Hyperproliferative liver acini after intraportal islet transplantation in streptozotocin-induced diabetic rats.

BACKGROUND

Since insulin is known to have growth-promoting effects, it seemed of interest to study whether a local hyperinsulinemia after intraportal islet transplantation would induce a focal proliferation of the hepatocytes.

EXPERIMENTAL DESIGN

Four, 11, and 21 days after isologous intraportal transplantation of 450 to 1000 islets of Langerhans in streptocotocin-induced diabetic adult male Lewis-rats (n = 12) the animals were perfused with 3% glutaraldehyde, and the livers were cut into sections of 0.5-mm thickness. Stereomicroscopically the islets and the accompanying acini could be identified. These areas were prepared for histologic examination (1-micron-thick sections, staining by Richardson). The islets of Langerhans in the portal triads had induced remarkable changes (accumulation of fat and glycogen) of the hepatocytes in the respective acini. Therefore, it was possible to identify them for the examination of local cell proliferation. The mitotic index (number of mitotic figures per 1000 hepatocytic nuclei) and the apoptotic index (number of apoptotic bodies per 1000 hepatocytic nuclei) of these altered acini (A) were compared with the adjacent nonaltered acini (NA). In a further nine islet-transplanted diabetic animals 5-bromo-2'-desoxyuridine (BrdU) was applicated by osmotic minipumps for 6 days before death (6, 13, and 21, days after islet transplantation). The immunohistochemical labeling indices for BrdU (BrdU-labeled hepatocytic nuclei per 100 hepatocytic nuclei) of A and NA were compared.

RESULTS

The mitotic indices in A and NA were 1.2 and 0.06 at day 4, 2.5 and 0.09 at day 11, and 6.4 and 0.25 at day 21, respectively. The apoptotic indices in A and NA were 2.9 and 0.63 at day 4, 4.1 and 0.54 at day 11, and 8.0 and 0.5 at day 21, respectively. The BrdU labeling indices in A and NA were 28.0 and 1.3 at day 6, 37.0 and 1.9 at day 13, and 17.5 and 0.9 at day 21.

CONCLUSIONS

These data show that after intraportal islet transplantation the proliferative activity and at the same time the apoptotic elimination of hepatocytes are significantly increased focally in the long-term hyperinsulinemic liver acini.