Different Diabetogenic Response to Moderate Doses of Streptozotocin in Pregnant Rats and Its Long-TermConsequences in the Offspring

摘要

Diabetes during pregnancy results in congenital malformations and long-term postnatal diseases. Experimental models are still needed to investigate the mechanism responsible for these alterations. Thus, by the administration of different doses of streptozotocin (STZ) (0, 25, 30, or 35 mg/kg body weight, intravenous) at the onset of pregnancy in rats, the present study sought an appropriate animal model for this pathology. At day 6 of pregnancy, plasma glucose was progressively higher with an increasing STZ dose, and in rats receiving the 35-mg dose, 2 subgroups were detected: some animals had plasma glucose levels above controls but below 200 mg/dL (mildly diabetic, MD), whereas others had levels above 400 mg/dL (severely diabetic, SD). At day 20 of pregnancy, the MD rats had normal glycemia, but after an oral glucose load (2 g/kg body weight), plasma glucose increased more and insulin increased less than in controls. The SD rats maintainedtheir hyperglycemia and had a greatly impairedoral glucose tolerance. At day 20, fetuses of SD dams werefewer, weighed less, and had enhanced plasma glucose andtriglycerides and decreased insulin, whereas those fromMD dams did not differ from controls. At birth, newbornsfrom MD dams had higher body weight, plasma insulin,and liver triglycerides as well as total body lipid concentrationsthan controls, and on day 21, remained macrosomic and showed higher plasma glucose and liver triglycerideconcentrations. At 70 days of age, offspring of MD dams hadimpaired oral glucose tolerance but normal plasma insulinchange in the case of females, whereas plasma insulin increasedless in males. These alterations were manifest morein those offspring from dams that had > 50% macrosomicnewborns than in those from dams that had < 50% macrosomicnewborns. In conclusion, whereas our MD rats mimicthe changes taking place in gestational diabetic women andshow the long-term risk of macrosomia, the SD rats aremore similar to uncontrolled diabetics. Thus these two ratmodels, obtained with moderate amounts of STZ, could beused to study the pathophysiological consequences of thesedifferent diabetic conditions.