Ontogeny of Endocrine Correlation 



607 



18H-day fetus within a few hours after the 

 vascular capillary network has developed 

 within the larger islets, a relationship of 

 probable functional significance. Only a few 

 beta cells with beginning granule formation 

 occur at this stage. During the succeeding 

 four days two significant changes take place. 

 (1) The number of beta cells in process of 

 differentiation rapidly increases, reaching a 

 peak in 20-day-old fetuses. (2) A concom- 

 itant increase in the accumulation of beta 

 granules occurs on the side of the cell toward 

 the capillary, becoming well marked in 

 many cells on the twenty-first day, an orien- 

 tation suggestive of an actively secreting beta 

 cell. The number of fully mature beta cells 

 packed with secretory granules reaches a 

 peak on the twenty-second day (birth). 



On the day of birth the prospective alpha 

 cells may be identified as cords or groups of 

 nongranular cells at the periphery of the 

 islet, i.e., about a core of beta cells. On the 

 second day after birth a few of these outer- 

 most cells begin to form secretion granules 

 in the area of cytoplasm adjacent to a cap- 

 illary. The number of such cells gradually 

 increases, so that by the fifth day the ma- 

 jority of them may be identified as alpha 

 cells, a few of them having attained a fully 

 mature state through a gradual increase in 

 number and size of the secretion granules. 

 The cytological picture is such as to indicate 

 actively secreting alpha cells by the fifth 

 day of postnatal life. 



The question next arises as to whether the 

 appearance of beta cells with secretory gran- 

 ules coincides in time with initial insulin 

 production and secretion into the blood of 

 the fetus. As an index of beginning func- 

 tional activity it is significant to note that 

 in the rat fetus near or at term (1) the islets 

 with differentiating beta cells are highly 

 vascularized, (2) the secretory granules of 

 the beta cells are oriented toward a capillary, 

 and (3) the number of fully mature beta 

 cells packed with secretory granules reaches 

 a peak. The total picture is such as to indi- 

 cate insulin secretory activity. 



However, information concerning the first 

 appearance of insulin in the pancreas and 

 the quantitive changes in content during 

 embryogenesis is meager, owing chiefly to 

 the lack of suitable microchemical or cyto- 

 chemical methods for its detection. Although 

 the earliest time of appearance has not been 

 determined, insulin is already present in the 

 pancreas of a 5-month fetal calf in propor- 

 tionally greater quantities than in pancreases 

 of older fetuses, of young calves, and even 



of the adult (Banting and Best, '22; Fischer 

 and Scott, '34). (See Table 27.) A progres- 

 sive decrease in quantity of insulin per gram 

 of pancreatic tissue seems to take place with 

 advance in ontogenetic age of the calf. Such 

 a decline with age may possibly represent a 

 change in balance between rates of produc- 

 tion and liberation of insulin, which in turn 

 may be related to the rate of utilization of the 

 hormone in the tissvies of the growing organ- 

 ism. It would be of considerable significance 

 in this connection to determine changes not 

 onlj'- in the cytological picture of the islets 

 but also in the ratio of islet tissue to acinar 

 tissue with increasing age and body weight 

 (cf. Hess and Root, '38). 



Certain indirect evidence presented by 

 Carlson et al. ('11, '14) and by Aron et al. 

 ('23) and Aron ('24) indicates that insulin 

 in both dog and cat fetuses is produced and 

 is liberated during the latter half of the 

 gestation period. If pregnant dogs or cats 

 are pancreatectomized early in the gestation 

 period, the mother develops hyperglycemia 

 resulting in death; if similar operations are 

 performed later in the gestation period, i.e., 

 after the seventh to ninth week of gestation, 

 no signs of hyperglycemia develop until after 

 parturition. Fetal insulin is, therefore, seem- 

 ingly protecting the mother after pancre- 

 atectomy. Whether this can be attribvited to 

 (1) passage of fetal insidin into the maternal 

 circulation, (2) oxidation or utilization of 

 excess blood sugar by the fetus, or (3) com- 

 pensatory adjustment of hormonal mecha- 

 nisms concerned in regulating carbohydrate 

 metabolism in the mother and placenta re- 

 mains unsettled. (For a comprehensive re- 

 view of the subject of carbohydrate and other 

 types of metabolism in the placenta and 

 fetus see Huggett, '41.) 



UNFOLDING OF MECHANISMS OF 



REGULATION OF INSULIN 



SECRETION 



Although in the postnatal mammal a num- 

 ber of regulating mechanisms are probably 

 involved either directly or indirectly, the 

 principal regulator of insulin secretion ap- 

 pears to be the blood svigar level itself. 

 Moreover, the amount of sugar in the blood 

 is governed in the main by an interlocking 

 relationship between liver function (glyco- 

 genesis and glycogenolysis) and the rate of 

 secretion of insulin by the islets. It would 

 appear possible, therefore, that a clue as to 

 the period of onset of insidin regulation of 

 sugar in the blood stream might be obtained 



