AIMS/HYPOTHESIS: New insulin analogues have been created by amino-acid exchange to provide an improved pharmacokinetic profile. However, safety issues have been raised regarding their use, as amino-acid exchange of insulin may induce altered metabolic and mitogenic effects. For example, the insulin analogue Asp(B10) causes breast cancer in rodents. The aim of this study was to compare two new insulin analogues HMR1964 (Lys[B3],Glu[B29]) (insulin glulisine) and HMR1423 (Gly[A21],His[B31],His[B32]) with regular insulin and the mitogenic analogue Asp(B10). MATERIALS AND METHODS: We analysed insulin receptor binding characteristics and dissociation kinetics, as well as insulin-induced receptor auto- and dephosphorylation kinetics, in rat-1 fibroblasts overexpressing the human insulin receptor isoform B. Mitogenic activity was tested in the non-malignant cell line MCF10. RESULTS: Regular insulin, HMR1964 and HMR1423 showed no significant differences in receptor association, dissociation and receptor binding affinity, while Asp(B10) displayed markedly increased insulin receptor affinity. All of the analogues induced rapid insulin receptor autophosphorylation, reaching a maximum 10 min after stimulation (10(-9) mmol/l insulin). In contrast, Asp(B10) induced a prolonged phosphorylation and dephosphorylation state of the 95 kDa insulin receptor beta-subunit. With respect to [3H]thymidine incorporation, the new analogues had similar (HMR1423) or even lower (HMR1964) effects than regular insulin in the mammary epithelial cell line MCF10, while Asp(B10) showed increased [3H]thymidine incorporation. CONCLUSIONS/ INTERPRETATION: HMR1964 and HMR1423 displayed the same association, dissociation and insulin receptor affinity kinetics as regular insulin, and might therefore be useful for the treatment of diabetes.
AIMS/HYPOTHESIS: New insulin analogues have been created by amino-acid exchange to provide an improved pharmacokinetic profile. However, safety issues have been raised regarding their use, as amino-acid exchange of insulin may induce altered metabolic and mitogenic effects. For example, the insulin analogue Asp(B10) causes breast cancer in rodents. The aim of this study was to compare two new insulin analogues HMR1964 (Lys[B3],Glu[B29]) (insulin glulisine) and HMR1423 (Gly[A21],His[B31],His[B32]) with regular insulin and the mitogenic analogue Asp(B10). MATERIALS AND METHODS: We analysed insulin receptor binding characteristics and dissociation kinetics, as well as insulin-induced receptor auto- and dephosphorylation kinetics, in rat-1 fibroblasts overexpressing the humaninsulin receptor isoform B. Mitogenic activity was tested in the non-malignant cell line MCF10. RESULTS: Regular insulin, HMR1964 and HMR1423 showed no significant differences in receptor association, dissociation and receptor binding affinity, while Asp(B10) displayed markedly increased insulin receptor affinity. All of the analogues induced rapid insulin receptor autophosphorylation, reaching a maximum 10 min after stimulation (10(-9) mmol/l insulin). In contrast, Asp(B10) induced a prolonged phosphorylation and dephosphorylation state of the 95 kDa insulin receptor beta-subunit. With respect to [3H]thymidine incorporation, the new analogues had similar (HMR1423) or even lower (HMR1964) effects than regular insulin in the mammary epithelial cell line MCF10, while Asp(B10) showed increased [3H]thymidine incorporation. CONCLUSIONS/ INTERPRETATION: HMR1964 and HMR1423 displayed the same association, dissociation and insulin receptor affinity kinetics as regular insulin, and might therefore be useful for the treatment of diabetes.
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