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Insulin Secretagogues, But Not Glucose, Stimulate an Increase in [Ca²⁺]_i in the Fetal Human and Porcine ß-Cell

Departments of Medicine (A.J.W., B.E.T.) and Physiology (A.J.W., P.P., D.I.C.), University of Sydney, NSW 2006; and Diabetes Transplant Unit (M.T.T., C.A.P., B.E.T.), Prince of Wales Hospital, University of New South Wales, Sydney, NSW 2031, Australia

Address all correspondence and requests for reprints to: B. E. Tuch, M.D., Ph.D., Diabetes Transplant Unit, Prince of Wales Hospital, High Street, Randwick, NSW 2031 Australia. E-mail: b.tuch{at}unsw.edu.au.

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.

This work was supported by a project grant from the National Health and Medical Research Council of Australia; an Overseas Postgraduate Research Award from the Australian Department of Employment, Education and Training (to A.J.W.); and a University of Sydney Postgraduate Research Award (to A.J.W.).

Abbreviations: ICC, Islet-like cell cluster; R, fura-2 ratios.

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