Preclinical studies on human insulin. I. Acute and subacute toxicity studies

Human insulin (prepared from porcine insulin) and porcine insulin were tested for acute toxicity by subcutaneous administration to unfasted mice and rats and fasted mice. The animals were observed for signs of reaction and post mortem examination was performed. LD50 values were calculated when possible. The LD50 values in the unfasted animals were several times higher than in the fasted mice, but similar for the two insulin preparations. The deaths and the signs observed were most probably caused by hypoglycaemia. No dose-related macroscopic organ changes were found. In a 28 day toxicity study rats were given human or porcine insulin subcutaneously at dosages of 2, 20 or 200 U/kg/day. The criteria examined included mortality, body-weight change, food consumption and utilization, haematology, blood chemistry, urinalysis, ophthalmoscopy, organ weights, gross- and histopathology. A few deaths occurred because of hypoglycaemia. In surviving rats from dosage groups 20 and 200 U/kg/day of either insulin preparation higher plasma glucose levels than in the control were observed 24 hours after dosing. Higher food intake and body-weight gains, lower plasma protein concentrations and higher urinary volumes with associated low specific gravity were observed in animals given either human or porcine insulin at 200 U/kg/day. No other adverse effects were registered, and no overt difference was found between the effect of human and porcine insulin.