REVERSAL OF DIABETES BY HUMAN FETAL PANCREAS: OPTIMIZATION... : Transplantation (original) (raw)

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OPTIMIZATION OF REQUIREMENTS IN THE HYPERGLYCEMIC NUDE MOUSE

Department of Medicine, University of Sydney, New South Wales, Australia

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Abstract

It has been established previously that the grafted human fetal pancreas takes 2–3 months to reverse diabetes in a recipient hyperglycemic immunoincompetent mouse. The factors responsible for this have never been clarified. It was the aim of these experiments to investigate the effect of grafting various amounts of human fetal pancreas of gestational age 14–20 weeks into these animals, to determine if the time required for normalization of blood glucose levels could be altered. The amount of tissue grafted ranged from 2.6–49 mg (median 12.6 mg), which is the equivalent of 8–100% (median 31%) of a complete pancreas. The 25 diabetic nude mice became normoglycemic 66 days (range 28–147) after administration of streptozotocin, with normal or better-than-normal responses in an oral glucose tolerance test, and detectable human C-peptide levels, which fluctuated in parallel with the glucose levels. The minimal time required for correction of diabetes was 28 days, this occurring when 49 mg of tissue was grafted. Blood glucose levels rose from 2.9±0.3 mmol/L to 21.3± 1.9 mmol/L after removal of the implants. Analysis of the results by stepwise multiple-linear-regression analysis revealed that the time required for normalization of blood glucose levels was dependent on three unrelated factors: the amount of tissue grafted (_P_=0.002); the age of the fetal pancreas, as determined by the heel-toe length (_P_=0.042); and the rate of growth of the implant (_P_=0.031). These data demonstrate that it is advantageous to graft as much human fetal pancreas as possible, ideally from fetuses as old as possible, in order to achieve the most rapid reversal of diabetes in athymic mice. The clinical relevance of this information remains to be established.