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

• Published in: Diabetes care Vol. 35; no. 12; pp. 2626 - 2630
• Main Authors: Bolli, Geremia B., Hahn, Annke D., Schmidt, Ronald, Eisenblaetter, Tanja, Dahmen, Raphael, Heise, Tim, Becker, Reinhard H.A.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.12.2012
• Subjects: Adult; Biological and medical sciences; Diabetes; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - drug therapy; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose Clamp Technique; Health aspects; Humans; Hyperglycemia; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - blood; Hypoglycemic Agents - metabolism; Hypoglycemic Agents - therapeutic use; Injections, Subcutaneous; Insulin; Insulin Glargine; Insulin, Long-Acting - administration & dosage; Insulin, Long-Acting - blood; Insulin, Long-Acting - metabolism; Insulin, Long-Acting - therapeutic use; Male; Medical sciences; Metabolic diseases; Metabolites; Middle Aged; Miscellaneous; Original Research; Pharmaceutical industry; Plasma; Plasma physics; Public health. Hygiene; Public health. Hygiene-occupational medicine; France; Endocrinopathy; Human; Immunopathology; Nutrition; Metabolite; Autoimmune disease; Metabolic diseases; Exposure; Blood plasma; Hypoglycemic agent; Insulin glargine; Treatment; Type 1 diabetes; Subcutaneous administration; Dose; Endocrinology
• ISSN: 0149-5992; 1935-5548; 1935-5548
• DOI: 10.2337/dc12-0270

In vivo, after subcutaneous injection, insulin glargine (21(A)-Gly-31(B)-Arg-32(B)-Arg-human insulin) is enzymatically processed into 21(A)-Gly-human insulin (metabolite 1 [M1]). 21(A)-Gly-des-30(B)-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. 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. 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 (AUC(0-30h)) 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-AUC(0-30h) 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. 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 (21(A)-Gly-human insulin), which mediates the metabolic effect of injected glargine.