Insulin secretagogues, but not glucose, stimulate an increase in [Ca2+]i in the fetal human and porcine Beta-cell

Fetal pancreatic ß-cells release insulin poorly in response to glucose; however, the cellular mechanism for this is unknown. By using fura-2 to measure changes in the cytoplasmic free Ca2+ concentration in ß-cells, we examined human/porcine fetal islet-like cell clusters (ICCs) and human adult islets for the presence of functional K+ATP and voltage-activated Ca2+ ion channels. The effects of glucose, glyceraldehyde, leucine, KCl, and the channel effectors glipizide and BAY K8644 were studied. In fetal human/porcine ICCs and adult islets, KCl, glipizide, and BAY K8644 increased [Ca2+]i. Both glucose and glyceraldehyde increased [Ca2+]i in islets but had no effect on ICCs. Leucine increased [Ca2+]i in islets and porcine but not human ICCs. We hypothesize that the beneficial effect of leucine in fetal porcine, but not human ICCs, is attributable to time-dependent maturation of the ß-cells, because porcine ICCs examined were at 87% of the gestational period, and human ICCs were at 42%. Our data demonstrate that both K+ATP and voltage-activated Ca2+ channels, required for glucose-stimulated increase in [Ca2+]i, are functional early in gestation. This suggests that the cause of the immaturity of fetal human/porcine ß-cells is at a more proximal step of glucose-induced metabolism than the channels on the cell surface.