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Mechanism of protracted metabolic effects of fatty acid acylated insulin, NN304, in dogs: retention of NN304 by albumin

Published on Oct 1, 1999in Diabetologia 7.11
· DOI :10.1007/s001250051301
Marianthe Hamilton-Wessler11
Estimated H-index: 11
(SC: University of Southern California),
Marilyn Ader28
Estimated H-index: 28
(SC: University of Southern California)
+ 4 AuthorsRichard N. Bergman103
Estimated H-index: 103
(SC: University of Southern California)
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Abstract
Aims/hypothesis. The provision of stable, reproducible basal insulin is crucial to diabetes management. This study in dogs examined the metabolic effects and interstitial fluid (ISF) profiles of fatty acid acylated insulin, LysB29-tetradecanoyl, des-(B30) human insulin (NN304). Methods. Euglycaemic clamps were carried out under inhalant anaesthesia during equimolar intravenous infusions (3.6 pmol · min–1· kg–1 for 480 min) of human insulin or NN304 (n = 8 per group). Results. Steady-state total NN304 (albumin-bound and unbound) was considerably higher in plasma compared with human insulin (1895 ± 127 vs 181 ± 10 pmol/l, p 0.40; NN304 and human insulin, respectively). Similar to interstitial fluid, half times for Rd and endogenous glucose production were delayed during NN304 infusion (162 vs 46 min and 80 vs 31 min, respectively; p < 0.01 vs human insulin). Conclusion/interpretation. Firstly equivalency of steady-state action is found at equimolar physiologic infusions of human insulin and NN304. Secondly NN304 binding to plasma albumin results in slower NN304 appearance in the interstitial compartment compared with human insulin. Thirdly the delay in appearance of NN304 in interstitial fluid may not in itself be a source of the protracted action of this insulin analogue. The protracted effect is due primarily to albumin binding of the insulin analogue NN304. [Diabetologia (1999) 42: 1254–1263]
  • References (27)
  • Citations (69)
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References27
Newest
Published on Apr 1, 1997in Diabetes 7.20
S. R. Myers13
Estimated H-index: 13
,
Fatima Emitsela Yakubu-Madus1
Estimated H-index: 1
+ 7 AuthorsVictor J. Chen21
Estimated H-index: 21
To test whether the binding of insulin to an endogenous serum protein can be used to extend the time action of insulin, human insulin was acylated at the epsilonamino group of Lys(B 29 ) with palmitic acid to promote binding to serum albumin. Size-exclusion chromatography was used to demonstrate specific binding of the resulting analog, [ N ∈ -palmitoyl Lys(B 29 )] human insulin, to serum albumin in vitro, and the time action and activity of the analog were determined in vivo using overnight-fas...
50 Citations Source Cite
Published on Jan 1, 1997in Recent Progress in Hormone Research
Bergman Rn1
Estimated H-index: 1
Insulin resistance is a precursor to and primary cause of Type 2 diabetes mellitus. In addition, insulin resistance is associated with other chronic diseases, including gestational diabetes, cardiovascular disease, and cancer. Resistance to insulin's effects on carbohydrate metabolism include diminished actions of insulin to enhance glucose uptake and suppress endogenous glucose production. This chapter introduces new concepts related to the mechanism by which insulin stimulates glucose utilizat...
92 Citations
Published on Mar 1, 1996in Journal of Pharmaceutical Sciences 3.20
Peter Kurtzhals15
Estimated H-index: 15
(Novo Nordisk),
Svend Havelund24
Estimated H-index: 24
(Novo Nordisk)
+ 3 AuthorsJan Markussen22
Estimated H-index: 22
(Novo Nordisk)
Insulins acylated with fatty acids at the e-amino group of LysB29 constitute a new class of insulin analogs, which are prolonged-acting due to albumin binding. In the present study it is shown that the affinity of fatty acid acylated insulins for albumin varies considerably (> 50-fold) among species. The relative affinities of acylated insulin for albumin in human, pig, and rabbit serum are about 1:1.5:35. The several fold higher binding affinity in rabbit serum than in pig serum is reflected in...
66 Citations Source Cite
Published on Mar 1, 1996in Diabetologia 7.11
Jan Markussen22
Estimated H-index: 22
(Novo Nordisk),
Svend Havelund24
Estimated H-index: 24
(Novo Nordisk)
+ 8 AuthorsKnud Vad7
Estimated H-index: 7
(Novo Nordisk)
We have synthesized insulins acylated by fatty acids in the e-amino group of LysB29. Soluble preparations can be made in the usual concentration of 600 nmol/ml (100 IU/ml) at neutral pH. The time for 50% disappearance after subcutaneous injection of the corresponding TyrA14(125I)-labelled insulins in pigs correlated with the affinity for binding to albumin (r=0.97), suggesting that the mechanism of prolonged disappearance is binding to albumin in subcutis. Most protracted was LysB29-tetradecanoy...
186 Citations Source Cite
Published on Dec 15, 1995in Biochemical Journal 4.33
Peter Kurtzhals15
Estimated H-index: 15
(Novo Nordisk),
Svend Havelund24
Estimated H-index: 24
(Novo Nordisk)
+ 4 AuthorsJan Markussen22
Estimated H-index: 22
(Novo Nordisk)
Albumin is a multifunctional transport protein that binds a wide variety of endogenous substances and drugs. Insulins with affinity for albumin were engineered by acylation of the epsilon-amino group of LysB29 with saturated fatty acids containing 10-16 carbon atoms. The association constants for binding of the fatty acid acylated insulins to human albumin are in the order of 10(4)-10(5) M-1. The binding apparently involves both non-polar and ionic interactions with the protein. The acylated ins...
300 Citations Source Cite
Published on Aug 1, 1995in Diabetes 7.20
Philip D. Miles17
Estimated H-index: 17
(UCSD: University of California, San Diego),
Matteo G. Levisetti16
Estimated H-index: 16
(UCSD: University of California, San Diego)
+ 3 AuthorsJerrold M. Olefsky106
Estimated H-index: 106
(UCSD: University of California, San Diego)
To examine the kinetic steps in insulin9s in vivo action, we have assessed the temporal relationship between arterial insulin, interstitial insulin, glucose disposal rate (GDR), and insulin receptor kinase (IRK) activity in muscle and between portal insulin, hepatic glucose production (HGP), and IRK activity in liver. Interstitial insulin, as measured by lymph-insulin concentration (muscle only), and IRK activity were used as independent methods to determine the arrival of insulin at its tissue ...
76 Citations Source Cite
Published on Dec 1, 1994in Hormone and Metabolic Research 2.42
Galloway Ja1
Estimated H-index: 1
,
Chance Re1
Estimated H-index: 1
77 Citations Source Cite
Published on Feb 1, 1994in Diabetes 7.20
Reneé A Poulin3
Estimated H-index: 3
,
Garry M. Steil40
Estimated H-index: 40
+ 2 AuthorsRichard N. Bergman103
Estimated H-index: 103
We previously reported a striking similarity between the dynamics of both glucose turnover and thoracic duct lymph insulin during euglycemic clamps ( J Clin Invest 84:1620, 1989), which suggested that transendothelial insulin transport (TET) is rate-limiting for insulin action in vivo. Thoracic duct lymph, however, is primarily derived from insulin-insensitive tissues, which raises questions as to the physiological significance of this relationship. The relationship between glucose turnover and ...
63 Citations Source Cite
Published on Jan 1, 1994in Journal of Clinical Investigation 12.28
Charles Castillo5
Estimated H-index: 5
,
C Bogardus15
Estimated H-index: 15
+ 2 AuthorsStephen Lillioja34
Estimated H-index: 34
Abstract Insulin action and obesity are both correlated with the density of muscle capillary supply in humans. Since the altered muscle anatomy in the obese might affect interstitial insulin concentrations and reduce insulin action, we have cannulated peripheral lymphatic vessels in lean and obese males, and compared peripheral lymph insulin concentrations with whole body glucose uptake during a euglycemic, hyperinsulinemic clamp. Lymph insulin concentrations in the lower limb averaged only 34% ...
125 Citations Source Cite
Published on Jan 1, 1994in Advances in Protein Chemistry 3.78
Daniel C. Carter23
Estimated H-index: 23
(MSFC: Marshall Space Flight Center),
Joseph X. Ho13
Estimated H-index: 13
(MSFC: Marshall Space Flight Center)
Publisher Summary This chapter provides an insight of the findings of past significant papers with the current knowledge of the recently determined high resolution X-ray structure of serum albumin. The most outstanding property of albumin is its ability to bind reversibly an incredible variety of ligands. The sequences of all albumins are characterized by a unique arrangement of disulfide double loops that repeat as a series of triplets. Albumin belongs to a multigene family of proteins that inc...
2,277 Citations Source Cite
Cited By69
Newest
Published on Feb 1, 2019in Journal of Controlled Release 7.90
Romel Menacho-Melgar1
Estimated H-index: 1
(Duke University),
John S. Decker (Duke University)+ 1 AuthorsMichael Lynch13
Estimated H-index: 13
(Duke University)
Abstract The use of biologics (peptide and protein based drugs) has increased significantly over the past few decades. However, their development has been limited by their short half-life, immunogenicity and low membrane permeability, restricting most therapies to extracellular targets and administration by injection. Lipidation is a clinically-proven post-translational modification that has shown great promise to address these issues: improving half-life, reducing immunogenicity and enabling in...
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Published on Mar 15, 2017in Bioconjugate Chemistry 4.35
Yang Liu1
Estimated H-index: 1
,
Juneyoung Lee8
Estimated H-index: 8
+ 4 AuthorsHeather D. Maynard44
Estimated H-index: 44
Biocompatible polymers such as poly(ethylene glycol) (PEG) have been successfully conjugated to therapeutic proteins to enhance their pharmacokinetics. However, many of these polymers, including PEG, only improve the in vivo lifetimes and do not protect proteins against inactivation during storage and transportation. Herein, we report a polymer with trehalose side chains (PolyProtek) that is capable of improving both the external stability and the in vivo plasma half-life of a therapeutic protei...
12 Citations Source Cite
Published on Dec 1, 2016in Cardiovascular Diabetology 5.95
Thorsten Hartmann2
Estimated H-index: 2
,
Sabrina Overhagen1
Estimated H-index: 1
+ 5 AuthorsJürgen Eckel45
Estimated H-index: 45
Background The effects of insulin on cardiomyocytes, such as positive inotropic action and glucose uptake are well described. However, in vitro studies comparing long-acting insulin analogues with regard to cardiomyocyte signalling and function have not been systematically conducted.
3 Citations Source Cite
Published on Apr 1, 2016in Nutrition Metabolism and Cardiovascular Diseases 3.34
Angelo Cignarelli14
Estimated H-index: 14
(University of Bari),
Sebastio Perrini23
Estimated H-index: 23
(University of Bari)
+ 8 AuthorsPuglisi F6
Estimated H-index: 6
(University of Bari)
Abstract Background and aims Since treatment with insulin detemir results in a lower weight gain compared to human insulin, we investigated whether detemir is associated with lower ability to promote adipogenesis and/or lipogenesis in human adipose stem cells (ASC). Methods and results Human ASC isolated from both the subcutaneous and visceral adipose tissues were differentiated for 30 days in the presence of human insulin or insulin detemir. Nile Red and Oil-Red-O staining were used to quantify...
3 Citations Source Cite
Published on Dec 1, 2015in Diabetes, Obesity and Metabolism 6.13
Manfred Bodenlenz13
Estimated H-index: 13
(Joanneum Research),
Martin Ellmerer25
Estimated H-index: 25
(Medical University of Graz)
+ 7 AuthorsThomas R. Pieber61
Estimated H-index: 61
(Joanneum Research)
Aims To find an explanation for the lower potency of insulin detemir observed in humans compared with unmodified human insulin by investigating insulin detemir and human insulin concentrations directly at the level of peripheral insulin-sensitive tissues in humans in vivo. Methods Euglycaemic-hyperinsulinaemic clamp experiments were performed in healthy volunteers. Human insulin was administered i.v. at 6 pmol/kg/min and insulin detemir at 60 pmol/kg/min, achieving a comparable steady-state phar...
4 Citations Source Cite
Published on Mar 5, 2015
Helena Ågerstam9
Estimated H-index: 9
,
Thoas Fioretos38
Estimated H-index: 38
+ 4 AuthorsKarin Von Wachenfeldt
La presente invention concerne un anticorps ou un fragment de liaison a l'antigene de ce dernier avec une specificite de liaison a la proteine accessoire du recepteur humain de l'interleukine 1 (IL1 RAP) ou l'anticorps ou le fragment de liaison a l'antigene est capable d'inhiber la liaison de l'anticorps "CAN04" a la IL1 RAP humaine. L'invention concerne en outre l'utilisation de tels anticorps ou fragments de liaison a l'antigene dans le traitement et/ou le diagnostic de maladies et d'etats ass...
Published on Feb 1, 2015in Diabetes, Obesity and Metabolism 6.13
Christian Höfferer4
Estimated H-index: 4
(Joanneum Research),
D. Tutkur1
Estimated H-index: 1
(Joanneum Research)
+ 8 AuthorsThomas R. Pieber61
Estimated H-index: 61
(Joanneum Research)
Aims To compare the time profile of insulin detemir and human insulin concentrations in the interstitial fluid (ISF) of subcutaneous adipose tissue during constant i.v. infusion and to investigate the relationship between the pharmacokinetics of both insulin molecules in plasma and the ISF of subcutaneous adipose tissue. Methods During a 6-h hyperinsulinaemic–euglycaemic clamp (plasma glucose level 8 mmol/l) human insulin (21 and 42 pmol/min/kg) or insulin detemir (209 and 417 pmol/min/kg) were ...
6 Citations Source Cite
Published on Jan 1, 2015
Richard W. Nelson37
Estimated H-index: 37
20 Citations Source Cite
Published on Apr 1, 2014in Médecine des Maladies Métaboliques
L. Monnier1
Estimated H-index: 1
,
C. Colette1
Estimated H-index: 1
Reume Depuis la decouverte de l’insuline, la mise au point des preparations insuliniques a fait l’objet d’une evolution incessante en termes de production, purification, formulation et methodes d’administration. Au cours de la derniere decennie, plusieurs nouvelles formes d’insulines lentes, c’est a dire d’analogues prolonges de l’insuline, ont ete commercialisees et/ou developpees dans le but de couvrir les besoins insuliniques de base chez les patients diabetiques insulino-traites. L’insuline ...
6 Citations Source Cite
Published on Dec 1, 2013in Diabetes & Metabolism 4.01
L. Monnier13
Estimated H-index: 13
,
C. Colette27
Estimated H-index: 27
,
David Raymond Owens51
Estimated H-index: 51
(Swansea University)
Abstract During the past 10years, several new basal insulin analogs have been developed. There has been for 3years controversy on the potential increased risk for cancer with insulin glargine, which ceased with the publication of the ORIGIN trial in 2012. In insulin-treated persons with type 2 diabetes, it is usual to recommend that plasma insulin concentrations remain within a 50–200pmol/L range in order to avoid overinsulinization, a potential causative factor for increased mitogenicity. Such ...
14 Citations Source Cite