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

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

doi:10.1016/j.bbagen.2013.03.011

Cited by 53Diabetes Treatment and ManagementPancreatic function and diabetesNatural Antidiabetic Agents Studies

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

Martin, Christine M.A., Irwin, Nigel, Flatt, Peter R., Gault, Victor A.·2013·Biochimica et Biophysica Acta (BBA) - General Subjects

DOI 10.1016/j.bbagen.2013.03.011

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Abstract

Background Rapid enzymatic degradation of the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), limits therapeutic use of the native peptide for diabetes. However, enzymatically stable analogues of GIP, such as (d-Ala(2))GIP, have been generated, but are still susceptible to renal filtration. Methods The present study examines the in vitro and in vivo biological actions of a novel, acylated GIP analogue, (d-Ala(2))GIP[Lys(37)PAL]. Results In BRIN-BD11 cells, (d-Ala(2))GIP[Lys(37)PAL] concentration-dependently stimulated (p<0.05 to p<0.001) insulin secretion at 5.6 and 16.7mM glucose. Intraperitoneal administration of (d-Ala(2))GIP[Lys(37)PAL] to normal mice 8h prior to a glucose load significantly reduced (p<0.05) the overall glycaemic excursion compared to controls, and increased (p<0.001) the insulinotropic response compared to (d-Ala(2))GIP and saline treated high fat control mice. Once daily administration of (d-Ala(2))GIP[Lys(37)PAL] for 21days in high fat fed mice did not affect energy intake, body weight or fat deposition. However, circulating blood glucose was significantly lower (p<0.05) accompanied by increased (p<0.05) insulin concentrations by day 21. In addition, (d-Ala(2))GIP[Lys(37)PAL] treatment significantly (p<0.01) reduced the overall glycaemic excursion and increased pancreatic insulin content (p<0.05) and the insulinotropic response (p<0.01) to an exogenous glucose challenge on day 21. Chronic treatment with (d-Ala(2))GIP[Lys(37)PAL] did not result in resistance to the metabolic effects of a bolus injection of native GIP. Finally, insulin sensitivity was significantly improved (p<0.001) in (d-Ala(2))GIP[Lys(37)PAL] treated mice compared to high fat controls. Conclusions These data confirm that (d-Ala(2))GIP[Lys(37)PAL] is a stable, long-acting potent GIP agonist. General significance (d-Ala(2))GIP[Lys(37)PAL] may be suitable for further evaluation and future clinical development.

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Activation of GIP receptors improved blood glucose levels in obese mouse models without altering body weight or fat tissue quantity.
“Activation of GIP receptors improved blood glucose levels in obese mouse models without altering body weight or fat tissue quantity [58]”
From New Developments in Pharmacological Treatment of Obesity and Type 2 Diabetes—Beyond and within GLP-1 Receptor Agonists (2024) · cites this paper as [58]

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Authors: Martin, C. M. A., Irwin, N., Flatt, P. R., & Gault, V. A.
Affiliations: University of Ulster (GB)
Corresponding author: Irwin, Nigel
ORCID: Irwin, Nigel
Flatt, Peter R.
Gault, Victor A.
Venue: Biochimica et Biophysica Acta (BBA) - General Subjects
Publisher: Elsevier BV
Published: 2013-06
Volume: 1830
Issue: 6
Pages: 3407-3413
ISSN: 0304-4165 (ISSN-L)
DOI: 10.1016/j.bbagen.2013.03.011
OpenAlex: W1988234896
Cited by: 53
References: 31
Citations by year: 2026: 1 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 1 · 2021: 2 · 2020: 4 · 2019: 10 · 2018: 8 · 2017: 1 · 2016: 6 · 2015: 7 · 2014: 2 · 2013: 2
FWCI: 4.45
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Biochimica et Biophysica Acta (BBA) - General Subjects (publishedVersion)
PubMed (publishedVersion)
Funders: Department of Education and Learning, Northern Ireland
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
Keywords: glucose-dependent insulinotropic polypeptide, acylated peptides, D-alanine substitution, lysine acylation, insulin secretion, insulin sensitivity, glycemic control, type 2 diabetes, fat deposition, high-fat diet, pancreatic beta cells, renal filtration, insulin resistance, energy intake, body weight, BRIN-BD11 cells
MeSH terms: Animals, Diabetes Mellitus, Experimental, Gastric Inhibitory Polypeptide, Gastrointestinal Agents, Glucose, Hypoglycemic Agents, Insulin, Male, Body Fat Distribution, Mice

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

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