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  • br Conflict of interest statement br Acknowledgements This w


    Conflict of interest statement
    Acknowledgements This work was supported by the National Health and Medical Research Council of Australia (NHMRC) (project grants [1061044], [1065410] and [1126857], and NHMRC program grant [1055134]); P.M.S. and A.C. are NHMRC Principal and Senior Principal Research Fellows, respectively. D.W. is an NHMRC Career Development Fellow. S.G.B.F is an ARC Future Fellow.
    Introduction Diabetes prevalence continues to increase, with over 420 million people now living with diabetes worldwide. Of these, ∼90% have type 2 diabetes (T2D), with the majority resulting from underlying obesity [15,30]. Fortunately, we have a number of therapies available to improve glycemia in patients with T2D, including the first-line therapy metformin, the sulfonylureas, the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists, the dipeptidylpeptidase-4 (DPP-4) inhibitors, and the sodium-glucose co-transporter 2 inhibitors. Despite the overall control of glycemia being for most part consistent among the majority of these therapies [47,58], the vast majority of T2D patients will eventually die from macrovascular cardiovascular disease (e.g. myocardial infarction (MI) and heart failure) [58]. Accordingly, all pharmaceutical companies developing therapies for T2D must now ensure that their therapies are cardiovascular safe versus standard-of-care in large-scale cardiovascular outcomes trials. Intriguingly, recent evidence indicates that GLP-1R agonists have favourable actions on cardiovascular risk, as liraglutide reduced the rates of cardiovascular death, while showing trends to also reducing NSC74859 hospitalization rates for heart failure in the LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results – A Long-Term Evaluation) [37]. Although the GLP-1R agonist semaglutide did not reduce rates of cardiovascular death in SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with T2D), it did reduce events rates from its primary outcome, which consisted of death from cardiovascular causes, or nonfatal MI or stroke [36]. In light of these exciting findings and evidence illustrating that ventricular cardiac myocytes do not express the GLP-1R [55,57], we recently evaluated whether indirect actions that influence cardiac NSC74859 metabolism might account for GLP-1R agonist-induced cardioprotection against macrovascular disease in patients with T2D [1]. Conversely, vascular smooth muscle cells (VSMCs) appear to express the GLP-1R, and GLP-1/GLP-1R agonists exhibit a number of salutary vascular/endothelial actions [48,57]. Accordingly, we herein will provide a brief overview of incretin hormone action, followed by in-depth descriptions of the vascular/endothelial actions mediated in response to GLP-1R activation. Moreover, we will discuss whether such GLP-1R-regulated actions contribute to GLP-1R agonist-induced cardioprotection against macrovascular disease in patients with T2D. For an in-depth analysis of the overarching cardiovascular actions of GLP-1 and GLP-1R agonists, we encourage the reader to read the many excellent reviews already published on this topic [17,34,51,56,57].
    The incretin hormones Two incretin hormones have been identified to date, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1, both of which are secreted from enteroendocrine cells after meal ingestion in a glucose-dependent manner and potentiate insulin secretion (please refer to [4,11,26] for extensive review of incretin hormone action and regulation). ∼50-70% of insulin secretion following oral glucose administration is attributed to the actions of gut-secreted GIP/GLP-1 on the endocrine pancreas, thereby defining the “incretin effect”. Both GIP and GLP-1 potentiate insulin secretion via activating related Class B Family G-protein coupled receptors (GPCRs) expressed on islet β-cells, and these 2 hormones are cleaved within minutes of release and subsequently inactivated via DPP-4. This limitation of incretin-hormone action inspired the development of DPP-4 inhibitors for the treatment of T2D, which primarily mediate their improvements in glycemia by preserving the biological activity of endogenously-released GIP/GLP-1 [40]. While both GIP and GLP-1 improve glucose homeostasis via augmenting insulin secretion, GLP-1 also produces additional glucose-lowering by delaying gastric emptying and inhibiting glucagon secretion in a glucose-dependent manner. GLP-1 and GLP-1R agonists also have a number of actions on the vasculature/endothelium, and the remainder of this review will focus on such actions, and whether they may contribute to GLP-1R agonist-induced cardioprotection in T2D. This review will not discuss the actions of DPP-4 inhibitors on the vasculature/endothelium, as these agents impact a broad range of circulating peptides, many of which can influence vascular/endothelial function independent of increases in GIP/GLP-1, and we encourage the reader to read the recent excellent reviews in this area [39,40].