Glargine metabolism over 24 h following its subcutaneous injection in patients with type 2 diabetes mellitus: A dose-response study

摘要

Background and aims: After subcutaneous injection insulin glargine is rapidly metabolized to M1 and M2. Invitro, both M1 and M2 have metabolic effects and bind to IGF-1R similarly to human insulin, whereas glargine exhibits a higher affinity for the IGF-1R and greater mitogenetic effects. The present study was specifically designed to establish the dose-response metabolism of glargine over 24h following s.c. injection in T2DM subjects on long-term use of glargine. Methods and results: Ten subjects with T2DM were studied during 24h after s.c. injection of 0.4 (therapeutic) and 0.8 (high dose) U/kg of glargine on two separate occasions during euglycaemic clamps (cross-over design). Glargine, M1 and M2 over 24h period were determined in appropriately processed plasma samples by a specific liquid chromatography-tandem mass spectrometry assay. Plasma M1 concentration (AUC0-24h) was detected in all subjects and increased by increasing the glargine dose from therapeutic to high dose (p=0.008). Glargine was detectable in 6 (therapeutic dose) and 9 (high dose) out of the 10 subjects and also increased by increasing the dose (p=0.031). However, glargine concentration (AUC0-24h - high dose) represented at most only 9.7% (4.6-15%) of the total amount of insulin measured in the blood. M2 was not detected at all. Conclusion: In T2DM people on long-term use of insulin glargine, even with higher doses (0.8U/kg), glargine is nearly totally metabolized to the active metabolite M1. Glargine is often detectable in plasma, but its concentration remains well below that needed invitro to potentiate IGF-1R binding and mitogenesis.