Day-night differences in the kinetics and dynamics of insulin: diabetic versus normal Yucatan minipigs

Time-dependent variations in the pharmacokinetics and pharmacodynamics of insulin were studied at two times, 10:30 and 20:30 during the same day in normal and streptozotocin (STZ)-induced diabetic minipigs housed in L(06:00):D(18:00) using the intravenous insulin tolerance test. Following intravenous insulin (0.1 IU/kg) administration in normal minipigs, the time for the glucose level to reach nadir (tnadir) was significantly longer in the evening than the morning [(A.M.; 30.4 (+/- 2.4) vs. P.M.: 38.5 (+/- 3.3) min] (p < 0.01), although maximum reduction of glucose level (nadir) in the morning and evening was not significantly different [A.M.: (-70 (+/- 2) vs. P.M.: -65 (+/- 5) %]. The rate of glucose decline (Kin) was significantly decreased in the evening [A.M.: 5.33 (+/- 0.71) vs. P.M.: 4.44 (+/- 0.54) %dBG/min] (p < 0.01), and the integrated glucose-lowering response (ABCB) was significantly higher in the evening than the morning [A.M.: 3.18 (+/- 0.38) vs. P.M.: 4.52 (+/- 0.30) (g/dl)* min] (p < 0.01). The area under the plasma insulin concentration curve was increased significantly in the evening [A.M.: 2.26 (+/- 0.174) vs. P.M.: 2.74 (+/- 0.18) (mU/ml)* min], while the morning plasma insulin half-life did not differ significantly from that in the evening [A.M.: 4.79 (+/- 0.36) vs. P.M.: 5.47 (+/- 0.47) min]. After induction of diabetes by intravenous STZ injections, minipigs became diabetic, baseline blood glucose was observed to increase from the range of 45-55 to 200-250 mg/dl while plasma insulin levels decreased from 7-12 to 3-5 uU/ml. In the STZ-induced diabetic minipigs, a higher dose (0.2 IU/kg) was used in the intravenous insulin tolerance test in an attempt to normalize the high glucose levels. Following intravenous administration of insulin, the evening Kin and ABCB were significantly higher than they were in the morning [Kin = A.M.: 0.99 (+/- 0.25) vs. P.M.: 1.75 (+/- 0.44) %dBG/min (p < 0.01); ABCB = A.M.: 12.63 (+/- 1.91) vs. P.M.: 19.09 (+/- 5.43) (g/dl)* min (p < 0.01)]. However, there was no significant difference between tnadir and nadir values obtained in the morning and evening [tnadir = A.M.: 81.4 (+/- 9.2) vs. P.M.: 92.8 (+/- 13.7) min; nadir = A.M.: 39.6 (+/- 5.2) vs P.M.: 48.0 (+/- 9.0) %]. The pharmacodynamics and pharmacokinetics of IV insulin both were found to be highly dose-dependent (r > 0.90).