A TRANSGENE CODING FOR A HUMAN INSULIN ANALOG HAS A MITOGENIC EFFECT ON MURINE EMBRYONIC BETA-CELLS

We have investigated the mitogenic effect of three mutant forms of hum an insulin on insulin-producing beta cells of the developing pancreas, We examined transgenic embryonic and adult mice expressing (i) human [Asp(B10)]-proinsulin/insulin ([Asp(B10)]ProIN/IN), produced by replac ement 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 va line in position 3 of the A chain, which exhibits decreased receptor b inding affinity; and (iii) human [Leu(A3), Asp(B10)]insulin ''double'' mutation. During development, beta cells of Asp(B10) embryos were twi ce as abundant and had a 3 times higher rate of proliferation compared with beta cells of littermate controls, The mitogenic effect of [Asp( B10)]ProIN/IN was specific for embryonic beta cells because the rate o f proliferation of beta cells of adults and of glucagon (ct) cells and adrenal chromaffin cells of embryos was similar in Asp(B10) mice and controls, In contrast to Asp(B10) embryos, the number of beta 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 i ncreased the rate of fetal beta-cell proliferation. The mechanism or m echanisms that mediate this mitogenic effect remain to be determined.