Stimulation of density‐inhibited cell cultures by insulin

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Abstract
Cell proliferation in density‐inhibited chick embryo cell cultures was induced by microgram quantities of insulin, neuraminidase, trypsin or papain. Other proteins tested, including albumin, fetuin, ribonuclease and hyaluronidase were inactive except in very high concentrations (> 100 μg/ml).The insulin chick embryo model was selected for detailed analysis of the initiation of proliferation. Insulin insolubilized by conjugation with Sepharose particles was also active, but only in so far as it was released in soluble form from the particles. This was measured by a radioimmunoassay. Under the conditions giving maximal cell proliferation less than 0.002‐0.2% of insulin was taken up by the cells. This suggests that an interaction of insulin with the cell surface only is sufficient to stimulate the cells. Insulin released the density‐inhibited cells from G1 phase to produce an almost synchronous wave of proliferation. The following sequence of events was characteristic of the cells after stimulation by insulin: an early increase in sugar uptake and decrease in leucine uptake, increase in cell volume, stimulation of RNA and protein synthesis, increase in thymidine uptake, DNA synthesis, mitosis and cell division.