title: Concentrations of insulin glargine and its metabolites during long-term insulin therapy in type 2 diabetic patients and comparison of effects of insulin glargine, its metabolites, IGF-I, and human insulin on insulin and igf-I receptor signaling.
abstract: We investigated 1) the ability of purified glargine (GLA), metabolites 1 (M1) and 2 (M2), IGF-I, and NPH insulin to activate the insulin receptor (IR)-A and IR-B and IGF-I receptor (IGF-IR) in vitro; 2) plasma concentrations of GLA, M1, and M2 during long-term insulin therapy in type 2 diabetic patients; and 3) IR-A and IR-B activation in vitro induced by serum from patients treated with GLA or NPH insulin. A total of 104 patients (age 56.3 ± 0.8 years, BMI 31.4 ± 0.5 kg/m(2), and A1C 9.1 ± 0.1% [mean ± SE]) were randomized to GLA or NPH insulin therapy for 36 weeks. Plasma concentrations of GLA, M1, and M2 were determined by liquid chromatography-tandem mass spectrometry assay. IR-A, IR-B, and IGF-IR autophosphorylation was induced by purified hormones or serum by kinase receptor activation assays. In vitro, M1 induced comparable IR-A, IR-B, and IGF-IR autophosphorylation (activation) as NPH insulin. After 36 weeks, M1 increased from undetectable (<0.2 ng/mL) to 1.5 ng/mL (0.9-2.1), while GLA and M2 remained undetectable. GLA dose correlated with M1 (r = 0.84; P < 0.001). Serum from patients treated with GLA or NPH insulin induced similar IR-A and IR-B activation. These data suggest that M1 rather than GLA mediates GLA effects and that compared with NPH insulin, GLA does not increase IGF-IR signaling during long-term insulin therapy in type 2 diabetes.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Aimee J
authors.initials: AJ
authors.lastname: Varewijck
authors.forename: Hannele
authors.initials: H
authors.lastname: Yki-Järvinen
authors.forename: Ronald
authors.initials: R
authors.lastname: Schmidt
authors.forename: Norbert
authors.initials: N
authors.lastname: Tennagels
authors.forename: Joseph A M J L
authors.initials: JA
authors.lastname: Janssen
mesh_terms: D002853:Chromatography, Liquid; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000069036:Insulin Glargine; D007336:Insulin, Isophane / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D049528:Insulin, Long-Acting / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D053719:Tandem Mass Spectrometry
chemical_list: D007004:Hypoglycemic Agents; D049528:Insulin, Long-Acting; D000069036:Insulin Glargine; D007336:Insulin, Isophane; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin