The work was designed with the purpose of groping for origins of diabetes mellitus. Change of the blood sugar level was pursued in hybrid mice of the CF#1 strain that were successively given a diabetogenic agent extending over five generations. In each generation, alloxan of 50mg per kg body weight was injected intravenously to matured virgin mice. The alloxanized female mice were mated with intact male mice of the same strain. Blood sugar in pregnant mice was determined on the fifth day of gestation, and that in the offspring, on the 90th day after birth. Mean of blood sugar levels following the alloxan injection rose above 200mg percent in each generation, but, in the offspring, levels were distributed around the normal. It was found that the average of blood sugar levels in offsprings born to mothers with hyperglycemia above 200mg percent was higher than that in offsprings from mothers showing blood sugar levels under 200mg percent. Regression coefficients of correlations between blood sugar levels of diabetic mothers and of their offsprings increased by degrees with going through five generations, but, on the other hand, no correlationship was found between blood sugar levels of grandmother mice and of their grandchildren. It appeared striking that a negative correlation existed between blood sugar levels before alloxan injection in mice of the fourth generation and blood sugar levels of their mothers in the third generation. After the alloxan injection in the fourth generation, correlation-ship became reversed. From the above-mentioned, the author infers that a fetus of a diabetic mother may be compelled hyperinsulinism in order to dispose hyperglycemia from the mother. Consequently, a tendency of overcompensation of the pancreatic beta-cells in the fetus may remain for a short period of time even after birth. However, as the necessary condition has already been extinguished, the pancreatic function may fall before long. Repetition of these phanomena in every generation may lead to an increased receptivity against a diabetogenic agent. In this connection, it would be important to realize that no correlaticn was seen between blood sugar levels of grandmother-and grandchild-animals. Excepting the genetic mechanism, therefore, intra-uterine environment seems to play a considerable role in the causation of diabetes mellitus.

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An attempt was made to investigate the prevention of congenital malformations in the offspring of alloxan-diabetic mice by the oral application of tolbutamide. Copulated primiparous CF#1 mice of 90 to 120 days of age were given 60mg/kg. b. wt. of alloxan intravenously on the 10th day of gestation, and then, the diabetic animals were controlled with tolubutamide of 400mg/kg. b. wt. every twelve hours from 48 hours after the alloxan injection to the 16th day of gestation by using a gastric tube (A-T group). Two other groups of mice were treated, one with only alloxan (A group) and one with only tolbutamide (T group) for comparison purposes. All mice were autopsied on the 19 th day of gestation and their fetuses were examined for external and oral malformations as well as skeletal abnormalities. In the A group, seven (14%) of 50 pregnant mice were delivered of more than one anomalous baby, and 13 (2.9%) of 454 live fetuses had malformations. In the A-T group, however, only one (1.9%) of 52 mothers produced a deformed baby (0.2% of 491 live borns). Statistical significance was found between these two groups in the number of mothers with malformed fetuses as well as deformed babies produced. In the T group, only one (0.2%) anomalous fetus was found among 498 live fetuses from 55 mothers. The oral administration of 400mg/kg. b. wt. of tolbutamide showed no teratogenic effects upon embryos of CF#1 mice. The results indicate that the prevention of the diabetic embryopathy may be possible by controlling the metabolic disorders of diabetes in the mother.

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Mice of the CF#1 strain were injected intramuscularly with protein-anabolic steroids (durabolin) of 25mg per kg body weight on the 9th day of gestation. Besides, alloxan of 80mg per kg body weight was given intravenously to the mice on the 10th day of gestation. Blood sugar level was determined on the 12th day of gestation. On the 19th day of gestation, pregnant mice were laparotomized and fetuses were examined. Changes of the maternal body weight during pregnancy and the fetal body weight just after the cesarean section were determined. As control groups, two groups of mice simply given alloxan and durabolin were set up. In the simply alloxanized group, 4.4 percent of the living fetuses were malformed, and in the alloxan-durabolin group, 8.8 percent were malformed. Between these two experimental groups, a significant difference was observed with the probability level of less than 0.05 by the t-test. On the other hand, however, 0.8 percent anomalous fetuses appeared in the durabolin group. Teratogenic capacity of this particular group of mice seems certainly more fragile as compared with the alloxanized as well as the durabolin-alloxan groups. From the findings above-mentioned, the author infers that fetal environment in the diabetic pregnancy may grow worse by the treatment with protein-anabolic steroids from a teratogenic point of view.

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