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


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.


CONCLUSIONS
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.
Department of Internal Medicine, University of Perugia, Perugia, Italy.
P
P
Lucidi
Department of Internal Medicine, University of Perugia, Perugia, Italy.
F
F
Porcellati
Department of Internal Medicine, University of Perugia, Perugia, Italy.
P
P
Candeloro
Department of Internal Medicine, University of Perugia, Perugia, Italy.
P
P
Cioli
Department of Internal Medicine, University of Perugia, Perugia, Italy.
A Marinelli
AM
Andreoli
Department of Internal Medicine, University of Perugia, Perugia, Italy.
S
S
Marzotti
Diabetes Division, Sanofi, Frankfurt, Germany.
R
R
Schmidt
Department of Internal Medicine, University of Perugia, Perugia, Italy. Electronic address: geremia.bolli@unipg.it.
G B
GB
Bolli
Department of Internal Medicine, University of Perugia, Perugia, Italy.
C G
CG
Fanelli
D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D023381:Endpoint Determination; D005934:Glucagon / Q000097:blood; D015309:Glucose Clamp Technique; D038321:Glycemic Index; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood* / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting / Q000097:blood* / Q000494:pharmacology*; D008875:Middle Aged; D053719:Tandem Mass Spectrometry
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D049528:Insulin, Long-Acting; D000069036:Insulin Glargine; D005934:Glucagon
Cancer; Glargine; IGF-1R; Insulin glargine metabolites; Pharmacokinetics and pharmacodynamics