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e-Letters: Observations

Low Levels of Unmodified Insulin Glargine in Plasma of People With Type 2 Diabetes Requiring High Doses of Basal Insulin

  1. Paola Lucidi1,
  2. Francesca Porcellati1,
  3. Hannele Yki-Järvinen2,
  4. Matthew C. Riddle3,
  5. Paola Candeloro1,
  6. Anna Marinelli Andreoli1,
  7. Geremia B. Bolli1⇑ and
  8. Carmine G. Fanelli1
  1. 1Department of Medicine, Perugia University School of Medicine, Perugia, Italy
  2. 2Department of Medicine, University of Helsinki, Helsinki, Finland
  3. 3Division of Endocrinology, Diabetes and Clinical Nutrition, Oregon Health & Science University, Portland, OR
  1. Corresponding author: Geremia B. Bolli, geremia.bolli{at}unipg.it.
Diabetes Care 2015 Jul; 38(7): e96-e97. https://doi.org/10.2337/dc14-2662
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Glargine metabolism has been studied in insulin-treated people with type 2 diabetes (T2D) at usual glargine doses of 0.4–0.8 units/kg/day (1,2). In some obese subjects with insulin-resistant T2D, higher basal insulin doses are needed, and the question of safety of glargine (3) is therefore still relevant. Epidemiological studies indicate that the risk of cancer is especially elevated in obese individuals with insulin-resistant diabetes requiring high insulin doses (4). Unmodified insulin glargine has been suggested to confer a higher risk of cancer (3), but prior studies have shown that, at usual doses, an active metabolite (M1) with actions similar to human insulin is the main circulating molecule after glargine injection (1,2).

The aim of the current study was to establish the plasma levels of insulin glargine (M0) and its metabolites M1 and M2 (1,2) in subjects with T2D treated long-term with glargine dose ≥1.2 units/kg/day.

Blood samples of 10 subjects with T2D (male/female 5/5, age 56 ± 10 years, BMI 37.9 ± 7.9 kg/m2, A1C 8.9 ± 1.3% [74 ± 15 mmol/mol], diabetes duration 19 ± 10 years, glargine dose 162 ± 63 units/day [1.49 ± 0.28 units/kg/day], prandial insulin dose 74 ± 37 units/day) (mean ± SD) were drawn in the fasting state, 12 ± 1 h after last subcutaneous glargine injection and processed as previously described (1,2). Plasma was stored at −80°C and analyzed within 6 months (to prevent possible deterioration) for M0, M1, and M2 (liquid chromatography–tandem mass spectrometry method, sensitivity 0.2 ng/mL for each analyte, ∼34 pmol/L) (for method details see ref. 2).

Plasma M0 was 31 ± 41.6 pmol/L, whereas M1 concentration was 457 ± 337 pmol/L in the 10 subjects studied. M0 represented 4.1 ± 6.1% and M1 represented 95.9 ± 6.1% of total plasma insulin. M2 was not detected in any of the subjects studied.

Plasma M0 was detected in only 4 out of the 10 subjects, whereas M1 was detectable in all 10 subjects (Fig. 1). In the 4 subjects in whom it was detectable, M0 had a concentration of 78 ± 19 pmol/L (subject 1, 53 pmol/L; subject 3, 96 pmol/L; subject 6, 89 pmol/L; subject 10, 74 pmol/L) (Fig. 1) and represented 10.4 ± 5.2% of the total circulating insulin. M1 had a concentration of 772 ± 321 pmol/L in the 4 subjects in whom M0 was detected and represented 89.6 ± 5.2% of total circulating insulin.

Figure 1
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Figure 1

Plasma concentrations of M0 and M1 in the individual subjects with T2D, presented in order of increase in insulin dose required (units/kg/day).

Study limitations are the sample size and only a single blood sample examined 12 ± 1 h after last glargine dosing, which expresses metabolism of glargine in a steady-state condition (2). The results are consistent with previous observations at lower glargine doses (≤0.8 units/kg) in which sampling at 12 h could still, in some cases, detect glargine (M0) in plasma (1,2). A previous study in T2D on high glargine doses failed to detect M0, but samples were determined only >6 years after storage of blood samples drawn and processed under unspecified conditions, likely not suitable to preserve M0 (5). In the current study, we found that, even at high doses of insulin glargine, M0 (glargine) represented only 10% of total insulin concentration and was detectable only in 40% of individuals and at a concentration no higher than 100 pmol/L. These results suggest that insulin glargine treatment does not confer a greater risk of cancer as compared with human insulin in people with T2D who require very high insulin doses and are at high cancer risk (4).

Article Information

Acknowledgments. The authors thank Ronald Schmidt from Diabetes Division, Sanofi, Frankfurt, Germany, for performing liquid chromatography–tandem mass spectrometry assays.

Duality of Interest. This is an investigator-initiated study supported by Sanofi. P.L. received travel grants for scientific meetings from Sanofi and Menarini. F.P. has received honoraria for speaker fees and/or travel grants from Sanofi, Eli Lilly, Bristol-Myers Squibb, and Merck Sharp & Dohme. H.Y.-J. has received honoraria for consulting and speaking from Eli Lilly, Boehringer Ingelheim, Sanofi, and Merck Sharp & Dohme. M.C.R. has received honoraria for consulting and/or lectures from Sanofi, Valeritas, Elcelyx, Eli Lilly, and Biodel and research grant support through his institution from AstraZeneca, Sanofi, Novo Nordisk, and Pfizer. G.B.B. received honoraria from Sanofi, MannKind, and Eli Lilly for scientific advising and consulting. C.G.F. has served on scientific advisory panels for Sanofi and received honoraria for speaker fees and/or travel grants from Bristol-Myers Squibb, Merck Sharp & Dohme, and Menarini. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. P.L. enrolled patients, analyzed all data, and reviewed and edited the manuscript. F.P., H.Y.-J., M.C.R., and A.M.A. enrolled patients and reviewed and edited the manuscript. P.C. processed samples, performed laboratory assays, and reviewed and edited the manuscript. G.B.B. wrote the manuscript, provided the study concept and design, and supervised the research protocol and organization. C.G.F. enrolled patients, analyzed data, performed statistical analysis, and reviewed and edited the manuscript. P.L. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

  • © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

References

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    1. Lucidi P,
    2. Porcellati F,
    3. Rossetti P, et al
    . Metabolism of insulin glargine after repeated daily subcutaneous injections in subjects with type 2 diabetes. Diabetes Care 2012;35:2647–2649
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    1. Lucidi P,
    2. Porcellati F,
    3. Candeloro P, et al
    . 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;24:709–716
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    1. Hemkens LG,
    2. Grouven U,
    3. Bender R, et al
    . Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 2009;52:1732–1744
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    . The epidemiology and molecular mechanisms linking obesity, diabetes, and cancer. Vitam Horm 2013;93:51–98
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    1. Varewijck AJ,
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    . 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
    OpenUrlAbstract/FREE Full Text
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Low Levels of Unmodified Insulin Glargine in Plasma of People With Type 2 Diabetes Requiring High Doses of Basal Insulin
Paola Lucidi, Francesca Porcellati, Hannele Yki-Järvinen, Matthew C. Riddle, Paola Candeloro, Anna Marinelli Andreoli, Geremia B. Bolli, Carmine G. Fanelli
Diabetes Care Jul 2015, 38 (7) e96-e97; DOI: 10.2337/dc14-2662

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Low Levels of Unmodified Insulin Glargine in Plasma of People With Type 2 Diabetes Requiring High Doses of Basal Insulin
Paola Lucidi, Francesca Porcellati, Hannele Yki-Järvinen, Matthew C. Riddle, Paola Candeloro, Anna Marinelli Andreoli, Geremia B. Bolli, Carmine G. Fanelli
Diabetes Care Jul 2015, 38 (7) e96-e97; DOI: 10.2337/dc14-2662
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