The Dosing-Ttme Dependent Influence of Chronic Cyclosporin a Treatment on Daily Profiles of Plasma Glucose and Insulin in the Wistar Rat

Abstract

The dosing-time dependent effects of cyclosporin A (CsA) on glucose and insulin plasma levels were evaluated in the light of possible alterations of their biological rhythms. Male Wistar rats weighing 200–250 g were habituated to a 12:12h light-dark cycle. At the beginning of the experiments, on day DO (before any treatment), significant rhythms were obtained for plasma glucose and immunoreactive insulin (IRI). The plasma glucose showed a 12h periodicity and the plasma IRI a more pronounced rhythm, with both 12h and 24h significant components. Plasma glucose and IRI were then determined in drug-treated (20 mg CsA/kg b.wt/day; dosing time point: T01, T07, T13, or T20) and control rats during and after a 21-day treatment period. The CsA-treated rats developed hyperglycemia and a marked enhancement of the amplitude of the daily glucose rhythm. The magnitude of these effects differed among the groups (p < 0.001). Most pronounced alterations were observed on day 21 (D21) in group T07: M - 22.5 ± 4.0 mmol/l; A = 9.2 ± 6.0 mmol/l. The mean plasma insulin showed little though significant (p<0.01) decreases. For instance, on D21 in group T01, M = 28.5 ±3.6 μU/ml, and in group T07, M = 28.7 ±2.5 (μU/ml. In parallel, plasma CsA levels increased during the 21-day period and differed among groups (p < 0.01). The highest levels (4–5 mg/l) were obtained in T07 and T19 on D21. After drug cessation, the levels of plasma glucose were reduced, but stayed higher than control values. Body weights were monitored; the rate of growth was lower (p < 0.01) in CsA-treated rats than in controls (2.93 ±0.11 versus 5.1 ±0.11 g/day, respectively). (Chronobiology International, 14(3), 275–285, 1997)