Normoglycemia Restores β-Cell Replicative Response to Glucose in Transplanted Islets Exposed to Chronic Hyperglycemia

We studied the effects of chronic hyperglycemia on β-cell replication and mass in transplanted (Tx) islets. Five groups of streptozocin-induced diabetic C57B1/6 mice were transplanted with 100 (Tx-100) syngeneic islets, an insufficient β-cell mass to restore normoglycemia. Groups 1 and 2 remained hyperglycemic throughout the study; after 30 days 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 the normal range. Tx-100 was harvested 14 (group 1), 60 (groups 2 and 3), 74 (group 4), and 90 (group 5) days after transplantation. Hyperglycemia increased β-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%) compared with islets exposed to normoglycemia (group 3: 0.51 ± 0.07%) (analysis of variance [ANOVA], P < 0.0002). β-Cell replication in group 4 increased after Tx-250 harvesting (0.94 ± 0.16%, P < 0.05). The initially Tx β-cell mass (0.21 ± 0.014 mg) was progressively reduced 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 normoglycemia after Tx-250 did not modify β-cell mass in Tx-100 grafts (group 3: 0.076 ± 0.008 mg). However, after Tx-250 harvesting, β-cell 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 with the initially Tx β-cell mass (P < 0.05). In summary, Tx islets exposed to severe chronic hyperglycemia showed a limited β-cell replication and a progressive reduction in β-cell mass. With normoglycemia, the Tx β-cells recovered the replicative response to glucose and partially restored the initially Tx β-cell mass, indicating that normoglycemia, even after long-term hyperglycemia, has a beneficial effect in islet transplantation.