DEVELOPMENT OF THE FUNCTION OF ENDOCRINE PANCREAS IN THE HUMAN FOETUS

Now it is known that the development of the function of the endocrine pancreas in man begins as early as in the prenatal period. For evaluating the role of insulin in the process of foetal development it is important to know the time when the hormone appears in the gland and begins to be secreted into the blood as well as the levels of insulin at various periods of time of prenatal life. It is also important to know the degree of maturation of the hormonal receptors in beta-cells during early ontogenesis in man.

The morphological differentiation of pancreas in the human foetus has been studied rather extensively. Differentiation of separate islet cells in human pancreas occurs by the end of the 9th week of prenatal life. During this period, alpha and beta cells acquire their typical granular structure. Discrete Langerhans islets may be found in human foetuses beginning with the 11 - 12 week, as shown by Pischinsky (1966).

The literature contains very few data about the functional development of endocrine pancreas in the human foetus.

In this connection, the first part of our work had the purpose to establish the time of appearance of immunoreactive insulin in foetal pancreas and to follow the changes in the content and concentrations of the hormone in the gland and the blood stream.

We used the glands of 285 human embryos and foetuses of both sexes aged 7 to 32 weeks. The material was obtained from foetuses delivered by hysterotomy. for therapeutic reasons or from spontaneous abortions.

The glands and sera were stored at a temperature -15°C. Insulin was measured by radioimmunoassay as described by Hales and Randle, using the kits supplied by the Sorin Company, France.

Pancreatic insulin was extracted and purified by Davoren’s method. Each pancreas from foetuses aged 7 weeks and 15 to 32 weeks was assayed individually. Glands from foetuses aged 8 to 14 weeks were pooled in three age groups.

Table 1 shows the weights of pancreases and the content and concentration of granular insulin in different age groups.

We found immunoreactive insulin in pancreases of all 7-week-old foetuses.

At this stage of gestation, the pancreas has a very low content (0.045 mU per gland) and concentration (0.03 mU per mg) of insulin.

In the 8-to-9-week-old embryos the levels of the hormone in the gland are significantly higher. Its content increases thirty times, and its concentration ten times. Both the content and the concentration of insulin rise with the age of the foetus.

This increase is especially pronounced during two periods: firstly, from the 7th to the 15th week; and secondly, from the 22nd to the 32nd week.

At the intermediate stage, from the 15th to the 21st week, the concentration of the hormone remains unchanged (2.0; 1.8; 2.0 mU per mg).

The concentration of insulin in the blood serum of foetuses aged 15 to 28 weeks is low (Table 2). From 28 to 32 weeks this level increases fivefold, up to 34.1 mU/ml.

Thus our results show that the functional development of endocrine pancreas occurs in man during early ontogenesis. Insulin is found in the pancreas as early as in the 7th week of prenatal life (Schaeffer et al., 1973).

Secretory granules in the beta-cells have been discovered by Poschinsky (1966) at 9-10 weeks. Grillo and Shima (1966) had reported the presence of immunoreactive insulin in the pancreas of the 80 mm (CR) human foetas i.e. by the 12th week.

Consequently, by means of radioimmunoassay, insulin may be revealed in the human foetal pancreas before the appearance of specific secretory granules in beta cells.

We have observed a good correlation between the periods of intensive insulin synthesis and the histological structure of the pancreas. Secretory granules in beta cells accumulate during the first four months of prenatal life. At the same time, the insulin level in the gland rises sharply. According to Pischinsky, specific granularity in islet cells decreases after 15 to 16 weeks. This may indicate that insulin is being secreted into the blood. Our data confirm this suggestion, because we have found insulin in foetal blood in the 15th to 16th week.

We have not assayed foetal blood for insulin prior to the 15th week, but Kaplan and her colleagues found the hormone in the blood stream as early as in the 11th week.

Before the 28th weeks of gestation, foetal blood contains little insulin. After 28 weeks, the concentration of insulin in the blood increases, achieving values typical for newborns (Steinke, 1965).

A similar increase in insulin blood level before term occurs in ovine, rabbit and calf foetuses (Willes, 1969).

Maternal insulin, as is known, normally does not cross the placenta (Adam et al., 1968). Thus the level of insulin in foetal blood may indicate the secretory activity of foetal pancreas.

The concentrations of insulin both in the gland and in the blood of the foetus are high before term. Apparently at this stage insulin is urgently required by the foetus, while the capacity for high synthesis and secretion of the hormone may reflect the extent of maturation of the pancreas.

The existence of a physiological relationship between the somatotropic function of the pituitary gland and the function of pancreatic beta cells has been firmly established. However, the data obtained concern only adults. There is practically no information about this relationship in the foetus.

Several years ago we had studied the pituitary somatotropic (STH) function in human foetuses, so we attempted to compare our present results with previous observations.

In Fig. 1 may be seen the changing concentrations of STH (the upper panel) and insulin (the lower panel) in the respective glands (continuous line) and the blood serum (dotted line) of human foetuses from the 7th to the 40th week of prenatal life. The curves showing the concentration of STH and that of insulin in the glands have a similar pattern. The STH concentration in foetal hypophysis increases up to the 20th week and remains unchanged approximately up to the 28th week, then it rises again. The concentration of insulin in the pancreas also changes in three phases: firstly, its level increases up to the 16th week; secondly, a plateau is maintained from the 16th to the 24th week and finally, the curve ascends again.

On the other hand, the curves depicting the concentrations of STH and insulin in the blood serum have different shapes. Thus the STH level in foetal serum is decreased after 28 weeks, but the insulin level is considerably increased.

It should be noted that foetal blood contains somewhat less insulin than that of the adults, while the STH blood level is up to a hundred times higher in foetuses as compared to adults.

The second part of our study, which is currently in progress, concerns the extent of maturation of the pancreatic islets during early ontogenesis in man.

It is well known that many agents, including glucosa, cyclic AMP, theophylline, tolbutamide, aminoacids, STH, ACTH, some ions and...