Synthesis-Secretion Coupling of Insulin: Effect of Cyclosporin

This study investigated the effects of cyclosporin (Cs) on insulin secretion and synthesis from the endocrine pancreas. With in vitro perfused pancreases from control and Cs-treated rats (1, 5,10, or 25 mg · kg⁻¹ · day⁻¹ for 2 wk), a dose-response relationship between Cs dose and inhibition of insulin secretion was demonstrated. Examination of the dynamic secretory response to a glucose stimulus (200 mg/dl) over a 3-h perfusion revealed an inhibition of all three secretory phases. Similarly, the ability of the pancreases to synthesize insulin decreased as a function of Cs dose. Reversibility of Cs toxicity on the pancreas was established by 2 wk after cessation of treatment. To evaluate the effect of Cs treatment in vivo, intravenous glucose tolerance tests were performed. Rats treated with 25 mg · kg⁻¹ · day⁻¹ Cs for 2 wk had significantly lower k values (slope of log glucose concentration over time) than controls. At 10 mg · kg⁻¹ · day¹, although curves that appeared abnormal were observed, k values were not significantly different from those of controls. In summary, this study demonstrates the profound inhibitory effect of Cs on the endocrine pancreas.