Dynamics and Regulation of Insulin Secretion in Pancreatic Islets from Normal Young Children

Abstract

Insulin secretion has only exceptionally been investigated in pancreatic islets from healthy young children. It remains unclear whether those islets behave like adult islets despite substantial differences in cellular composition and higher β-cell replication rates. Islets were isolated from 5 infants/toddlers (11–36 month-old) and perifused to characterize their dynamics of insulin secretion when subjected to various stimuli and inhibitors. Their insulin responses were compared to those previously reported for similarly treated adult islets. Qualitatively, infant islets responded like adult islets to stimulation by glucose, tolbutamide, forskolin (to increase cAMP), arginine and the combination of leucine and glutamine, and to inhibition by diazoxide and CaCl2 omission. This similarity included the concentration-dependency and biphasic pattern of glucose-induced insulin secretion, the dynamics of the responses to non-glucose stimuli and metabolic amplification of these responses. The insulin content was not different, but fractional insulin secretion rates were lower in infant than adult islets irrespective of the stimulus. However, the stimulation index was similar because basal secretion rates were also lower in infant islets. In conclusion, human β-cells are functionally mature by the age of one year, before expansion of their mass is complete. Their responsiveness (stimulation index) to all stimuli is not smaller than that of adult β-cells. Yet, under basal and stimulated conditions, they secrete smaller proportions of their insulin stores in keeping with smaller in vivo insulin needs during infancy.

Immaturity of insulin secretion by pancreatic islets isolated from one human neonate

“…(e,f) The insulin secretion rate in islets from the neonate was averaged over the perifusion periods in G1, G15 alone and G15 with tolbutamide and diazoxide, and is shown by open bars. For comparison (black bars; mean ± SE), results previously obtained under identical conditions in islets from five infants are shown. Note the difference of scale between the two panels.…”

“…The insulin content of newborn islets (4.1 ng/islet) was much lower than that of infant islets (13.8 ng/islet, range 9.8–18.9 ng/islet). During perifusion without forskolin, switching from zero to 1 mmol/L glucose (G0 to G1) caused a tiny increase in insulin secretion, but further stepwise increases in glucose were ineffective, whereas returning from G10 to G1 induced a paradoxical off‐response (Figure a, open circles).…”

“…The concentration of glucose (G in mmol/L) was increased and decreased as indicated in parallel experiments carried out in the absence (open circles) or presence (filled circles) of 1 μmol/L forskolin (Fk). (b,c) Insulin secretion rates in islets from the neonate are compared with those previously measured in islets from five infants (aged 11–36 months; mean ± SE). Note the difference of scale between the two panels.…”

“…The pancreas was retrieved after 25 min of cardiac arrest. The procedure of islet isolation was similar to that reported for adult or infant islets. We received 2,400 islets with a purity of 25% (owing to only partial purification) and 87% viability.…”

“…In vitro studies have established that pancreatic β‐cells are functionally immature, with virtually no response to glucose, in human fetuses between 12 and 22 weeks‐of‐gestation. Using islets isolated from five infants, we recently showed that β‐cells reach functional maturity by the age of 1 year. Characterization of insulin secretion between birth and 1 year‐of‐age would thus be necessary to identify the timeline and mechanisms of human β‐cell maturation, but such studies are very rare.…”