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

Hasib, Annie; Ng, Ming T.; Gault, Victor; Khan, Dawood; Parthsarathy, Vadivel; Flatt, Peter R.; Irwin, Nigel

doi:10.1007/s00125-016-4186-y

Cited by 28 publications

(26 citation statements)

References 51 publications

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“…At the end of the experimental period (day 40), pancreatic tissues were excised for analysis of insulin content [ 36 , 37 ]. Blood was taken from fasted mice for measurement of lipid profiles including HDL-cholesterol, LDL-cholesterol and triglyceride levels by an ILab 650 Clinical Analyser (Instrumentation Laboratory, Warrington, UK).…”

Section: Methodsmentioning

confidence: 99%

Long-term treatment with acylated analogues of apelin-13 amide ameliorates diabetes and improves lipid profile of high-fat fed mice

et al. 2018

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Previous studies have shown that modified apelin analogues exhibited enzyme resistance in plasma and improved circulating half-life compared to apelin-13. This study investigated the antidiabetic effects of chronic administration of stable long acting fatty acid modified apelin analogues, namely, (Lys8GluPAL)apelin-13 amide and pGlu(Lys8GluPAL)apelin-13 amide, in high-fat fed obese-diabetic mice. Male NIH Swiss mice (groups n = 8) were maintained either on a high-fat diet (45% fat) from 8 to 28 weeks old, or control mice were fed a normal diet (10% fat). When diet induced obesity-diabetes was established after high-fat feeding, mice were injected i.p. once daily with apelin analogues, liraglutide (25 nmol/kg) or saline (controls). Administration of (Lys8GluPAL)apelin-13 amide and pGlu(Lys8GluPAL)apelin-13 amide for 28 days significantly reduced food intake and decreased body weight. Non-fasting glucose was reduced (p<0.01 to p<0.001) and plasma insulin concentrations increased (p<0.01 to p<0.001). This was accompanied by enhanced insulin responses (p<0.01 to p<0.001) and significant reductions in glucose excursion after oral (p<0.01) or i.p. (p<0.01) glucose challenges and feeding. Apelin analogues also significantly improved HbA1c (p<0.01), enhanced insulin sensitivity (p<0.01), reduced triglycerides (p<0.001), increased HDL-cholesterol (p<0.01) and decreased LDL-cholesterol (p<0.01), compared to high-fat fed saline treated control mice. Cholesterol levels were decreased (p<0.01) by pGlu(Lys8GluPAL)apelin-13 amide and both apelin treated groups showed improved bone mineral content, reduced fat deposits and increased plasma GLP-1. Daily treatment with liraglutide mirrored many of these changes (not on bone or adipose tissue), but unlike apelin analogues increased plasma amylase. Consumption of O2, production of CO2, respiratory exchange ratio and energy expenditure were improved by apelin analogues. These results indicate that long-term treatment with acylated analogues (Lys8GluPAL)apelin-13 amide and particularly pGlu(Lys8GluPAL)apelin-13 amide resulted in similar or enhanced therapeutic responses to liraglutide in high-fat fed mice. Fatty acid derived apelin analogues represent a new and exciting development in the treatment of obesity-diabetes.

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Section: Methodsmentioning

confidence: 99%

Long-term treatment with acylated analogues of apelin-13 amide ameliorates diabetes and improves lipid profile of high-fat fed mice

et al. 2018

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“…More intriguingly, the C‐terminal octapeptide of xenin‐25‐Gln, named xenin‐8‐Gln (Table ), was demonstrated to retain all the gluco‐regulatory and antidiabetic actions of the full‐length stable analogue . This observation led to the recent generation of a novel GIP/xenin hybrid peptide, (D‐Ala 2 )GIP/xenin‐8‐Gln, that combined an enzymatically stable form of the 14 amino acid bioactive N‐terminal region of GIP, with xenin‐8‐Gln . (D‐Ala 2 )GIP/xenin‐8‐Gln retained xenin and GIP like biological actions, and markedly improved glucose tolerance, insulin resistance, GIP bioactivity as well as enhanced pancreatic beta‐cell area in high fat fed diabetic mice .…”

Section: Xenin‐25 Fragment Peptidesmentioning

confidence: 99%

“…This observation led to the recent generation of a novel GIP/xenin hybrid peptide, (D‐Ala 2 )GIP/xenin‐8‐Gln, that combined an enzymatically stable form of the 14 amino acid bioactive N‐terminal region of GIP, with xenin‐8‐Gln . (D‐Ala 2 )GIP/xenin‐8‐Gln retained xenin and GIP like biological actions, and markedly improved glucose tolerance, insulin resistance, GIP bioactivity as well as enhanced pancreatic beta‐cell area in high fat fed diabetic mice . Whilst further studies are necessary for complete functional characterisation of (D‐Ala 2 )GIP/xenin‐8‐Gln, initial observations are favourable.…”

Section: Xenin‐25 Fragment Peptidesmentioning

confidence: 99%

Emerging therapeutic potential for xenin and related peptides in obesity and diabetes

Craig

Gault

Irwin

2018

Diabetes Metabolism Res

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Xenin-25 is a 25-amino acid peptide hormone co-secreted from the same enteroendocrine K-cell as the incretin peptide glucose-dependent insulinotropic polypeptide. There is no known specific receptor for xenin-25, but studies suggest that at least some biological actions may be mediated through interaction with the neurotensin receptor. Original investigation into the physiological significance of xenin-25 focussed on effects related to gastrointestinal transit and satiety. However, xenin-25 has been demonstrated in pancreatic islets and recently shown to possess actions in relation to the regulation of insulin and glucagon secretion, as well as promoting beta-cell survival. Accordingly, the beneficial impact of xenin-25, and related analogues, has been assessed in animal models of diabetes-obesity. In addition, studies have demonstrated that metabolically active fragment peptides of xenin-25, particularly xenin-8, possess independent therapeutic promise for diabetes, as well as serving as bioactive components for the generation of multi-acting hybrid peptides with antidiabetic potential. This review focuses on continuing developments with xenin compounds in relation to new therapeutic approaches for diabetes-obesity.

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“…Thus, several stable xenin and hybrid GIP–xenin analogues have been generated, and shown to exhibit improved biological properties over the native peptide. Importantly, stable xenin analogues augment the action of GIP in cellular and animal models . However, teasing out the molecular mechanisms underlying xenin‐based peptide action is not straightforward as there is no known ‘xenin’ receptor, so further detailed studies characterizing these beneficial actions are required.…”

Section: Therapeutic Role For Gip In Human Type 2 Diabetesmentioning

confidence: 99%

RD Lawrence Lecture 2017 Incretins: the intelligent hormones in diabetes

Gault

2017

Diabet. Med.

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The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have attracted considerable scientific and clinical interest due largely to their insulin-releasing and glucose-lowering properties. Indeed, GLP-1-based therapies are now key treatment options for many people with diabetes worldwide. In contrast, GIP-based agents have yet to reach the clinic based primarily on the impaired insulinotropic action of GIP observed in people with diabetes. Nevertheless, GIP is a key physiological regulator of insulin secretion and stable forms of GIP show much promise in rodent models to alleviate diabetes-obesity. Recent studies suggest that GIP may have an important role to play in a combination therapeutic approach or bioengineered with other gut peptides. Moreover, recent experimental studies indicate that incretins also exert pleiotropic effects in regions of the brain associated with learning and memory, thereby supporting preclinical data demonstrating that incretin-based drugs improve cognitive function. This review article, based on the RD Lawrence Lecture presented at Diabetes UK Annual Professional Conference (2017), provides a brief overview of incretins with a major focus on GIP, the development of designer GIP analogues, and how these molecules can improve cognition. Thus, incretins can be considered as 'the intelligent hormones' and may hold the key to successfully treating the alarming rise in neurodegenerative disorders.

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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

Cited by 28 publications

References 51 publications

Long-term treatment with acylated analogues of apelin-13 amide ameliorates diabetes and improves lipid profile of high-fat fed mice

Long-term treatment with acylated analogues of apelin-13 amide ameliorates diabetes and improves lipid profile of high-fat fed mice

Emerging therapeutic potential for xenin and related peptides in obesity and diabetes

RD Lawrence Lecture 2017 Incretins: the intelligent hormones in diabetes

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