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

Fetal pancreatic β-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 β-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 β-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 β-cells is at a more proximal step of glucose-induced metabolism than the channels on the cell surface.