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Title: Reduced peripheral activity leading to hepato‐preferential action of basal insulin peglispro compared with insulin glargine in patients with type 1 diabetes

Abstract

Aims Basal insulin peglispro ( BIL ), a novel PEGylated basal insulin with a large hydrodynamic size, has a delayed absorption and reduced clearance that prolongs the duration of action. The current study compared the effects of BIL and insulin glargine ( GL ) on endogenous glucose production ( EGP ), glucose disposal rate ( GDR ) and lipolysis in patients with type 1 diabetes. Materials and Methods This was a randomized, open‐label, four‐period, crossover study. Patients received intravenous infusions of BIL and GL , each at two dose levels selected for partial and maximal suppression of EGP , during an 8 to 10 h euglycemic clamp procedure with d ‐[3‐ 3 H] glucose. Results Following correction for equivalent human insulin concentrations ( EHIC ), low‐dose GL infusion resulted in similar EGP at the end of the clamp compared to low‐dose BIL infusion ( GL / BIL ratio of 1.03) but a higher GDR ( GL / BIL ratio of 2.42), indicating similar hepatic activity but attenuated peripheral activity of BIL . Consistent with this, the EHIC ‐corrected GDR / EGP at the end of the clamp was 1.72‐fold greater for GL than BIL following low‐dose administration. At the lowermore » dose of BIL and GL (concentrations in the therapeutic range), BIL produced less suppression of lipolysis compared with GL as indicated by free fatty acid and glycerol levels at the end of the clamp. Conclusions Compared with GL , BIL restored the hepato‐peripheral insulin action gradient seen in normal physiology via its peripherally restricted action on target tissues related to carbohydrate and lipid metabolism.« less

Authors:
 [1];  [1];  [1];  [2];  [2];  [3];  [4];  [5];  [4];  [5];  [4];  [3];  [4];  [4];  [4];  [4]
+ Show Author Affiliations
  1. Veterans Affairs San Diego Healthcare System San Diego CA USA, Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego CA USA
  2. Veterans Affairs San Diego Healthcare System San Diego CA USA
  3. Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego CA USA
  4. Eli Lilly and Company Indianapolis IN USA
  5. Eli Lilly and Company Singapore Singapore
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1401715
Resource Type:
Publisher's Accepted Manuscript
Journal Name:
Diabetes, Obesity and Metabolism
Additional Journal Information:
Journal Name: Diabetes, Obesity and Metabolism Journal Volume: 18 Journal Issue: S2; Journal ID: ISSN 1462-8902
Publisher:
Wiley-Blackwell
Country of Publication:
Country unknown/Code not available
Language:
English

Citation Formats

Mudaliar, S., Henry, R. R., Ciaraldi, T. P., Armstrong, D. A., Burke, P. M., Pettus, J. H., Garhyan, P., Choi, S. L., Knadler, M. P., Lam, E. C. Q., Prince, M. J., Bose, N., Porksen, N. K., Sinha, V. P., Linnebjerg, H., and Jacober, S. J. Reduced peripheral activity leading to hepato‐preferential action of basal insulin peglispro compared with insulin glargine in patients with type 1 diabetes. Country unknown/Code not available: N. p., 2016. Web. doi:10.1111/dom.12753.
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Mudaliar, S., Henry, R. R., Ciaraldi, T. P., Armstrong, D. A., Burke, P. M., Pettus, J. H., Garhyan, P., Choi, S. L., Knadler, M. P., Lam, E. C. Q., Prince, M. J., Bose, N., Porksen, N. K., Sinha, V. P., Linnebjerg, H., & Jacober, S. J. Reduced peripheral activity leading to hepato‐preferential action of basal insulin peglispro compared with insulin glargine in patients with type 1 diabetes. Country unknown/Code not available. https://doi.org/10.1111/dom.12753
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Mudaliar, S., Henry, R. R., Ciaraldi, T. P., Armstrong, D. A., Burke, P. M., Pettus, J. H., Garhyan, P., Choi, S. L., Knadler, M. P., Lam, E. C. Q., Prince, M. J., Bose, N., Porksen, N. K., Sinha, V. P., Linnebjerg, H., and Jacober, S. J. Mon . "Reduced peripheral activity leading to hepato‐preferential action of basal insulin peglispro compared with insulin glargine in patients with type 1 diabetes". Country unknown/Code not available. https://doi.org/10.1111/dom.12753.
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@article{osti_1401715,
title = {Reduced peripheral activity leading to hepato‐preferential action of basal insulin peglispro compared with insulin glargine in patients with type 1 diabetes},
author = {Mudaliar, S. and Henry, R. R. and Ciaraldi, T. P. and Armstrong, D. A. and Burke, P. M. and Pettus, J. H. and Garhyan, P. and Choi, S. L. and Knadler, M. P. and Lam, E. C. Q. and Prince, M. J. and Bose, N. and Porksen, N. K. and Sinha, V. P. and Linnebjerg, H. and Jacober, S. J.},
abstractNote = {Aims Basal insulin peglispro ( BIL ), a novel PEGylated basal insulin with a large hydrodynamic size, has a delayed absorption and reduced clearance that prolongs the duration of action. The current study compared the effects of BIL and insulin glargine ( GL ) on endogenous glucose production ( EGP ), glucose disposal rate ( GDR ) and lipolysis in patients with type 1 diabetes. Materials and Methods This was a randomized, open‐label, four‐period, crossover study. Patients received intravenous infusions of BIL and GL , each at two dose levels selected for partial and maximal suppression of EGP , during an 8 to 10 h euglycemic clamp procedure with d ‐[3‐ 3 H] glucose. Results Following correction for equivalent human insulin concentrations ( EHIC ), low‐dose GL infusion resulted in similar EGP at the end of the clamp compared to low‐dose BIL infusion ( GL / BIL ratio of 1.03) but a higher GDR ( GL / BIL ratio of 2.42), indicating similar hepatic activity but attenuated peripheral activity of BIL . Consistent with this, the EHIC ‐corrected GDR / EGP at the end of the clamp was 1.72‐fold greater for GL than BIL following low‐dose administration. At the lower dose of BIL and GL (concentrations in the therapeutic range), BIL produced less suppression of lipolysis compared with GL as indicated by free fatty acid and glycerol levels at the end of the clamp. Conclusions Compared with GL , BIL restored the hepato‐peripheral insulin action gradient seen in normal physiology via its peripherally restricted action on target tissues related to carbohydrate and lipid metabolism.},
doi = {10.1111/dom.12753},
journal = {Diabetes, Obesity and Metabolism},
number = S2,
volume = 18,
place = {Country unknown/Code not available},
year = {Mon Oct 10 00:00:00 EDT 2016},
month = {Mon Oct 10 00:00:00 EDT 2016}
}
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https://doi.org/10.1111/dom.12753
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