Metabolic effects of combined glucagon receptor antagonism and glucagon-like peptide-1 receptor agonism in high fat fed mice

Franklin, Zara J.; Lafferty, Ryan A.; Flatt, Peter; McShane, Laura; O’Harte, Finbarr; Irwin, Nigel

doi:10.1016/j.biochi.2022.04.005

Cited by 5 publications

(12 citation statements)

References 53 publications

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“…Unfortunately, we were unable to measure circulating GLP-1 concentrations in the current study due to the limited volume of blood that can be withdrawn from mice. However, we have recently shown that combined administration of a peptidic GCGR antagonist, with the well-characterised GLP-1 receptor mimetic exendin-4, exerts limited additive metabolic benefits ( Franklin et al 2022 ). Thus, activation of receptors for the sister incretin hormone of GLP-1, namely glucose-dependent insulinotropic polypeptide, may offer a more attractive paradigm in terms of combination therapy with GCGR antagonism ( McShane et al 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…Although all approaches possess robust glucose-lowering actions, the adverse side effect profile of each has been questioned ( Patil et al 2020 , Lafferty et al 2021 ). To date, it appears that peptide-based GCGR antagonists offer the best efficacy vs side effect profile ( Irwin et al 2013 , O’Harte et al 2013 , Franklin et al 2014 , 2022 , McShane et al 2014 ). Whether this relates to the composition of the compounds in question, or overall potency and degree of GCGR blockade, remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

“…Whether this relates to the composition of the compounds in question, or overall potency and degree of GCGR blockade, remains to be determined. However, a wealth of data suggests that organic peptides, such as desHis 1 Pro 4 Glu 9 -glucagon, represent highly effective GCGR antagonists ( O’Harte et al 2013 , Franklin et al 2022 ). Indeed, other truncated glucagon-based peptides have recently been shown to yield selective, high potency, GCGR antagonists ( Yang et al 2021 ), supporting this as an effective approach to decrease GCGR activity.…”

Section: Introductionmentioning

confidence: 99%

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Sustained glucagon receptor antagonism in insulin-deficient high-fat-fed mice

Lafferty

McShane

Franklin

et al. 2022

Journal of Endocrinology

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Discerning modification to the amino acid sequence of native glucagon can generate specific glucagon receptor (GCGR) antagonists, that include desHis1Pro4Glu9-glucagon and the acylated form desHis1Pro4Glu9(Lys12PAL)-glucagon. In the current study, we have evaluated the metabolic benefits of once daily injection of these peptide-based GCGR antagonists for 18 days in insulin-resistant high fat fed (HFF) mice with streptozotocin (STZ)-induced insulin deficiency, namely HFF-STZ mice. Administration of desHis1Pro4Glu9-glucagon moderately (P<0.05) decreased STZ-induced elevations of food intake. Body weight was not different between groups of HFF-STZ mice and both treatment interventions delayed (P<0.05) the onset of hyperglycaemia. The treatments reduced (P<0.05 - P<0.001) circulating and pancreatic glucagon, whilst desHis1Pro4Glu9(Lys12PAL)-glucagon also substantially increased (P<0.001) pancreatic insulin stores. Oral glucose tolerance was appreciably improved (P<0.05) by both antagonists, despite lack of augmentation of glucose-stimulated insulin release. Interestingly, positive effects on intraperitoneal glucose tolerance were less obvious suggesting important beneficial effects on gut function. Metabolic benefits were accompanied by decreased (P<0.05 - P<0.01) locomotor activity and increases (P<0.001) in energy expenditure and respiratory exchange ratio in both treatment groups. In addition, desHis1Pro4Glu9-glucagon increased (P<0.01 - P<0.001) O2 consumption and CO2 production. Together, these data provide further evidence that peptidic GCGR antagonists are effective treatment options for obesity-driven forms of diabetes, even when accompanied by insulin deficiency.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sustained glucagon receptor antagonism in insulin-deficient high-fat-fed mice

Lafferty

McShane

Franklin

et al. 2022

Journal of Endocrinology

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“…Kínálkozó lehetőséget jelenthet bizonyos tekintetben a Gc-antagonista és GLP1-receptor-agonista kombináció is. Ismertek ilyen vegyülettel folytatott állatkísérletes vizsgálat eredményei is [36]. Az eddigi adatok azt támasztják alá, hogy noha a diabeteses anyagcsere javítható, egyéb metabolikus előny -beleértve a testsúly vagy a zsíranyagcsere változását − nem igazolható.…”

Section: Hormonreceptor-agonisták a T2dm éS Az Elhízás Kezelésébenunclassified

A GLP1-receptor-agonistáktól a glükagonreceptor-agonizmussal kiegészített hármashormonreceptor-aktiválásig.

Winkler,

Kis,

Arapovicsné Kiss

et al. 2023

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A mono-, majd duális hormon(inkretin)receptor-agonisták terápiába állítását követően a 2-es típusú diabetes és az elhízás gyógyszeres kezelésének egyik új lehetőségeként a hármashormonreceptor-stimulálás, a glükagonreceptor kiegészítő aktiválása felé fordult a figyelem. A dolgozat a szénhidrát-anyagcserében betöltött szerepe mellett áttekinti a glükagon további élettani feladatait, kiemelten az intrainsularis parakrin szabályozásban, az energiaforgalomban és az étvágy befolyásolásában való részvételét. Kitér a hármas kombináció lehetséges előnyeire, és röviden érinti az első hármashormonreceptor-agonistával, a retatrutiddal kapcsolatos preklinikai humán vizsgálatok hatékonysággal és biztonságossággal kapcsolatos adataira is. A biztató eredmények további megerősítése előrelépést jelenthet e kórformák és kísérő állapotaik – így a steatosis hepatis − kezelésében. Orv Hetil. 2023; 164(42): 1656–1664.

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“…For example, desHis 1 Pro 4 Glu 9 -glucagon, which incorporates removal of the His 1 residue as well as Gly 4 to Pro 4 and Asp 9 to Glu 9 amino acid substitutions of native glucagon, residues known to be essential for GCGR activation (Unson et al, 1989;Ahn et al, 2001;Hruby, 1982), annuls glucagon signalling in vitro and in vivo (O'Harte et al, 2013). We have previously demonstrated desHis 1 Pro 4-Glu 9 -glucagon to be effective in managing diet-induced obesity in high-fat fed (HFF) mice, both alone and when combined with GLP-1, or especially glucose-dependent insulinotropic peptide (GIP), receptor agonists (McShane et al, 2016;Franklin et al, 2022). Further modification of desHis 1 Pro 4 Glu 9 -glucagon, through covalent attachment of palmitic acid to Lys 12 via a γ-glutamyl spacer molecule, to generate desHis 1-Pro 4 Glu 9 -glucagon (Lys 12 PAL), does not impede bioactivity of the molecule and prolongs circulating half-life (O'Harte et al, 2013).…”

Section: Introductionmentioning

confidence: 99%