NORMOGLYCEMIA RESTORES BETA-CELL REPLICATIVE RESPONSE TO GLUCOSE IN TRANSPLANTED ISLETS EXPOSED TO CHRONIC HYPERGLYCEMIA

We studied the effects of chronic hyperglycemia on beta-cell replicati on and mass in transplanted (Tx) islets. Five groups of streptozocin-i nduced diabetic C57Bl/6 mice were transplanted with 100 (Tx-100) synge neic islets, an insufficient beta-cell mass to restore normoglycemia, Groups 1 and 2 remained hyperglycemia throughout the study; after 80 d ays of hyperglycemia, a second transplantation of 250 islets (Tx-250) restored normoglycemia in groups 3, 4, and 5. Tx-250 was harvested on day 60 in all three groups, and transient mild hyperglycemia developed (10-12 days); thereafter, Tx-100 maintained blood glucose values in t he normal range, Tx-100 was harvested 14 (group 1), 60 (groups 2 and 3 ), 74 (group 4), and 90 (group 5) days after transplantation. Hypergly cemia increased beta-cell replication after 14 days (group, 1: 1.26 +/ - 0.18%, P < 0.05) but not after 60 days (group 2: 0.59 +/- 0.13%) com pared with islets exposed to normoglycemia (group 3: 0.51 +/- 0.07%) ( analysis of variance [ANOVA], P < 0.0002), beta-Cell replication in gr oup 4 increased after Tx-250 harvesting (0.94 +/- 0.16%, P < 0.05). Th e initially Tx beta-cell mass (0.21 +/- 0.014 mg) was progressively re duced in hyperglycemic groups (group 1: 0.13 +/- 0.020 mg; group 2: 0. 048 +/- 0.012 mg; P < 0.05) (ANOVA, P = 0.0001). Restoration of normog lycemia after Tx-250 did not modify beta-cell mass in Tx-100 grans (gr oup 3: 0.076 +/- 0.008 mg), However, after Tx-250 harvesting, beta-cel l mass increased progressively (group 4: 0.11 +/- 0.018 mg; group 5: 0 .14 +/- 0.026 mg, P < 0.05), although it was still reduced compared wi th the initially Tx beta-cell mass (P < 0.05), In summary, Tx islets e xposed to severe chronic hyperglycemia showed in limited beta-cell rep lication and a progressive reduction in beta-cell mass, With normoglyc emia, the Tx beta-cells recovered the replicative response to glucose and partially restored the initially Tx beta-cell mass, indicating tha t normoglycemia, even after long-term hyperglycemia, has a beneficial effect in islet transplantation.