REGULATION OF BLOOD GLUCOSE TO HUMAN LEVELS BY HUMAN FETAL PANCREATIC XENOGRAFTS

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Abstract
Previous experiments xenografting human fetal pancreas into athymic mice made diabetic with streptozotocin have demonstrated that normoglycemia can be achieved 1-3 months after implantation, but that the blood glucose levels obtained were significantly lower than those of control mice. These lower levels could be due either to genetic regulation by the grafted human beta cell--human neonatal blood glucose levels are lower than those of athymic mice--or to excess release of insulin from the increasing number of beta cells in the implant. In order to address the latter possibility, human fetal pancreas was grafted beneath the renal capsule of athymic mice, the pancreas of which was intact, and they and their ungrafted litter mates monitored during their life span--71 +/- 17 weeks after surgery for the 4 successfully grafted mice. The random blood glucose level in all mice was the same initially and remained so until a significant lowering 20 weeks later--2.0 +/- 0.2 vs. 3.4 +/- 0.4; this difference was maintained thereafter. Data obtained from the oral glucose tolerance tests conducted at 8 weekly intervals paralleled these results. Human C-peptide was detectable in blood by 26 weeks, with a rise demonstrable during the oral glucose tolerance test. Peak levels did not change during the ensuing year. At no stage did any of the mice develop clinical hypoglycemia, despite an annual 23 +/- 6-fold increase in size of the graft and the presence of 0.3-9.2 U insulin therein. The insulin content of the mouse pancreas (0.08 +/- 0.03 U) was unaffected by the presence of the human fetal beta cells. These data show that the xenografted human fetal pancreas grows and releases insulin in a controlled but not excessive manner, with the blood glucose levels probably being determined by genetic information stored in the grafted beta cell.

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