title: Pharmacokinetics and pharmacodynamics of insulin glargine given in the evening as compared with in the morning in type 2 diabetes.
abstract: OBJECTIVE
  To compare pharmacokinetics (PK) and pharmacodynamics (PD) of insulin glargine in type 2 diabetes mellitus (T2DM) after evening versus morning administration.
  
  
  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 (AUC0-24h) was similar in the evening and morning studies (1,058 ± 571 and 995 ± 691 mg/kg × 24 h, P = 0.503), but the first 12 h (AUC0-12h) was lower with evening versus morning glargine (357 ± 244 vs. 593 ± 374 mg/kg × 12 h, P = 0.004), whereas the opposite occurred for the second 12 h (AUC12-24h 700 ± 396 vs. 403 ± 343 mg/kg × 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 (AUC0-24h 1,533 ± 656 vs. 1,120 ± 344 ng/L/h, P = 0.027) and lipolysis (free fatty acid AUC0-24h 7.5 ± 1.6 vs. 8.9 ± 1.9 mmol/L/h, P = 0.005; β-OH-butyrate AUC0-24h 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.
authors.affiliation: Department of Medicine, University of Perugia Medical School, Perugia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Porcellati
authors.affiliation: Department of Medicine, University of Perugia Medical School, Perugia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Lucidi
authors.affiliation: Department of Medicine, University of Perugia Medical School, Perugia, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Cioli
authors.affiliation: Department of Medicine, University of Perugia Medical School, Perugia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Candeloro
authors.affiliation: Department of Medicine, University of Perugia Medical School, Perugia, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Marinelli Andreoli
authors.affiliation: Department of Medicine, University of Perugia Medical School, Perugia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Marzotti
authors.affiliation: Department of Medicine, University of Perugia Medical School, Perugia, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Ambrogi
authors.affiliation: Department of Medicine, University of Perugia Medical School, Perugia, Italy geremia.bolli@unipg.it.
authors.forename: Geremia B
authors.initials: GB
authors.lastname: Bolli
authors.affiliation: Department of Medicine, University of Perugia Medical School, Perugia, Italy.
authors.forename: Carmine G
authors.initials: CG
authors.lastname: Fanelli
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000097:blood; D002940:Circadian Rhythm; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D004334:Drug Administration Schedule; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005947:Glucose / Q000008:administration & dosage / Q000493:pharmacokinetics; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007267:Injections; D000069036:Insulin Glargine; D007333:Insulin Resistance; D049528:Insulin, Long-Acting / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D049528:Insulin, Long-Acting; D000069036:Insulin Glargine; D005947:Glucose