Pharmacokinetics and Pharmacodynamics of Insulin Glargine Given in the Evening as Compared With in the Morning in Type 2 Diabetes

OBJECTIVE To compare pharmacokinetics (PK) and pharmacodynamics (PD) of insulin glargine in type 2 diabetes mellitus (T2DM) after evening versus morning administration. RESEARCH DESIGN AND METHODS Ten T2DM insulin-treated persons were studied during 24-h euglycemic glucose clamp, after glargine injection (0.4 units/kg s.c.), either in the evening (2200 h) or the morning (1000 h). RESULTS The 24-h glucose infusion rate area under the curve (AUC(0-24h)) was similar in the evening and morning studies (1,058 +/- 571 and 995 +/- 691 mg/kg X 24 h, P = 0.503), but the first 12 h (AUC(0-12h)) was lower with evening versus morning glargine (357 +/- 244 vs. 593 +/- 374 mg/kg X 12 h, P = 0.004), whereas the opposite occurred for the second 12 h (AUC(12-24h) 700 +/- 396 vs. 403 +/- 343 mg/kg X 24 h, P = 0.002). The glucose infusion rate differences were totally accounted for by different rates of endogenous glucose production, not utilization. Plasma insulin and C-peptide levels did not differ in evening versus morning studies. Plasma glucagon levels (AUC(0-24h) 1,533 +/- 656 vs. 1,120 +/- 344 ng/L/h, P = 0.027) and lipolysis (free fatty acid AUC(0-24h) 7.5 +/- 1.6 vs. 8.9 +/- 1.9 mmol/L/h, P = 0.005; beta-OH-butyrate AUC(0-24h) 6.8 +/- 4.7 vs. 17.0 +/- 11.9 mmol/L/h, P = 0.005; glycerol, P < 0.020) were overall more suppressed after evening versus morning glargine administration. CONCLUSIONS The PD of insulin glargine differs depending on time of administration. With morning administration insulin activity is greater in the first 0-12 h, while with evening administration the activity is greater in the 12-24 h period following dosing. However, glargine PK and plasma C-peptide levels were similar, as well as glargine PD when analyzed by 24-h clock time independent of the time of administration. Thus, the results reflect the impact of circadian changes in insulin sensitivity in T2DM (lower in the night-early morning vs. afternoon hours) rather than glargine per se.