Plasma Exposure to Insulin Glargine and Its Metabolites M1 and M2 After Subcutaneous Injection of Therapeutic and Supratherapeutic Doses of Glargine in Subjects With Type 1 Diabetes
- Geremia B. Bolli, MD1⇓,
- Annke D. Hahn, PHD2,
- Ronald Schmidt, PHD2,
- Tanja Eisenblaetter, PHD2,
- Raphael Dahmen, MD2,
- Tim Heise, MD3 and
- Reinhard H.A. Becker, MD, PHD2
- 1Department of Internal Medicine, University of Perugia, Perugia, Italy
- 2sanofi-aventis, Frankfurt/Main, Germany
- 3Profil Institut für Stoffwechselforschung, Neuss, Germany
- Corresponding author: Geremia B. Bolli, .
OBJECTIVE In vivo, after subcutaneous injection, insulin glargine (21A-Gly-31B-Arg-32B-Arg-human insulin) is enzymatically processed into 21A-Gly-human insulin (metabolite 1 [M1]). 21A-Gly-des-30B-Thr-human insulin (metabolite 2 [M2]) is also found. In vitro, glargine exhibits slightly higher affinity, whereas M1 and M2 exhibit lower affinity for IGF-1 receptor, as well as mitogenic properties, versus human insulin. The aim of the study was to quantitate plasma concentrations of glargine, M1, and M2 after subcutaneous injection of glargine in male type 1 diabetic subjects.
RESEARCH DESIGN AND METHODS Glargine, M1, and M2 were determined in blood samples obtained from 12, 11, and 11 type 1 diabetic subjects who received single subcutaneous doses of 0.3, 0.6, or 1.2 units · kg−1 glargine in a euglycemic clamp study. Glargine, M1, and M2 were extracted using immunoaffinity columns and quantified by a specific liquid chromatography-tandem mass spectrometry assay. Lower limit of quantification was 0.2 ng · mL−1 (33 pmol · L−1) per analyte.
RESULTS Plasma M1 concentration increased with increasing dose; geometric mean (percent coefficient of variation) M1-area under the curve between time of dosing and 30 h after dosing (AUC0–30h) was 1,261 (66), 2,867 (35), and 4,693 (22) pmol · h · L−1 at doses of 0.3, 0.6, and 1.2 units · kg−1, respectively, and correlated with metabolic effect assessed as pharmacodynamics-AUC0–30h of the glucose infusion rate following glargine administration (r = 0.74; P < 0.01). Glargine and M2 were detectable in only one-third of subjects and at a few time points.
CONCLUSIONS After subcutaneous injection of glargine in male subjects with type 1 diabetes, exposure to glargine is marginal, if any, even at supratherapeutic doses. Glargine is rapidly and nearly completely processed to M1 (21A-Gly-human insulin), which mediates the metabolic effect of injected glargine.
This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc12-0270/-/DC1.
A slide set summarizing this article is available online.
Clinical trial reg. no. EudraCT 2009-016052-44, https://eudract.ema.europa.eu/.
- Received February 8, 2012.
- Accepted July 10, 2012.
- © 2012 by the American Diabetes Association.
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