The importance of low blood glucose in the development of fetal sheep pancreatic endocrine cells transplanted into athymic mice.

The major problem in using fetal sheep pancreas as a transplantable source of insulin-producing cells to reverse diabetes is that beta cells do not differentiate well. Glucotoxicity is a potential explanation for this because the blood glucose level of recipient mice is higher than that of fetal sheep (7 vs. 1.5 mM). To test the effect of approximating these fetal conditions blood glucose levels of recipient athymic mice were lowered for 4 weeks from 7.3 +/- 1.6 mM to a nadir of 3.7 +/- 1.7 mM by administration of insulin pellets. This resulted in a 2.7-fold increase in the percentage of beta cells and a 5.9-fold increase in the number of glucagon-containing alpha cells. The increase in endocrine cells was probably due to improved formation from undifferentiated cells, but greater proliferation of the mature cells is also a possibility. The effect was transient with endocrine cell numbers diminishing once the effect of insulin administration ceased. It is concluded that while transplanted fetal sheep pancreas may not be suitable for reversal of diabetes, it is a useful model for studying how pancreatic endocrine cells develop.