Session: MON 842-862-Insulin Signaling & Action
Poster Board MON-848
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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