cataract models suffer from congenital cataracts, and only a few develop cataracts in old age. Therefore, the mouse cataract models contributed rather to the understanding of lens development than to the ageing process taking place in the lens. A prerequisite for molecular analysis is the chromosomal localization of the gene. In this review, several mouse models will be discussed with emphasis on the underlying genetic basis rather than the morphological features as exemplified by the following: (i) the most frequent mutations in congenital cataracts affect genes coding for gamma-crystallins (gene symbol: Cryg); (ii) some postnatal, progressive cataracts have been characterized by mutations in the beta-crystallin encoding genes (Cryb); (iii) mutations in genes coding for membrane proteins like MIP or connexins lead to congenital cataracts; (iv) mutations in genes coding for transcription factors such as FoxE3, Maf, Sox1, and Six5 cause cataracts; (v) mouse models suffering from hereditary age-related cataracts (e.g. Emory cataract) have not yet been characterized genetically. In conclusion, a broad variety of hereditary congenital cataracts are well understood at the molecular level. Further, expression patterns of the affected genes in several other tissues and organs outside the eye, is making it increasingly clear that isolated cataracts are the exception rather than the rule. By further understanding the pleiotropic effects of these genes, we might recognize cataracts as an easily visible biomarker for a number of systemic syndromes.
    Article · Dec 2009
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