The agouti gene product stimulates pancreatic beta-cell Ca2+ signaling andinsulin release

Ubiquitous expression of the mouse agouti gene results in obesity and hyper insulinemia. Human agouti is expressed in adipose tissue, and we found reco mbinant agouti protein to stimulate lipogenesis in adipocytes in a Ca2+-dep endent fashion. However, adipocyte-specific agouti transgenic mice only bec ame obese in the presence of hyperinsulinemia. Because intracellular Ca2+ c oncentration ([Ca2+](i)) is a primary signal for insulin release, and we ha ve shown agouti protein to increase [Ca2+](i) in several cell types, we exa mined the effects of agouti on [Ca2+](i) and insulin release. We demonstrat ed the expression of agouti in human pancreas and generated recombinant ago uti to study its effects on Ca2+ signaling and insulin release. Agouti (100 nM) stimulated Ca2+ influx, [Ca2+](i) increase, and a marked stimulation o f insulin release in two beta-cell lines (RIN-5F and HIT-T15; P < 0.05). Ag outi exerted comparable effects in isolated human pancreatic islets and bet a-cells, with a 5-fold increase in Ca2+ influx (P < 0.001) and a 2.2-fold i ncrease in insulin release (P < 0.01). These data suggest a potential role for agouti in the development of hyperinsulinemia in humans.