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The impact of type 1 diabetes mellitus on liver gamma-glutamyltranspeptidase, a premalignant marker, was studied. Diabetes was induced in male Sprague Dawley and Fischer 344 rats by administration of Streptozotocin, which produced a stable and moderately severe diabetic state. In liver homogenates, gamma-glutamyltranspeptidase was increased over control levels: 1.2, 8.1 and 13.2 fold in Sprague-Dawley rats; 4.8, 58.4 and 84.7 fold in Fischer 344 rats; at 1, 3 and 6 weeks following Streptozotocin treatment. In plasma membranes isolated from the livers of Fischer 344 rats, gamma-glutamyltranspeptidase was increased over control levels: 5.6, 75 and 127 fold at weeks 1, 3 and 6 following Streptozotocin treatment. The relative specific activity of 5'-nucleotidase was found to be similar: 9-14, indicating comparable degrees of plasma membrane purity. Plasma glutamate-pyruvate transaminase levels were minimally and similarly affected at all time points indicating lack of association of increasing gamma-glutamyltranspeptidase activity with overt liver damage. Thyroid hormone replacement, with both T3 (0.6 micrograms/Kg) once a day and T4 (6.0 micrograms/kg) twice a day for three days elicited a further 30% increment in enzyme activity. Insulin replacement (20-40 units/200 g body weight) twice a day for five days reduced enzyme activity 51% at week 6. This was associated with an increase in gamma-glutamyltranspeptidase in the plasma from 14 fold over control levels in the diabetic state at week 6 to 53 fold over control levels after insulin replacement at week 6. It is proposed that the diabetes-induced increase in gamma-glutamyltranspeptidase is reduced by an insulin-directed shedding of the enzyme into the plasma.