Single Dose GLP-1-Tf Ameliorates Myocardial Ischemia/Reperfusion Injury

Matsubara, Muneaki; Kanemoto, Shinya; Leshnower, Bradley G.; Albone, Earl F.; Hinmon, Robin; Plappert, Theodore; Gorman, Joseph H.; Gorman, Robert C.

doi:10.1016/j.jss.2009.03.016

Cited by 52 publications

(50 citation statements)

References 32 publications

(34 reference statements)

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“…Other long-acting GLP-1 receptor agonists include CJC1134 (ConjuChem, Inc., Montreal, QC, Canada), a protein that contains an exenatide moiety covalently linked to human albumin through a chemical linkage (Baggio et al, 2008), and LY2428757, a pegylated GLP-1 molecule: longterm therapeutic efficacy of these promising molecules however is not yet fully known. In addition to their euglycemic activities, it is interesting to note that GLP-1-Tf analogs also have recently been shown to possess therapeutic benefit in cardiovascular disorders, because GLP-1-Tf can attenuate myocardial reperfusion injury (Matsubara et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

Transferrin Fusion Technology: A Novel Approach to Prolonging Biological Half-Life of Insulinotropic Peptides

Kim¹,

Zhou²,

Martin³

et al. 2010

J Pharmacol Exp Ther

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Fusion proteins made up of glucagon-like peptide 1 (GLP-1) and exendin-4 (EX-4) fused to a nonglycosylated form of human transferrin (GLP-1-Tf or EX-4-Tf) were produced and characterized. GLP-1-Tf activated the GLP-1 receptor, was resistant to inactivation by peptidases, and had a half-life of approximately 2 days, compared with 1 to 2 min for native GLP-1. GLP-1-Tf retained the acute, glucose-dependent insulin-secretory properties of native GLP-1 in diabetic animals and had a profound effect on proliferation of pancreatic ␤-cells. In addition, Tf and the fusion proteins did not cross the blood-brain-barrier but still reduced food intake after peripheral administration. EX-4-Tf proved to be as effective as EX-4 but had longer lived effects on blood glucose and food intake. This novel transferrin fusion technology could improve the pharmacology of various peptides.

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Section: Discussionmentioning

confidence: 99%

Transferrin Fusion Technology: A Novel Approach to Prolonging Biological Half-Life of Insulinotropic Peptides

Kim¹,

Zhou²,

Martin³

et al. 2010

J Pharmacol Exp Ther

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“…Administration of GLP-1-Tf could effectively reduce the infarct size in rabbits, given either before or after coronary occlusion. 31 Recently, albiglutide, another GLP-1 analogue, has been shown to increase cAMP in an ischaemic myocardium and improve cardiac metabolic efficiency by increasing glucose metabolism and reducing fat oxidation, which results in 26% reduction of infarct size. 32 In a pig model, exenatide has been shown to reduce the infarct size, 33 whereas the other two studies with a shorter period of I/R using recombinant GLP-1 (rGLP-1) 34 or liraglutide 35 could not demonstrate any improvement in infarct size (Table 2).…”

Section: Effects Of Glp-1 On the Infarct Sizementioning

confidence: 99%

“…The administration of GLP-1 as a post-conditioning agent, which demonstrated a higher plasma GLP-1 level, could improve LV performance by decreasing the wall motion abnormality, and increasing the ejection fraction and LV developed pressure, 29,31 compared with giving GLP-1 as a pre-conditioning agent, which has a lower plasma GLP-1 level. 31 Nevertheless, it is possible that the time for which GLP-1 was given as a preconditioning treatment in those studies was too short, thus allowing insufficient time for its action. This is supported by a report by Noyan-Ashraf and colleagues which demonstrated that the GLP-1 analogue required the optimal pre-treatment time and dose for the activation of the cardiac gene and protein to promote LV enhancement.…”

Section: Effects Of Glp-1 On Left Ventricular Functionmentioning

confidence: 99%

“…Surprisingly, the cardioprotective effect of GLP-1 and GLP-1 analogue was not associated with any improvement in haemodynamic parameters (Table 4). 26,[31][32][33][34][35]44,47 Unlike GLP-1, information regarding the effects of DPP-4 inhibitor on the I/R heart is scarce and controversial. [48][49][50] DPP-4 inhibitors inhibit the enzyme activity of DPP-4, resulting in decreasing degradation rate, thereby maintaining higher GLP-1 levels.…”

Section: Effects Of Glp-1 On Left Ventricular Functionmentioning

confidence: 99%

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Cardioprotective effects of incretin during ischaemia-reperfusion

Chinda

Chattipakorn

2012

Diabetes and Vascular Disease Research

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Incretin is a gut derived peptide hormone secreted in the intestine after food ingestion, and is degraded rapidly after secretion by dipeptidyl peptidase (DPP)-4. Incretin-based therapy, such as glucagon-like peptide (GLP)-1 and the DPP-4 inhibitor, has been proposed as a new therapeutic approach for the treatment of type 2 diabetic patients. In the past few years, growing evidence also demonstrated the cardioprotective effects of incretin-based therapy, especially during ischaemia-reperfusion (I/R) injury in both the animal models and in clinical studies. However, inconsistent reports exist regarding the use of these pharmacological interventions. In this article, a comprehensive review regarding both basic and clinical studies reporting the effects of GLP-1 and DPP-4 inhibitors on I/R hearts is presented and discussed. The consistent findings as well as controversial results are summarised, focusing on the effects of incretin on the infarct size, left ventricular function and haemodynamic improvement during an I/R injury.

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“…13 DPP-4-resistant GLP-1 analogs fused to non-glycosylated human transferrin possess anti-apoptotic properties accompanied by a reduction in the infarct size and improvements in wall motion abnormalities and the ejection fraction (EF) in a model of myocardial IR in rabbits. 14 The infusion of GLP-1 or the exenatide analog at 2 weeks after coronary ligation significantly increases the LVEF, while also reducing the incidence of adverse LV remodeling and improving survival. 15 Exenatide reduces the infarct size and reactive oxygen species (ROS) production and inhibits caspase-3 expression and DNA fragmentation in a porcine model of myocardial IR injury.…”

Section: Biology Of Incretinsmentioning

confidence: 99%

Incretin Therapy and Heart Failure

Oyama

Node

2014

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp large bowel, and glucose-dependent insulinotropic polypeptide (GIP), which is derived from the K cells of the proximal small intestine. GLP-1 and GIP are glucose-lowering agents that can interfere with postprandial hyperglycemia, which has been demonstrated as associated with cardiovascular complications. The biologically active forms of GLP-1 include GLP-1(7-37) and GLP-1(7-36)amide. These peptides arise from the selective cleavage of the proglucagon molecule. GLP-1(7-36)amide is abundant in the circulation after meals and stimulates insulin secretion by interacting with the GLP-1 receptors on pancreatic beta cells. DPP-4 degrades GLP-1(7-36)amide to inactive GLP-1(9-36)amide, and DPP-4 inhibitors bind to DPP-4 to prevent the breakdown of GLP-1 and GIP, 5 thereby increasing the half-life and bioavailability of active incretins, ultimately enhancing their physiological effects. GLP-1(7-36)amide has been widely studied for its role as an active incretin and is referred to as GLP-1, unless otherwise specified. GLP-1(9-36) amide is thought to be an inactive metabolite because of its 1,000-fold lower affinity for GLP-1R and action as a weak competitive antagonist without incretin activity at pharmacological doses. However, GLP-1(9-36)amide may have potent effects on the cardiovascular system, similar to GLP-1(7-36) amide. Although it remains controversial, GLP-1 may undergo multiple cycles of enzymatic degradation by DPP-4 and neprilysin. Therefore, the precise biological pathways of GLP-1 and related enzymes and the roles of metabolites in each step of the process in vivo need to be elucidated in the near future. Effects of Incretins on Cardiac FunctionCardiomyocytes in Vitro GLP-1 rapidly increases the 3'-5'-cyclic adenosine monophosphate (cAMP) levels in adult rat ventricular cardiac myocytes, consistent with its effect on pancreatic beta cells, in a manner ype 2 diabetes (T2DM) is one of the most important risk factors for the development of cardiovascular disease, as it promotes both systemic atherosclerosis and lifestyle-associated diseases. Incretin-based therapies, including treatment with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists and dipeptidyl peptidase (DPP)-4 inhibitors, have become widely used as a new class of antidiabetic drugs that exhibit different mechanisms of action from those of conventional antidiabetic agents. Incretin hormones depend on blood glucose to stimulate insulin. Because the use of DPP-4 inhibitors is associated with a lower incidence of hypoglycemia than is observed with conventional hypoglycemic drugs, they potentially improve the mortality rate of patients with T2DM by achieving strict glycemic control without causing fatal hypoglycemia. The GLP-1R has been detected in coronary endothelial cells, coronary smooth muscle cells, cardiomyocytes and human umbilical vein endothelial cells, as well as monocytes and macrophages. 1-4 Interestingly, GLP-1 acts on multiple organ...

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Single Dose GLP-1-Tf Ameliorates Myocardial Ischemia/Reperfusion Injury

Cited by 52 publications

References 32 publications

Transferrin Fusion Technology: A Novel Approach to Prolonging Biological Half-Life of Insulinotropic Peptides

Transferrin Fusion Technology: A Novel Approach to Prolonging Biological Half-Life of Insulinotropic Peptides

Cardioprotective effects of incretin during ischaemia-reperfusion

Incretin Therapy and Heart Failure

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