Hyperinsulinemia-induced hypoglycemia is enhanced by overexpression of connexin 43

To assess whether cell to cell communications via connexins (Cx) participate to insulin secretion in vivo, we studied insulinoma cells (INS1) implanted in rats after stable transfection with connexin 43 (Cx43). We found that compared to wild-type and transfected cells, which in vivo express modest levels of Cx43 and junctional communication, cells overexpressing Cx43 communicated extensively, featured decreased growth, and induced a much higher hyperinsulinemia. As a result, rats with insulinomas made of these cells became more severely hypoglycemic than rats implanted with either wild-type, neomycin-transfected cells or cells transfected with a Cx43 antisense complementary DNA. Rats implanted with transfected cells that expressed modest level of Cx43 showed levels of circulating insulin similar to those in rats implanted with wild-type INS1 cells. The data show that overexpression of Cx43 influences the growth and secretion of the implanted insulinoma cells, providing evidence for a contribution of Cx-mediated cell to cell communication in the functioning of insulin-producing cells in vivo.