GIP analogues augment bone strength by modulating bone composition in diet-induced obesity in mice

Vyavahare, Sagar; Mieczkowska, Aleksandra; Flatt, Peter; Chappard, Daniel; Irwin, Nigel; Mabilleau, Guillaume

doi:10.1016/j.peptides.2019.170207

Cited by 20 publications

(16 citation statements)

References 45 publications

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“…However, overall effects of GIP at pharmacological concentrations are likely to be protective against atherosclerosis both in non-diabetic and diabetic conditions in vivo. Furthermore, recent in vivo studies have demonstrated multiple beneficial effects of GIP on diabetes-related diseases, such as Alzheimer's disease [129][130][131][132][133][134] and osteoporosis [135][136][137][138][139][140][141][142][143][144][145][146]. These findings suggest that dual or triple agonists including GIPR, which will be available in the near future [54][55][56], could be comprehensive treatment for diabetes and its related disorders.…”

Section: Discussionmentioning

confidence: 95%

GIP as a Potential Therapeutic Target for Atherosclerotic Cardiovascular Disease–A Systematic Review

Mori

Matsui

Hirano

et al. 2020

IJMS

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Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut hormones that are secreted from enteroendocrine L cells and K cells in response to digested nutrients, respectively. They are also referred to incretin for their ability to stimulate insulin secretion from pancreatic beta cells in a glucose-dependent manner. Furthermore, GLP-1 exerts anorexic effects via its actions in the central nervous system. Since native incretin is rapidly inactivated by dipeptidyl peptidase-4 (DPP-4), DPP-resistant GLP-1 receptor agonists (GLP-1RAs), and DPP-4 inhibitors are currently used for the treatment of type 2 diabetes as incretin-based therapy. These new-class agents have superiority to classical oral hypoglycemic agents such as sulfonylureas because of their low risks for hypoglycemia and body weight gain. In addition, a number of preclinical studies have shown the cardioprotective properties of incretin-based therapy, whose findings are further supported by several randomized clinical trials. Indeed, GLP-1RA has been significantly shown to reduce the risk of cardiovascular and renal events in patients with type 2 diabetes. However, the role of GIP in cardiovascular disease remains to be elucidated. Recently, pharmacological doses of GIP receptor agonists (GIPRAs) have been found to exert anti-obesity effects in animal models. These observations suggest that combination therapy of GLP-1R and GIPR may induce superior metabolic and anti-diabetic effects compared with each agonist individually. Clinical trials with GLP-1R/GIPR dual agonists are ongoing in diabetic patients. Therefore, in this review, we summarize the cardiovascular effects of GIP and GIPRAs in cell culture systems, animal models, and humans.

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Section: Discussionmentioning

confidence: 95%

GIP as a Potential Therapeutic Target for Atherosclerotic Cardiovascular Disease–A Systematic Review

Mori

Matsui

Hirano

et al. 2020

IJMS

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“…GLP‐1 receptor mediated improvements in bone strength and quality have also been demonstrated in various distinct forms of diabetes including insulin‐deficient type 1 diabetic mice (Mansur et al, 2015), insulin‐resistant high fat fed diabetic mice (Mansur et al, 2019a) as well as genetically induced type 2 diabetic animal models (Sun, Lu, et al, 2016). The observed positive actions of sitagliptin on bone are likely due to the elevations of both GLP‐1 and GIP levels (Mansur et al, 2019b), given that GIP has well documented benefits on bone in animals and humans (Gobron et al, 2020; Mabilleau et al, 2016; Mabilleau, Gobron, et al, 2018; Stensen et al, 2020; Vyavahare et al, 2020). In the clinic, recent reports show exenatide to have no impact on bone fractures, whereas lixisenatide and liraglutide reduce fracture occurrence (Cheng et al, 2019).…”

Section: Glp‐1 and The Endocrine Pancreasmentioning

confidence: 99%

Metabolic responses and benefits of glucagon‐like peptide‐1 (GLP‐1) receptor ligands

Tanday

Flatt

Irwin

2021

British J Pharmacology

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Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has undergone a revolutionary turnaround from discovery to clinically approved therapeutic. Rapid progress in drug design and formulation has led from initial development of short-and long-acting drugs suitable for daily or weekly parenteral administration, respectively, through to the most recent approval of an orally active GLP-1 agent. The current review outlines the biological action profile of GLP-1 including the various beneficial metabolic responses in pancreatic and extrapancreatic tissues, including the gastrointestinal tract, liver, bone and kidney as well as the reproductive cardiovascular and central nervous systems. We then briefly consider clinically approved GLP-1 receptor ligands and recent advances in this field. Given sustained evolution in the area of GLP-1 drug development and excellent safety profile, as well as the plethora of metabolic benefits, clinical approval for use in diseases beyond diabetes and obesity is very much conceivable.

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“…However, only Ac3IV significantly reduced circulating LDL-cholesterol and triglyceride levels, highlighting this as a distinct advantage over exendin-4, given that diabetes and obesity represent key risk factors for cardiovascular disease. 46 In addition, obesity-driven forms of diabetes are also associated with increased occurrence of bone fragility fractures, 47,48 and both Ac3IV and exendin-4 augment bone mineral content and density, implying another potentially important therapeutic benefit. Despite this, it should also be noted that increased levels of copeptin, a peptide co-secreted with AVP and considered as an excellent surrogate marker for assessing circulating AVP concentrations, 49 is associated with metabolic dysregulation and onset of diabetes.…”

Section: Both Peptide Interventions Decreased Circulating Glucose Bodymentioning

confidence: 99%

Weight‐reducing, lipid‐lowering and antidiabetic activities of a novel arginine vasopressin analogue acting at the V1a and V1b receptors in high‐fat‐fed mice

Mohan

Flatt

Irwin

et al. 2021

Diabetes Obesity Metabolism

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Aim To assess the beneficial metabolic effects of the nonapeptide hormone, arginine vasopressin (AVP), on metabolism. Materials and Methods We exchanged amino acids at position 3 and 8 of AVP, namely phenylalanine and arginine, with those of oxytocin, to generate novel analogues with altered receptor selectivity. Secondary modification by N‐terminal acetylation was used to impart stability to circulating endopeptidases. Analogues were screened for degradation, bioactivity in rodent/human clonal beta cells and primary murine islets, together with evaluation of receptor activation profile. Results Analogue Ac3IV, which lacked effects at the V2 receptors responsible for modulation of fluid balance, was selected as the lead compound for assessment of antidiabetic efficacy in high‐fat‐fed mice. Twice‐daily administration of Ac3IV, or the gold standard control exendin‐4, for 22 days, reduced energy intake as well as body weight and fat content. Both interventions decreased circulating glucose levels, enhanced insulin sensitivity, and substantially improved glucose tolerance and related insulin secretion in response to an intraperitoneal or oral glucose challenge. The peptides decreased total‐ and increased HDL‐cholesterol, but only Ac3IV decreased LDL‐cholesterol, triglyceride and non‐fasting glucagon concentrations. Elevations of islet and beta‐cell areas were partially reversed, accompanied by suppressed islet cell proliferation, decreased beta‐cell apoptosis and, in the case of exendin‐4, also decreased alpha‐cell apoptosis. Conclusion AVP‐based therapies that exclusively target V1a and V1b receptors may have significant therapeutic potential for the treatment of obesity and related diabetes, and merit further clinical exploration.

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GIP analogues augment bone strength by modulating bone composition in diet-induced obesity in mice

Cited by 20 publications

References 45 publications

GIP as a Potential Therapeutic Target for Atherosclerotic Cardiovascular Disease–A Systematic Review

GIP as a Potential Therapeutic Target for Atherosclerotic Cardiovascular Disease–A Systematic Review

Metabolic responses and benefits of glucagon‐like peptide‐1 (GLP‐1) receptor ligands

Weight‐reducing, lipid‐lowering and antidiabetic activities of a novel arginine vasopressin analogue acting at the V1a and V1b receptors in high‐fat‐fed mice

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