Insulin dosing affects plasma levels of biochemical parameters in a time-dependent manner in Sprague-Dawley rats

Abstract

Changes in levels of various biochemical blood parameters are used as indicators of metabolic effects or potential toxicity when performing non-clinical safety studies of new drug candidates in rats. Additionally, since biochemical blood parameters are often affected during safety testing of new insulin analogues the effect of insulin dosing on these parameters was investigated. Non-diabetic rats were dosed with either vehicle or insulin once daily for 28 days. On Day 28, biochemical blood parameters as well as insulin exposure were measured, at two hour intervals during a 24 h period, to investigate time-dependent as well as time-independent changes. Insulin dosing lowered plasma glucose level for 4 h, corresponding to the peak plasma insulin level. Chronic insulin dosing increased food consumption and bodyweights. Additionally, plasma urea as well as CK and LDH levels increased. Hyperphagia was most likely driven by hypoglycaemia thereby also increasing body weight through insulin-stimulated fatty acid uptake into adipose tissue. Increased urea, CK and LDH levels, suggests that the return to normoglycaemia was driven mainly by increased hepatic gluconeogenesis, as reflected by increased ureagenesis and skeletal muscle proteolysis (increased CK and LDH). A better understanding of insulin-induced changes to biochemical blood parameters may aid the interpretation of changes in these parameters in non-clinical safety studies with new drugs