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    • As cardiovascular disease accounts for the

    2022-09-28

    As cardiovascular disease accounts for the majority of deaths in subjects with T2D, it is imperative that we better characterize the cardiovascular risks and benefits of the various therapies we prescribe to these individuals to control their glycemia. Indeed, the potential to identify subsets of diabetic subjects that may respond favourably to the cardioprotective actions of GLP-1R agonists, or any other therapy for T2D, has vast clinical utility. Recent evidence from the LEADER and SUSTAIN-6 trials demonstrates that the GLP-1R agonists liraglutide and semaglutide improve cardiovascular outcomes in patients with T2D, though whether this represents a drug-class effect remains unknown. Similarly, the mechanisms of action by which GLP-1R agonists improve CV outcomes and protect against macrovascular disease in subjects with T2D is also unknown. The lack of GLP-1R Fmoc-Ser(tBu)-OH in ventricular cardiac myocytes is suggestive that a component of GLP-1R mediated cardioprotection likely involves indirect actions on peripheral tissues other than the heart. Conversely, despite the ongoing debate regarding GLP-1R expression in the vascular endothelium, a multitude of studies support salutary vascular/endothelial actions of GLP-1/GLP-1R agonists that could contribute to their cardioprotection against macrovascular disease. Studies in vitro demonstrate that GLP-1/GLP-1R agonists exhibit antiproliferative actions, reductions in ROS generation, and increases in NO formation, which could explain the antihypertensive and/or antiatherosclerotic beneficial actions observed in both animals and humans with T2D. However, indirect actions of GLP-1/GLP-1R agonists that reduce inflammation or improve circulating lipid profiles could also contribute to their antihypertensive and/or antiatherosclerotic actions. Therefore, further research is necessary to understand how GLP-1/GLP-1R agonists influence the vascular endothelium in health and disease, which will undoubtedly answer and raise new questions regarding the specific role of this drug-class in the clinical management of T2D.
    Disclosures
    Acknowledgements This review was supported by a Project Grant from the Canadian Institutes of Health Research (CIHR) to JRU. JRU is a Scholar of Diabetes Canada and a New Investigator of the Heart and Stroke Foundation of Alberta, NWT & Nunavut. RA is supported by Postdoctoral Fellowships from the CIHR and Diabetes Canada. MA is supported by a King Abdullah Scholarship from the Saudi Arabian Ministry of Higher Education. The authors also sincerely thank Wafa Hamad Alanazi for her assistance with the illustration in Fig. 1.
    Introduction The peptide hormone glucagon is secreted from pancreatic alpha-cells in response to low circulating blood glucose concentrations in order to restore normoglycaemia (Ali and Drucker, 2009). Given this important role in blood glucose homeostasis, it is not surprising that alterations in circulating glucagon levels are heavily implicated in the metabolic dysregulation of type 2 diabetes. Thus, hyperglucagonaemia contributes to the unwanted hyperglycaemia in type 2 diabetes (Baron et al., 1987, Reaven et al., 1987, Farhy and McCall, 2011) and is an early indicator of possible impending type 2 diabetes (Knop et al., 2012). In diabetic subjects, hyperglucagonaemia occurs in both the fasting and postprandial state and may be due to impaired pancreatic alpha-cell sensing, or lack of appropriate alpha-cell response to other secretagogues such as insulin (Ali and Drucker, 2009). Therefore, inhibition of glucagon receptor signalling represents an attractive therapeutic option for the treatment of type 2 diabetes. As such, glucagon neutralizing antibodies (Tan et al., 1985, Sloop et al., 2005) and small molecular weight glucagon receptor antagonists have been developed (Qureshi et al., 2004, Lau et al., 2007, Liang et al., 2007, Kim et al., 2008, Madsen et al., 2009, Mu et al., 2012) and shown to effectively annul glucagon receptor signalling. More recently, glucagon receptor antisense oligonucleotides have been pursued as possible therapeutic agents for type 2 diabetes (Estall and Drucker, 2006). However, there are issues in relation to safety, tolerability and induction of adverse immune responses with the aforementioned methods to ablate glucagon receptor action. Therefore, peptide-based glucagon receptor antagonists may well offer a more favourable therapeutic option (Hruby, 1982, Unson et al., 1989, Franklin et al., 2010). In this regard, development of such compounds has largely focused on modifications to the primary structure of native glucagon using knowledge that the N-terminal His1 and the Asp9 amino acid residues are essential for normal agonist activity (Hruby, 1982, Unson et al., 1991, Unson et al., 1993). Recognition of the extensive early contribution of leading synthetic groups of Hruby and Merrifield to this work, using structure function analysis of glucagon analogues, should not be underestimated (Hruby, 1982, Unson et al., 1987, Unson et al., 1989). In addition, the Gly4 residue was later shown to be important for receptor binding activity (Ahn et al., 2001). Based on these earlier structure function studies, we have now developed two novel Pro4 substituted glucagon analogues, namely desHis1Pro4-glucagon and desHis1Pro4Glu9-glucagon, with possible glucagon receptor antagonistic actions.