Decreased apoptosis as a mechanism for hepatomegaly in streptozotocin-induced diabetic rats

Insulin-dependent diabetes mellitus in both humans and animals leads to str uctural and functional changes including hepatomegaly. This study examined hypertrophy, hyperplasia, and apoptosis, three basic aspects of tissue grow th, in livers of Sprague-Dawley and Wistar rats made diabetic by iv injecti on of streptozotocin 8, 30, or 90 days previously. Immunohistochemical meas urement of proliferating cell nuclear antigen revealed that hepatic DNA lab eling indices were similar in normal control animals and diabetic rats 30 o r 90 days post diabetic induction, but were reduced to 45 to 50% of control in insulin-treated diabetic animals, perhaps due to altered receptor activ ity or to partial insulin resistance, as reported previously. Flow cytometr y indicated a 613% increase in diploid hepatocytes in the livers of diabeti c rats 30 days after the onset of diabetes, compared to control. Diabetic l ivers contained 29% fewer tetraploid cells, 81% fewer octaploid cells, and 20% more binucleated hepatocytes than normal controls. At 90 days, the over all smaller size of hepatocytes in diabetic tissue was evidenced by more ce lls per area. Insulin treatment prevented some of these changes, but did no t restore ploidy to a normal distribution. Mitosis, while 300% of normal at 8 days after streptozotocin injection, was reduced to 25% of nor mal after 90 days of diabetes. The morphological evidence of apoptosis was decreased by 23% to 76% in the diabetic liver, and was reversed but not normalized b y insulin treatment. This study indicates that the hepatomegaly observed in streptozotocin-induced experimental diabetes may be due primarily to early hyperplasia, and later decreased apoptosis.