Glucagon receptor antagonist and GIP agonist combination for diet-induced obese mice

McShane, Laura; Irwin, Nigel; O'Flynn, D.P.; Franklin, Zara J.; Hewage, Chandralal M.; O’Harte, Finbarr

doi:10.1530/joe-15-0463

Cited by 12 publications

(7 citation statements)

References 57 publications

(65 reference statements)

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“…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 ). However, intestinal L-cell number has also been demonstrated to be reduced by STZ administration ( Vasu et al 2015 ), which could represent another confounding factor in our current observations.…”

Section: Discussionmentioning

confidence: 99%

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%

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

Lafferty

McShane

Franklin

et al. 2022

Journal of Endocrinology

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“…Interestingly, xenin-6, but not Ψ-xenin-6, had a strong tendency to reverse GIP-mediated increases in glucagon release. This is interesting, as both augmentation and blockade of glucagon receptor signalling has been advocated as being beneficial in diabetes (Pathak et al, 2015;McShane et al, 2016). The difference in biological activity between the two xenin C-terminal hexapeptides is intriguing and presumably not related to the enhanced stability of Ψ-xenin-6 noted here and elsewhere (Feurle et al, 2002).…”

Section: Previous Reports Have Established That Chemical Manipulationmentioning

confidence: 67%

Effects of an enzymatically stable C-terminal hexapseudopeptide fragment peptide of xenin-25, ψ-xenin-6, on pancreatic islet function and metabolism

Craig

Gault

McClean

et al. 2019

Molecular and Cellular Endocrinology

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Xenin-25 undergoes rapid enzyme metabolism following secretion. Early studies demonstrated bioactivity of a C-terminal hexapeptide fragment of xenin-25, namely xenin-6, which were enhanced through introduction of a reduced N-terminal peptide bond, to yield Ψ-xenin-6. The present study was undertaken to define the biological actions and potential antidiabetic properties of Ψ-xenin-6. In vitro enzymatic stability, insulin and glucagon secretory activity, as well as effects on beta-cell survival were determined. Studies in mice were used to assess the impact of Ψ-xenin-6 on glucose homeostasis and satiety. Ψ-xenin-6 was resistant to murine plasma degradation. In BRIN-BD11 cells and isolated murine islets, Ψ-xenin-6 significantly stimulated insulin secretion, and prominently enhanced the insulinotropic actions of GIP. Xenin-6 and Ψ-xenin-6 had no impact on glucagon secretion, although xenin-6 partially reversed the glucagonotropic action of GIP. Further in vitro investigations revealed that, similar to GLP-1, Ψ-xenin-6 significantly augmented proliferation of human and rodent clonal betacells, whilst also fully protecting against cytokine-induced beta-cell cytotoxicity, with greater potency than xenin-25 and xenin-6. When administered to mice in combination with glucose, Ψ-xenin-6 significantly reduced glucose levels and enhanced glucose-induced insulin release, with a duration of biological action beyond 8 hours. Ψ-xenin-6 also significantly enhanced the glucose-lowering action of GIP in vivo. In overnight fasted mice, Ψ-xenin-6 exhibited satiety actions at both 25 and 250 nmol/kg. These data demonstrates that Ψ-xenin-6 is a metabolically stable C-terminal fragment analogue of xenin-25, with a metabolic action profile that merits further study as a potential antidiabetic compound.

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“…Glucagon receptor knockout mice display reduced glycemia in response to exogenous insulin (Gelling et al, 2003) and require greater amounts of glucose to maintain euglycemia during hyperinsulinemiceuglycemic clamp experiments (Longuet et al, 2013;Sørensen et al, 2006). These improvements in peripheral insulin sensitivity have also been reported in mice where glucagon receptor signaling has been pharmacologically inhibited (McShane et al, 2016;Sharma et al, 2018). When liver-specific glucagon receptor knockout models are employed, insulin sensitivity is increased to a level comparable to global knockouts (Longuet et al, 2013), indicating that hepatic glucagon receptor signaling is the primary mediator for these benefits.…”

Section: Discussionmentioning

confidence: 95%

Distinct physiological characteristics and altered glucagon signaling in GHRH knockout mice: Implications for longevity

Lasher,

Sun

2023

Aging Cell

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Our previous research has demonstrated that mice lacking functional growth hormone‐releasing hormone (GHRH) exhibit distinct physiological characteristics, including an extended lifespan, a preference for lipid utilization during rest, mild hypoglycemia, and heightened insulin sensitivity. They also show a further increase in lifespan when subjected to caloric restriction. These findings suggest a unique response to fasting, which motivated our current study on the response to glucagon, a key hormone released from the pancreas during fasting that regulates glucose levels, energy expenditure, and metabolism. Our study investigated the effects of an acute glucagon challenge on female GHRH knockout mice and revealed that they exhibit reduced glucose production, likely due to suppressed gluconeogenesis. However, these mice showed an increase in energy expenditure. We also observed alterations in pancreatic islet architecture, with smaller islets and a reduction of insulin‐producing beta cells but no changes in glucagon‐producing alpha cells. Additionally, the analysis of hepatic glucagon signaling showed a decrease in glucagon receptor expression and phosphorylated CREB. In conclusion, our findings suggest that the unique metabolic phenotype observed in these long‐lived mice may be partly explained by changes in glucagon signaling. Further exploration of this pathway may lead to new insights into the regulation of longevity in mammals.

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Glucagon receptor antagonist and GIP agonist combination for diet-induced obese mice

Cited by 12 publications

References 57 publications

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

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

Effects of an enzymatically stable C-terminal hexapseudopeptide fragment peptide of xenin-25, ψ-xenin-6, on pancreatic islet function and metabolism

Distinct physiological characteristics and altered glucagon signaling in GHRH knockout mice: Implications for longevity

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