Comparison of effects of insulin glargine, its metabolites, IGF-I and human insulin on insulin- and IGF-I receptor signaling in type 2 diabetic patients

Presentation Number: MON-848
Date of Presentation: June 17th, 2013

Aimee J Varewijck*1, Hannele Yki-Jarvinen2, Ronald Schmidt3, Norbert Tennagels3 and Joseph A M J L Janssen1
1Erasmus MC, Rotterdam, Netherlands, 2University of Helsinki and Minerva Foundation Institute for Medical Research, 3DSAR sanofi

Abstract

Context Insulin glargine (GLA) is a long-acting insulin analogue which is rapidly converted into metabolites M1 and M2 in vivo. In vitro, these metabolites have metabolic and mitogenic profiles comparable to human insulin. It is unknown to what extent GLA vs. M1 and M2 are found in the circulation during long-term insulin therapy in type 2 diabetic patients. It is also unknown whether GLA compared to NPH insulin therapy has different effects on serum bioactivity mediated by insulin receptor isoforms A (IR-A) and B (IR-B).

 

Aims To measure 1) in vitroeffects of insulin glargine (GLA), its metabolites (M1, M2), IGF-I and NPH insulin on activation of insulin receptor isoforms A (IR-A) and IR-B and IGF-I receptor (IGF-IR), 2) concentrations of GLA, M1, M2 during insulin therapy in type 2 diabetic patients and 3) activation of IR-A and IR-B by serum from patients treated with GLA or NPH insulin.

Methods 104 type 2 diabetic patients (age 56.3±0.8 yrs, BMI 31.4±0.5 kg/m2, A1c 9.1±0.1 % (mean±se) randomized to GLA or NPH insulin therapy with metformin for 36 weeks. GLA, M1 and M2 were determined by LCMS, IR-A, IR-B and IGF-IR activation by kinase receptor activation assays which quantify receptor autophosphorylation in Human Embryonic Kidney cells overexpressing respective receptors.

Results In vitro, M1 induced comparable IR-A, IR-B and IGF-IR activation as NPH insulin. After 36 weeks, M1 increased from undetectable (<0.2 ng/mL) to 1.5 ng/mL [0.9-2.1]; 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 activation (68±3 vs. 68±4 pmol/L, p=0.98). M1 concentrations and NPH insulin dose correlated with serum-induced IR-A activation (r=0.33, p=0.01; r=0.39, p=0.008, respectively).

Conclusions In vitro, M1 induced comparable IR-A, IR-B and IGF-IR activation as NPH insulin. M1, but not GLA or M2, was detectable in serum of patients after long term GLA treatment. M1 concentrations correlated with GLA dose and serum-induced IR-A activation. This suggests that GLA therapy is not mitogenic via increased IGF-IR signaling in vivo.

 

Disclosure: RS: Employee, Sanofi. NT: Employee, Sanofi. Nothing to Disclose: AJV, HY, JAMJLJ