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

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 842-862-Insulin Signaling & Action
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-848
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
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

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Sources of Research Support: The LANMET study was sponsored by sanofi-aventis but the present study was investigator-initiated. The present study was supported by an unrestricted grant from sanofi-aventis (Frankfurt, Germany). Sanofi-aventis had no involvement in the study design, in the collection and interpretation of data. The measurement in plasma of insulin glargine, M1 and M2 was performed at and supported by sanofi-aventis. R. and N. are employees at sanofi-aventis. All other authors have nothing to disclose.