Abstract
Cardiovascular disease is a common co-morbidity and leading cause of death in patients with type 2 diabetes mellitus (T2DM). Glucagon-like peptide 1 (GLP-1) is a peptide hormone produced by intestinal L cells in response to feeding. Native GLP-1 (7-36) amide is rapidly degraded by diaminopeptidyl peptidase-4 (DPP4) to GLP-1 (9-36) amide, making 9-36a the major circulating form. While it is 7-36a, and not its metabolites, which exerts trophic effects on islet β-cells, recent studies suggest that both 7-36a and its metabolites have direct cardiovascular effects, including preserving cardiomyocyte viability, ameliorating cardiac function, and vasodilation. In particular, the difference in cardiovascular effects between 7-36a and 9-36a is attracting attention. Growing evidence has strengthened the presumption that their cardiovascular effects are overlapping, but distinct and complementary to each other; 7-36a exerts cardiovascular effects in a GLP-1 receptor (GLP-1R) dependent pathway, whereas 9-36a does so in a GLP-1R independent pathway. GLP-1 therapies have been developed using two main strategies: DPP4-resistant GLP-1 analogs/GLP-1R agonists and DPP4 inhibitors, which both aim to prolong the life-time of circulating 7-36a. One prominent concern that should be addressed is that the cardiovascular benefits of 9-36a are lacking in these strategies. This review attempts to differentiate the cardiovascular effects between 7-36a and 9-36a in order to provide new insights into GLP-1 physiology, and facilitate our efforts to develop a superior GLP-1-therapy strategy for T2DM and cardiovascular diseases.
Highlights
Cardiovascular complications are the primary co-morbidity and leading cause of death in patients with type 2 diabetes mellitus (T2DM; Killilea, 2002; Mazzone et al, 2008)
In another study by Ban et al effects of 7-36a and 936a on isolated mouse hearts undergoing ischemia-reperfusion injury were studied (Ban et al, 2008). They demonstrated that pretreatment with 7-36a but not 9-36a, and post-treatment with 9-36a resulted in significant functional recovery from the ischemia-reperfusion injury in both wild-type and GLP-1 receptor (GLP-1R)−/− hearts compared with untreated controls
In the PROLOGUE study, no evidence was provided during the 24-month follow-up period that sitagliptin in addition to conventional therapy could slow the progression of carotid intima-media thickening, a surrogate marker for evaluating atherosclerotic cardiovascular disease, in patients with T2DM compared with conventional therapy alone (Oyama et al, 2016)
Summary
Cardiovascular complications are the primary co-morbidity and leading cause of death in patients with type 2 diabetes mellitus (T2DM; Killilea, 2002; Mazzone et al, 2008). Besides its indirect cardiac actions through the control of glucose and lipid metabolism by modulating insulin and glucagon secretion, GLP-1 may exert direct effects on heart and blood vessels (Ravassa et al, 2012; Ussher and Drucker, 2012). One major focus of this review is to examine cardiovascular effects which differ between 7-36a and its metabolites, 9-36a and 28-36a, and to dissect the interplay of GLP-1R in the heart. Numerous studies have shown that GLP-1 exerts cardioprotective actions These include preserving cardiomyocyte and endothelial cell viability in vitro (Oeseburg et al, 2010), reducing infarct size and ameliorating cardiac function after myocardial ischemia/reperfusion injury ex vivo (Bose et al, 2005), and improving left ventricular function following heart failure in an animal model (Nikolaidis et al, 2004a).
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