A novel acylated form of (d-Ala2)GIP with improved antidiabetic potential, lacking effect on body fat stores

Martin, Christine M.; Irwin, Nigel; Flatt, Peter R.; Gault, Victor

doi:10.1016/j.bbagen.2013.03.011

Cited by 47 publications

(45 citation statements)

References 27 publications

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“…Even 4 h after a single injection of (DAla 2 )GIP/xenin-8-Gln or (DAla 2 )GIP, glucose-lowering and insulin-releasing actions were clearly evident. This presumably relates to enhanced enzymatic stability of (DAla 2 ) modified GIP-forms and corresponds well with the findings of other studies [28,29]. Development of a specific assay to directly measure (DAla 2 )GIP/xenin-8-Gln in plasma would be useful to determine the pharmacokinetic profile of the hybrid peptide.…”

Section: Resultssupporting

confidence: 51%

“…As expected, the parent peptides, (DAla 2 )GIP and xenin-8-Gln, stimulated insulin release from clonal pancreatic BRIN-BD11 beta cells at physiological and elevated glucose concentrations [24,29]. To determine the influence of both GIP and xenin pathways on induction of bioactivity by (DAla 2 )GIP/ xenin-8-Gln, we utilised the specific GIP receptor antagonist GIP(6-30)Cex-K 40 [Pal] [32] and the commercially available neurotensin receptor antagonist, SR142948A.…”

Section: Resultsmentioning

confidence: 89%

“…Assessment of DPP-4 degradation Peptide (20 μg) DPP-4 degradation profiles (5 μl purified DPP-4, 5 mU; SigmaAldrich, UK) were assessed as described previously [29]. Xenin-based peptides have been shown to be resistant to DPP-4 [10,24].…”

Section: Methodsmentioning

confidence: 99%

“…Peptides were characterised in-house using HPLC and matrix-assisted laser desorption ionisation time-of-flight (MALDI-TOF) mass spectrometry (ESM Table 2), as described previously [29].…”

Section: Methodsmentioning

confidence: 99%

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An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

Hasib

Gault

et al. 2016

Diabetologia

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Aims/hypothesis Glucose-dependent insulinotropic polypeptide (GIP) and xenin, regulatory gut hormones secreted from enteroendocrine K cells, exert important effects on metabolism. In addition, xenin potentiates the biological actions of GIP. The present study assessed the actions and therapeutic utility of a (DAla 2 )GIP/xenin-8-Gln hybrid peptide, in comparison with the parent peptides (DAla 2 )GIP and xenin-8-Gln. Methods Following confirmation of enzymatic stability, insulin secretory activity of (DAla 2 )GIP/xenin-8-Gln was assessed in BRIN-BD11 beta cells. Acute and persistent glucose-lowering and insulin-releasing effects were then examined in vivo. Finally, the metabolic benefits of twice daily injection of (DAla 2 )GIP/xenin-8-Gln was determined in high-fat-fed mice.

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Section: Resultssupporting

confidence: 51%

Section: Resultsmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

“…Peptides were characterised in-house using HPLC and matrix-assisted laser desorption ionisation time-of-flight (MALDI-TOF) mass spectrometry (ESM Table 2), as described previously [29].…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

Hasib

Gault

et al. 2016

Diabetologia

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“…As a pharmaceutical tool, lipidation of peptides and proteins can be used to increase the circulation time in the bloodstream, and thus increase the therapeutic efficacy of biomolecular compounds [4][5][6] . However, modifying soluble proteins with a hydrophobic moiety such as a lipid tail will inevitably have an effect on the physiochemical properties of the protein, including its physical stability [7][8][9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

Lipidation Effect on Surface Adsorption and Associated Fibrillation of the Model Protein Insulin

et al. 2016

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Citation for published version (APA):Fogh Hedegaard, S., Cardenas, M., Barker, R., Jorgensen, L., & van der Weert, M. (2016). Lipidation effect on surface adsorption and associated fibrillation of the model protein insulin. Langmuir, 32(28), 7241-7249. DOI: 10.1021/acs.langmuir.6b00522 General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain.• You may freely distribute the URL identifying the publication in the public portal. Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. ABSTRACTLipidation of proteins is used in the pharmaceutical field to increase the therapeutic efficacy of proteins. In this study, we investigate the effect of a 14-carbon fatty acid modification on the adsorption behavior of human insulin to a hydrophobic solid surface and the subsequent fibrillation development under highly acidic conditions and elevated temperature by comparing to the fibrillation of human insulin. At these stressed conditions, the lipid modification accelerates the rate of fibrillation in bulk solution. With the use of several complementary surface-sensitive techniques, including quartz crystal microbalance with dissipation monitoring (QCM-D), atomic force microscopy (AFM) and neutron reflectivity (NR), we show that there are two levels of structurally different protein organization at a hydrophobic surface for both human insulin and the lipidated analogue: a dense protein layer formed within minutes on the surface and a diffuse outer layer of fibrillar structures which took hours to form. The two layers may only be weakly connected and proteins from both layers are able to desorb from the surface. The lipid modification increases the protein surface coverage and the thickness of both layer organizations. 2Upon lipidation not only the fibrillation extent but also the morphology of the fibrillar structures changes from fibril clusters on the surface to a more homogenous network of fibrils covering the entire hydrophobic surface.

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Gut Peptide Agonism in the Treatment of Obesity and Diabetes

Grandl

Novikoff

DiMarchi

et al. 2019

Comprehensive Physiology

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Obesity is a global healthcare challenge that gives rise to devastating diseases such as the metabolic syndrome, type-2 diabetes (T2D), and a variety of cardiovascular diseases. The escalating prevalence of obesity has led to an increased interest in pharmacological options to counteract excess weight gain. Gastrointestinal hormones such as glucagon, amylin, and glucagon-like peptide-1 (GLP-1) are well recognized for influencing food intake and satiety, but the therapeutic potential of these native peptides is overall limited by a short half-life and an often dose-dependent appearance of unwanted effects. Recent clinical success of chemically optimized GLP-1 mimetics with improved pharmacokinetics and sustained action has propelled pharmacological interest in using bioengineered gut hormones to treat obesity and diabetes. In this article, we summarize the basic biology and signaling mechanisms of selected gut peptides and discuss how they regulate systemic energy and glucose metabolism. Subsequently, we focus on the design and evaluation of unimolecular drugs that combine the beneficial effects of selected gut hormones into a single entity to optimize the beneficial impact on systems metabolism.

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A novel acylated form of (d-Ala2)GIP with improved antidiabetic potential, lacking effect on body fat stores

Cited by 47 publications

References 27 publications

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

Lipidation Effect on Surface Adsorption and Associated Fibrillation of the Model Protein Insulin

Gut Peptide Agonism in the Treatment of Obesity and Diabetes

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