Beneficial long‐term antidiabetic actions of <scp>N</scp>‐ and <scp>C</scp>‐terminally modified analogues of apelin‐13 in diet‐induced obese diabetic mice

Parthsarathy, Vadivel; Hogg, Chris; Flatt, Peter R.; O’Harte, Finbarr

doi:10.1111/dom.13068

Cited by 21 publications

(26 citation statements)

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“…Consistent with this view, recent work in our laboratory has shown that therapeutic natural and stable analogues of apelin-13 stimulate insulin secretion, enhance cellular glucose uptake and improve acute glucose tolerance in animal models of obesity-diabetes [ 27 , 34 ]. Native apelin undergoes extensive enzymatic degradation and rapid plasma clearance in vivo .…”

Section: Discussionmentioning

confidence: 82%

“…Numerous studies indicate an emerging involvement of apelin in energy metabolism and the pathophysiology of obesity [ 39 – 42 ]. Both apelin and APJ receptors are present in many tissues including mouse, human and rat adipose tissue and pancreatic islets [ 20 ; 34 , 43 , 44 ]. Circulating apelin concentrations are increased in obese humans and rodent models of obesity only when accompanied by hyperinsulinaemia [ 20 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

“…Fat mass, bone mineral content (BMC) and bone mineral density (BMD) were assessed using the PIXImus DEXA scanner. Measurements of indirect calorimetry, energy expenditure and locomotor activity were assessed using comprehensive laboratory animal monitoring system (CLAMS) metabolic chambers as described previously [ 34 ]. Although the main intervention study was carried out for a period of 28 days, the various peptide treatments were extended beyond that period to allow for all of the additional investigations to be performed while maintaining the once daily peptide treatment regime.…”

Section: Methodsmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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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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“…In conclusion, the present study has shown that once daily administration of (Lys 8 gluPAL)apelin-13 amide or pGlu(Lys 8 gluPAL)apelin-13 amide ameliorated diabetes, evoked weight loss and decreased circulating lipids in DIO mice, with effects equivalent to or better than liraglutide. Overall the pGlu(Lys 8 gluPAL)apelin-13 amide was the most effective analogue and was better than it equivalent nonacylated analogue tested previously [7].…”

Section: Discussionmentioning

confidence: 75%

“…The improvements may also reflect improvement in insulin action as evidenced by enhanced hypoglycaemic action of exogenous insulin. Apelin and its APJ receptors have been detected in the arcuate and paraventricular nuclei of hypothalamus, known to be key sites in central control of feeding behaviour and energy expenditure [7,8]. Apelin could also alter body adiposity independent of food intake by increasing energy expenditure [9].…”

Section: Discussionmentioning

confidence: 99%

The design and assessment of the therapeutic potential of apelin-13 peptide mimetics for alleviating metabolic dysfunction in diabetes and obesity

O’Harte¹

2018

Proceedings of the 35th European Peptide Symposium

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Effects of Incretin Therapy on Skeletal Health in Type 2 Diabetes—A Systematic Review

Viggers,

Rasmussen,

Vestergaard

2023

JBMR Plus

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Diabetes poses a significant risk to bone health, with Type 1 diabetes (T1D) having a more detrimental impact than Type 2 diabetes (T2D). The group of hormones known as incretins, which includes gastric inhibitory peptide (GIP) and glucagon‐like peptide 1 (GLP‐1), play a role in regulating bowel function and insulin secretion during feeding. GLP‐1 receptor agonists (GLP‐1 RAs) are emerging as the primary treatment choice in T2D, particularly when atherosclerotic cardiovascular disease is present. Dipeptidyl peptidase 4 inhibitors (DPP‐4is), although less potent than GLP‐1 RAs, can also be used. Additionally, GLP‐1 RAs, either alone or in combination with GIP, may be employed to address overweight and obesity. Since feeding influences bone turnover, a relationship has been established between incretins and bone health. To explore this relationship, we conducted a systematic literature review following the PRISMA guidelines. While some studies on cells and animals have suggested positive effects of incretins on bone cells, turnover, and bone density, human studies have yielded either no or limited and conflicting results regarding their impact on bone mineral density (BMD) and fracture risk. The effect on fracture risk may vary depending on the choice of comparison drug and the duration of follow‐up, which was often limited in several studies. Nevertheless, GLP‐1 RAs may hold promise for people with T2D who have multiple fracture risk factors and poor metabolic control. Furthermore, a potential new area of interest is the use of GLP‐1 RAs in fracture prevention among overweight and obese people. Based on this systematic review, existing evidence remains insufficient to support a positive or a superior effect on bone health to reduce fracture risk in people with T2D. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Beneficial long‐term antidiabetic actions of N‐ and C‐terminally modified analogues of apelin‐13 in diet‐induced obese diabetic mice

Abstract: These data indicate the therapeutic potential of stable apelin-13 analogues, with effects equivalent to or better than those of exendin-4.

Cited by 21 publications

References 44 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

The design and assessment of the therapeutic potential of apelin-13 peptide mimetics for alleviating metabolic dysfunction in diabetes and obesity

Effects of Incretin Therapy on Skeletal Health in Type 2 Diabetes—A Systematic Review

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