Biological rhythms and chronotherapy of diabetic minipigs

Chronotherapy has gained increasing recognition in clinical medicine for medications which have narrow therapeutic windows and severe adverse effects. A knowledge of dosing time-dependent therapeutic effects can be useful in enhancing the efficacy as well as reducing the toxicity of these drugs. Diabetes mellitus is one of the leading cause of death in the United States. The therapeutic window for the treatment of diabetes using insulin has been reported to be fairly narrow. Thus, the knowledge on the chronopharmacokinetic (chrono-PK) and chronopharmacodynamics (chrono-PD) of insulin may help to significantly improve its efficacy as well reduce its adverse effects in the treatment of diabetes mellitus.;The objective of this research project is to study the circadian rhythms of insulin and its chronotherapy in Type I diabetes mellitus. For achieving the objective; a unique diabetic minipig model was developed. The circadian variations of pharmacokinetics and pharmacodynamics of insulin were investigated and these chrono-PK and chrono-PD profiles in the STZ-induced diabetic minipigs were compared with the healthy non-diabetic ones. Significant circadian variations in insulin pharmacodynamics were observed in normal minipigs, even though there was no circadian variations observed in the plasma insulin and blood glucose profiles. The results of intravenous insulin tolerance tests demonstrated that insulin-mediated glucose metabolism (Kitt) was lower, while integrated glucose-lowering effects (ABCB(0-240)) was higher; and the time for glucose levels to reach the nadir (t;A STZ-induced diabetic minipig model was successfully developed in this dissertation research. Diabetic animals with high glycemic levels (200-250 mg/dL) and low plasma insulin levels (;Significant circadian variations in insulin pharmacodynamics were also observed in diabetic minipigs: Kitt, ABCB, t;A minimal model analysis of the data generated from the frequent sampling intravenous glucose tolerance test was performed to evaluate time-dependent insulin sensitivity and glucose effectiveness in the diabetic minipigs. Results indicated that insulin sensitivity is significantly higher in the night time than in the day time, while glucose effectiveness is not time dependent.