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

Nutr Metab Cardiovasc Dis. 2014 Jul;24(7):709-16. doi: 10.1016/j.numecd.2014.02.008. Epub 2014 Feb 22.

Abstract

Background and aims: After subcutaneous injection insulin glargine is rapidly metabolized to M1 and M2. In vitro, 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 24 h following s.c. injection in T2DM subjects on long-term use of glargine.

Methods and results: Ten subjects with T2DM were studied during 24 h 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 24 h period were determined in appropriately processed plasma samples by a specific liquid chromatography-tandem mass spectrometry assay. Plasma M1 concentration (AUC0-24 h) 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 (AUC0-24 h--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 (0.8 U/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 in vitro to potentiate IGF-1R binding and mitogenesis.

Keywords: Cancer; Glargine; IGF-1R; Insulin glargine metabolites; Pharmacokinetics and pharmacodynamics.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Blood Glucose / metabolism
  • Chromatography, Liquid
  • Cross-Over Studies
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Endpoint Determination
  • Glucagon / blood
  • Glucose Clamp Technique
  • Glycemic Index
  • Humans
  • Hypoglycemic Agents / blood*
  • Hypoglycemic Agents / pharmacology*
  • Injections, Subcutaneous
  • Insulin Glargine
  • Insulin, Long-Acting / blood*
  • Insulin, Long-Acting / pharmacology*
  • Middle Aged
  • Tandem Mass Spectrometry

Substances

  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin, Long-Acting
  • Insulin Glargine
  • Glucagon