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

Nutrition, Metabolism and Cardiovascular Diseases

Volumn 24, Issue 7, 2014, Pages 709-716

  Lucidi, P ^a   Porcellati, F ^a   Candeloro, P ^a   Cioli, P ^a   Marinelli Andreoli, A ^a   Marzotti, S ^a   Schmidt, R ^b   Bolli, G B ^a   Fanelli, C G ^a  

^a UNIVERSITY OF PERUGIA   (Italy)

^b Diabetes Division   (Germany)

Author keywords

Cancer; Glargine; IGF 1R; Insulin glargine metabolites; Pharmacokinetics and pharmacodynamics

Indexed keywords

3 HYDROXYBUTYRIC ACID; FATTY ACID; GLUCAGON; GLYCEROL; HEMOGLOBIN A1C; IMMUNOREACTIVE INSULIN; INSULIN; INSULIN GLARGINE; SOMATOMEDIN C RECEPTOR; ANTIDIABETIC AGENT; GLARGINE; GLUCOSE BLOOD LEVEL; LONG ACTING INSULIN;

ADULT; AREA UNDER THE CURVE; ARTICLE; BLOOD GLUCOSE MONITORING; BODY MASS; CLINICAL ARTICLE; CONTROLLED STUDY; CROSSOVER PROCEDURE; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; DRUG DOSE COMPARISON; DRUG DOSE INCREASE; DRUG DOSE TITRATION; DRUG METABOLISM; GLUCOSE CLAMP TECHNIQUE; GLUCOSE UTILIZATION; GLYCEMIC CONTROL; HUMAN; LIMIT OF QUANTITATION; LIQUID CHROMATOGRAPHY; MAXIMUM PLASMA CONCENTRATION; NON INSULIN DEPENDENT DIABETES MELLITUS; PHARMACODYNAMICS; PRIORITY JOURNAL; RADIOIMMUNOASSAY; RANDOMIZED CONTROLLED TRIAL; TANDEM MASS SPECTROMETRY; TIME TO MAXIMUM PLASMA CONCENTRATION; AGED; BIOASSAY; BLOOD; DIABETES MELLITUS, TYPE 2; GLUCOSE BLOOD LEVEL; GLYCEMIC INDEX; METABOLISM; MIDDLE AGED; SUBCUTANEOUS DRUG ADMINISTRATION;

AGED; BLOOD GLUCOSE; CHROMATOGRAPHY, LIQUID; CROSS-OVER STUDIES; DIABETES MELLITUS, TYPE 2; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; ENDPOINT DETERMINATION; GLUCAGON; GLUCOSE CLAMP TECHNIQUE; GLYCEMIC INDEX; HUMANS; HYPOGLYCEMIC AGENTS; INJECTIONS, SUBCUTANEOUS; INSULIN, LONG-ACTING; MIDDLE AGED; TANDEM MASS SPECTROMETRY;

EID: 84901918304     PISSN: 09394753     EISSN: 15903729     Source Type: Journal    
DOI: 10.1016/j.numecd.2014.02.008     Document Type: Article

References (30)

1. Hemkens L.G., Grouven U., Bender R., Günster C., Gutschmidt S., Selke G.W., et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 2009, 52:1732-1744.
2. Jonasson J.M., Ljung R., Talback M., Haglund B., Gudbjornsdottir S., Steineck G. Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden. Diabetologia 2009, 52:1745-1754.
3. Colhoun H.M. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 2009, 52:1755-1765. SDRN Epidemiology group.
4. Currie C.J., Poole C.D., Gale E.A.M. The influence of glucose lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009, 52:1766-1777.
5. EMA/329790/2013. Outcome of review of new safety data on insulin glargine. Data from population-based studies and the scientific literature do not indicate an increased risk of cancer. Available from:, [accessed 10.06.13]. http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2013/05/WC500143823.pdf.
6. Kurtzhals P., Schaffer L., Sorensen A., Kristensen C., Jonassen I., Schmid C., et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 2000, 49:999-1005.
7. Kuerzel G.U., Shukla U., Scholtz H.E., Pretorius S.G., Wessels D.H., Venter C., et al. Biotransformation of insulin glargine after subcutaneous injection in healthy subjects. Curr Med Res Opin 2003, 19:34-40.
8. Agin A., Jeandidier N., Gasser F., Grucker D., Sapin R. Glargine blood biotransformation: invitro appraisal with human insulin immunoassay. Diabetes Metab 2007, 33:205-212.
9. Kohn W.D., Micanovic R., Myers S.L., Vick A.M., Kahl S.D., Zhang L., et al. pI-shifted insulin analogs with extended invivo time action and favorable receptor selectivity. Peptides 2007, 28:935-948.
10. Sommerfeld M.R., Muller G., Tschank G., Seipke G., Habermann P., Kurrle R., et al. Invitro metabolic and mitogenic signaling of insulin glargine and its metabolites. PLOS ONE 2010, 5:e9540.
11. Thevis M., Thomas A., Delahaut P., Bosseloir A., Schanzer W. Qualitative determination of synthetic analogues of insulin in humanplasma by immunoaffinity purification and liquid chromatography-tandem mass spectrometry for doping control purposes. Anal Chem 2005, 77:3579-3585.
12. Bolli G.B., Hahn A.D., Schmidt R., Eisenblaetter T., Dahmen R., Heise T., et al. Plasma exposure to insulin glargine and its metabolites M1 and M2 after subcutaneous injection of therapeutic and supratherapeutic doses of glargine in subjects with type 1 diabetes. Diabetes Care 2012, 35:2626-2630.
13. Danne T., Johnston P., Xiang G., Cali A., Dain M.-P., Philotheou A. Insulin glargine metabolite M1 is the principal insulin component circulating in plasma of young children with type 1 diabetes: results from the PRESCHOOL study. Diabetologia 2012, 55(Suppl. 1):PS946.
14. Lucidi P., Porcellati F., Rossetti P., Candeloro P., Andreoli A.M., Cioli P., et al. Metabolism of insulin glargine after repeated daily subcutaneous injections in subjects with type 2 diabetes. Diabetes Care 2012, 35:2647-2649.
15. Varewijck A.J., Yki-Järvinen H., Schmidt R., Tennagels N., Janssen J.A. Concentrations of insulin glargine and its metabolites during long-term insulin therapy in type 2 diabetic patients and comparison of effects of insulin glargine, its metabolites, IGF-i, and human insulin on insulin and IGF-i receptor signaling. Diabetes 2013, 62:2539-2544.
16. Ewing D.J., Clarke B.F. Diagnosis and management of diabetic autonomic neuropathy. Br Med J 1982, 285:916-918.
17. Andres R., Swerdoff T., Pozefsky T., Coleman D. Manual feedback technique for the control of blood glucose concentration. Automation in analytical chemistry 1966, 486-491. Mediad, New York. L.T. Skeggs (Ed.).
18. Lalli C., Ciofetta M., Del Sindaco P., Torlone E., Pampanelli S., Compagnucci P., et al. Long-term intensive treatment of type 1 diabetes with the short-acting insulin analogue lispro in variable combination with NPH insulin at mealtime. Diabetes Care 1999, 22:468-477.
19. Porcellati F., Rossetti P., Busciantella N.R., Marzotti S., Lucidi P., Luzio S., et al. Comparison of pharmacokinetics and dynamics of the long-acting insulin analogs glargine and detemir at steady state in type 1 diabetes: a double-blind, randomized, crossover study. Diabetes Care 2007, 30:2447-2452.
20. Lucidi P., Rossetti P., Porcellati F., Pampanelli S., Candeloro P., Andreoli A.M., et al. Mechanisms of insulin resistance after insulin-induced hypoglycaemia in humans: the role of lipolysis. Diabetes 2010, 59:1349-1357.
21. Kuzuya H., Blix P.M., Horwitz D.L., Steiner D.F., Rubenstein A.H. Determination of free and total insulin and C-peptide in insulin-treated diabetics. Diabetes 1977, 26:22-29.
22. Wolfe R.R. Radioactive and stable isotope tracers in biomedicine: principles and practice of kinetic analysis 1992, 425-426. Wiley-Liss, New York.
23. Ciaraldi T.P., Carter L., Seipke G., Mudaliar S., Henry R.R. Effects of the long-acting insulin analog insulin glargine on cultured human skeletal muscle cells: comparisons to insulin and IGF-I. J Clin Endocrinol Metab 2001, 86:5838-5847.
24. Shukla A., Grisouard J., Ehemann V., Hermani A., Enzmann H., Mayer D. Analysis of signaling pathways related to cell proliferation stimulated by insulin analogs in human mammary epithelial cell lines. Endocr Relat Cancer 2009, 16:429-441.
25. Sandow J. Growth effects of insulin and insulin analogues. Arch Physiol Biochem 2009, 115:72-85.
26. Pierre-Eugene C., Pagesy P., Nguyen T.T., Neuillé M., Tschank G., Tennagels N., et al. Effect of insulin analogues on insulin/IGF1 hybrid receptors: increased activation by glargine but not by its metabolites M1 and M2. PLOS ONE 2012, 7:e41992.
27. Sciacca L., Cassarino M.F., Genua M., Pandini G., Le Moli R., Squatrito S., et al. Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling. Diabetologia 2010, 53:1743-1753.
28. Yki-Järvinen H., Kauppinen-Mäkelin R., Tiikkainen M., Vähätalo M., Virtamo H., Nikkilä K., et al. Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study. Diabetologia 2006, 49:442-451.
29. Bolli G.B., Consoli A., Giaccari A. Early insulin treatment in type 2 diabetes: ORIGINal sin or valuable choice as ORIGINal treatment? an open debate on the ORIGIN study results. Nutr Metab Cardiovasc Dis 2012, 22:1007-1012.
30. Gerstein H.C., Bosch J., Dagenais G.R., Díaz R., Jung H., Maggioni A.P., et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012, 367:319-328. ORIGIN Trial Investigators.