The agouti gene product stimulates pancreatic β-cell Ca²⁺ signaling and insulin release

Ubiquitous expression of the mouse agouti gene results in obesity and hyperinsulinemia. Human agouti is expressed in adipose tissue, and we found recombinant agouti protein to stimulate lipogenesis in adipocytes in a Ca²⁺-dependent fashion. However, adipocyte-specific agouti transgenic mice only became obese in the presence of hyperinsulinemia. Because intracellular Ca²⁺ concentration ([Ca²⁺]_i) is a primary signal for insulin release, and we have shown agouti protein to increase [Ca²⁺]_i in several cell types, we examined the effects of agouti on [Ca²⁺]_i and insulin release. We demonstrated the expression of agouti in human pancreas and generated recombinant agouti to study its effects on Ca²⁺ signaling and insulin release. Agouti (100 nM) stimulated Ca²⁺ influx, [Ca²⁺]_i increase, and a marked stimulation of insulin release in two β-cell lines (RIN-5F and HIT-T15; P < 0.05). Agouti exerted comparable effects in isolated human pancreatic islets and β-cells, with a 5-fold increase in Ca²⁺ influx (P < 0.001) and a 2.2-fold increase in insulin release (P < 0.01). These data suggest a potential role for agouti in the development of hyperinsulinemia in humans.