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
| Autor: | Geremia B. Bolli, Raphael Dahmen, Annke D. Hahn, Ronald Schmidt, Reinhard H.A. Becker, Tanja Eisenblaetter, Tim Heise |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
medicine.medical_specialty Cardiovascular and Metabolic Risk Endocrinology Diabetes and Metabolism Metabolite medicine.medical_treatment Insulin Glargine chemistry.chemical_compound Subcutaneous injection In vivo Internal medicine Diabetes mellitus Internal Medicine medicine Humans Hypoglycemic Agents Original Research Advanced and Specialized Nursing Type 1 diabetes business.industry Insulin glargine Insulin Glucose clamp technique medicine.disease Insulin Long-Acting Endocrinology Diabetes Mellitus Type 1 chemistry Diabetes Mellitus Type 2 Female business medicine.drug |
| Zdroj: | Diabetes Care |
| ISSN: | 1935-5548 0149-5992 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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