A transgene coding for a human insulin analog has a mitogenic effect on murine embryonic β cells

We have investigated the mitogenic effect of three mutant forms of human insulin on insulin-producing β cells of the developing pancreas. We examined transgenic embryonic and adult mice expressing (i) human [Asp(B10)]- proinsulin/insulin ([Aspa(B10)]ProIN/IN), produced by replacement of histidine by aspartic acid at position 10 of the B chain and characterized by an increased affinity for the insulin receptor; (ii) human [Leu(A3)]insulin, produced by the substitution of leucine for valine in position 3 of the A chain, which exhibits decreased receptor binding affinity; and (iii) human [Leu(A3), Asp(B10)]insulin 'double' mutation. During development, β cells of Asp(B10) embryos were twice as abundant and had a 3 times higher rate of proliferation compared with β cells of littermate controls. The mitogenic effect of [Asp(B10)] ProIN/IN was specific for embryonic β cells because the rate of proliferation of β cells of adults and of glucagon (α) cells and adrenal chromaffin cells of embryos was similar in Asp(B10) mice and controls. In contrast to Asp(B10) embryos, the number of β cells in the Leu(A3) and 'double' mutant lines was similar to the number in controls. These findings indicate that the [Asp(B10)] ProIN/IN analog increased the rate of fetal β-cell proliferation. The mechanism or mechanisms that mediate this mitogenic effect remain to be determined.