Cyclosporine's effect on canine pancreatic endocrine function

Abstract

This study was designed to investigate the mechanism, and reversibility, of glucose intolerance following the acute administration of cyclosporine (CsA) in a canine model. Three groups underwent a baseline intravenous glucose tolerance test (IVGTT; 0.5 g/kg of glucose), with simultaneous insulin determinations. In groups A and B, repeat IVGTTs were performed, at three-day intervals, after 2, 4, and 6 mg/kg of intravenous CsA + solvent (group A; n = 8), or the solvent alone (group B; n = 5). Repeat IVGTTs were performed in group A, 24 and 72 hr after the last CsA infusion. In group C (n = 5), IVGTTs were performed, 4, 24, 48, and 72 hr after oral CsA (12.5 mg/kg). In each group, the rate of glucose clearance (k value,--per cent min), and basal-to-peak insulin difference (uU/ml), for each IVGTT were compared with the baseline results. In group A, the basal-to-peak insulin difference was significantly lower than baseline (81.9 +/- 13.6) after 2 mg/kg (27.3 +/- 3.1; P less than 0.005), 4 mg/kg (22.7 +/- 3.7; P less than 0.001); and 6 mg/kg (16.8 +/- 3.2; P less than 0.001) of CsA, and returned to baseline within 24 hr (81.4 +/- 3.7). Corresponding K values were also significantly different in group A. In group B, there were no significant differences in these parameters from controls, at the equivalent doses of the solvent alone. At 4 hr after oral CsA (group C), there was a reduction in the basal-to-peak insulin difference (37.2 +/- 9.1 vs. 22.5 +/- 4.1) and K values (-3.20 +/- 0.4 vs. -1.96 +/- 0.3), with the change in K values being statistically significant (P less than 0.05). A return to baseline levels was present at 24 h. This study demonstrates that, in the canine model, therapeutic doses of intravenous and oral CsA acutely impair glucose regulation. This acute effect is secondary to decreased peripheral insulin levels, is reversible at 24 h, and is not evident with CsA solvent alone. The mechanism of decreased insulin secretion following CsA administration requires further elucidation.