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Summary. Tolbutamide and glibenelamide (glyburide) were administered to normal hamsters, mice or rats in daily doses proportional to their body weight and equivalent to those used in human therapy. The animals were sacrificed after 6 to 8 weeks of treatment. Pieces of pancreas or isolated pancreatic islets were incubated or perifused in a medium containing glucose or tolbutamide, with or without leueine-114C or glucose-U-14C. The results indicate that the B cells of sulfonylurea treated animals synthesized and released less insulin and oxidized less glucose than those of insulin or saline treated controls. Accordingly, at least in the glibenelamide treated animals, the tolerance for glucose and the insulinogenie response to a glucose load in vivo were suppressed. Although insular function tended to return.to normal after treatment was discontinued, the results reported in this paper do not support the generally aeeepted view that the lasting therapeutic effectiveness of the sulfonylureas is due to a beta-cytotrophie action.

Perinatal maturation of the pancreatic beta cells was studied in the rat. Insulin synthesis proceeded rapidly between the twentieth gestational day and the third postnatal day. The insulin concentration in the pancreas and the amount of insulin available per gram of body weight reached a maximum sixty hours after birth and then decreased slowly toward the values observed in the adult rat. The pancreatic beta cells became responsive to glucose and to tolbutamide during the twenty-third day after fertilization. This phenomenon seemed to be related to the gestational age and not to act of birth or to feeding, although feeding appeared to increase the insulinogenic response to glucose. DIABETES 20: 586-91, September, 1971. The fetal pancreas synthesizes proinsulin and converts it into insulin. 1 ' 2 The embryologic age at which insulin is found, however, depends upon the sensitivity of the methods used for its detection. Thus, the presence of the hormone has been demonstrated in the pancreas of seventeen or eighteen-day-old rat fetus by histologic and histochemical means, 3 ' 4 in that of fourteen-day-old fetus by means of a bioassay 5 and in that of eleven-day-old

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ExtractThe secretion of insulin in vivo and its synthesis and release by pancreatic islets in vitro were studied in rats at various stages of development. An oral glucose load caused a rapid and significant increase in the serum insulin level of pregnant rats and a slower response in their 21-day-old fetuses. Circulating free fatty acids (FFA) decreased in the dams, but did not change in the fetuses. A relative glucose intolerance was found in pups 1 hr, 5 days, and 10 days after birth. This was accompanied by delayed insulin response and by little or no decrease of circulating FFA. After weaning, the glucose tolerance and the insulin and FFA responses gradually improved. The oral administration of a 10-amino acid mixture caused a greater insulin release in newborn and nursing rats than in 21-day-old fetuses or inyoung adult rats. Total serum lipids were higher in I-, 5-, lo-, and 20-day-old rats than in fetuses and adult animals, whether fed or fasted, but 18 hr of fasting decreased total lipids and phospholipids in all age groups. Thus, the age of relative hyperlipidemia corresponded with that of relative glucose intolerance. The secretion of insulin in vitro by pancreatic islets of 5-, lo-, 20-, 30-, and 45-day-old rats increased significantly when the concentration of glucose in the incubation medium was increased from 30 to 300 mg/ml. The islets of 30-and 45-day-old rats secreted the largest amount of insulin. The insulin content of pancreatic islets was higher and the percentage of insulin secreted in relation to the hormonal content was smaller in the islets of nursing rats. Islets of fetal, nursing, and adult rats incorporated L -[ 4 ,~-~~] l e u c i n e into proinsulin and insulin, but the conversion of proinsulin to insulin was minimal in the 1-day-old rat. This incorporation was greater when the glucose concentration of the medium or the incubation time were increased. Thus, birth appears to be associated with a temporary decrease in the ability to release insulin and to dispose of an exogenous glucose load. Speculation large masses of insulin-responsive tissues. Gluconeogenesis continues to be a major source of glucose throughout the nursing age, when the animal consumes a diet rich in protein and fat and low in carbohydrate. Although the fetal pancreas can synthesize insulin, the mechanism for its release and hence the ability to dispose of a glucose load do not reach full maturity until weaning, when the dietary intake of carbohydrate increases and the level of serum lipids decreases toward I the values characteristic of the adult animal. 1The synthesis and storage of insulin in the pancreatic B cells of the rat appear to start during the 1 l t h day of gestation (36, 59). However, the precise time at which the insulin-releasing mechanism begins to function has not been determined and may vary with the nature of the stimulus. Thus, the fetal pancreas, even though insensitive to glucose (4, SO), may respond to other substances (see Reference 37) so that, toward the end of pregnancy, the fetal serum ...