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 hous ed in L(06:00):D(18:00) using the intravenous insulin tolerance test. Following intravenous insulin (0.1 IU/kg) administration in normal min ipigs, the time for the glucose level to reach nadir (t(nadir)) was si gnificantly 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 significa ntly different [A.M.: (-70 (+/-2) vs. P.M.: -65 (+/-5) %]. The rate of glucose decline (K-itt) 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 hig her 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 insul in 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 m orning 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 be came diabetic, baseline blood glucose was observed to increase from th e range of 45-55 to 200-250 mg/dl while plasma insulin levels decrease d from 7-12 to 3-5 uU/ml. In the STZ-induced diabetic minipigs, a high er dose (0.2 IU/kg) was used in the intravenous insulin tolerance test in an attempt to normalize the high glucose levels. Following intrave nous administration of insulin, the evening K-itt and ABCB were signif icantly higher than they were in the morning [K-itt = 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 t(nadir) and nadir values obtained in the morning and evening [t(nadir) = A.M.: 81.4 (+/-9.2) v s. 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).