Glucagon-like peptide-1 protects mesenteric endothelium from injury during inflammation

Dozier, Kristopher C.; Cureton, Elizabeth L.; Kwan, Rita O.; Curran, Brian; Sadjadi, Javid; Victorino, Gregory P.

doi:10.1016/j.peptides.2009.06.019

Cited by 50 publications

(31 citation statements)

References 41 publications

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“…Experimental evidence suggests beneficial effects of GLP-1 during sepsis, with reduced mortality being found in endotoxin-challenged DPP-4 knockout rats and activation of the GLP-1 receptor improving prognosis in the same model (39). Mechanistically this might be mediated by anti-inflammatory capacities of GLP-1, leading to reduced oxidative stress and tissue protection (40,41).…”

Section: Discussionmentioning

confidence: 99%

GLP-1 Secretion Is Increased by Inflammatory Stimuli in an IL-6–Dependent Manner, Leading to Hyperinsulinemia and Blood Glucose Lowering

et al. 2014

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Hypoglycemia and hyperglycemia are both predictors for adverse outcome in critically ill patients. Hyperinsulinemia is induced by inflammatory stimuli as a relevant mechanism for glucose lowering in the critically ill. The incretine hormone GLP-1 was currently found to be induced by endotoxin, leading to insulin secretion and glucose lowering under inflammatory conditions in mice. Here, we describe GLP-1 secretion to be increased by a variety of inflammatory stimuli, including endotoxin, interleukin-1β (IL-1β), and IL-6. Although abrogation of IL-1 signaling proved insufficient to prevent endotoxin-dependent GLP-1 induction, this was abolished in the absence of IL-6 in respective knockout animals. Hence, we found endotoxin-dependent GLP-1 secretion to be mediated by an inflammatory cascade, with IL-6 being necessary and sufficient for GLP-1 induction. Functionally, augmentation of the GLP-1 system by pharmacological inhibition of DPP-4 caused hyperinsulinemia, suppression of glucagon release, and glucose lowering under endotoxic conditions, whereas inhibition of the GLP-1 receptor led to the opposite effect. Furthermore, total GLP-1 plasma levels were profoundly increased in 155 critically ill patients presenting to the intensive care unit (ICU) in comparison with 134 healthy control subjects. In the ICU cohort, GLP-1 plasma levels correlated with markers of inflammation and disease severity. Consequently, GLP-1 provides a novel link between the immune system and the gut with strong relevance for metabolic regulation in context of inflammation.

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Section: Discussionmentioning

confidence: 99%

GLP-1 Secretion Is Increased by Inflammatory Stimuli in an IL-6–Dependent Manner, Leading to Hyperinsulinemia and Blood Glucose Lowering

et al. 2014

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“…Thus, sitagliptin might exert anti-inflammatory action in the kidney through GLP-1 receptor by increasing active GLP-1, possibly leading to the reduction of albuminuria. Another anti-inflammatory property of GLP-1 including involvement of the cAMP/PKA pathway might also contribute to reducing albuminuria [8]. It has been reported that treatment with liraglutide resulted in a clinically significant reduction in blood pressure, which could not be fully accounted for by the reduction in body weight [9,10].…”

Section: Conflicts Of Interestsmentioning

confidence: 99%

Sitagliptin reduces albuminuria in patients with type 2 diabetes [Rapid Communication]

Hattori¹

2011

Endocr J

145

113

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“…Besides these direct effects on the pancreas, GLP-1 reduces gastric emptying and appetite, improves peripheral glucose uptake, and limits hepatic glucose production, thus also indirectly contributing to glucose homeostasis. Moreover, recent data suggest that GLP-1 has direct effects on endothelial function [2,3], inflammatory cell activation [4] and myocardial function [5]. Furthermore, the stable GLP-1 analogue exendin-4 stimulates the proliferation of human coronary artery endothelial cells in vitro through phosphoinositide 3-kinase/Akt-and endothelial nitric oxide synthasedependent pathways, effects that are shared by both native GLP-1 and its major metabolite GLP-1 [6].…”

Section: Introductionmentioning

confidence: 99%

Sitagliptin reduces plaque macrophage content and stabilises arteriosclerotic lesions in Apoe −/− mice

et al. 2012

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Aims/hypothesis Inhibitors of dipeptidyl peptidase-IV (DPP-IV), such as sitagliptin, increase glucagon-like peptide-1 (GLP-1) concentrations and are current treatment options for patients with type 2 diabetes mellitus. As patients with diabetes exhibit a high risk of developing severe atherosclerosis, we investigated the effect of sitagliptin on atherogenesis in Apoe −/− mice. Methods Apoe−/− mice were fed a high-fat diet and treated with either sitagliptin or placebo for 12 weeks. Plaque size and plaque composition were analysed using Oil Red O staining and immunohistochemistry. Furthermore, in vitro experiments with the modified Boyden chamber and with gelatine zymography were performed to analyse the effects of GLP-1 on isolated human monocyte migration and metalloproteinase-9 (MMP-9) release.Results Treatment of Apoe −/− mice with sitagliptin significantly reduced plaque macrophage infiltration (the aortic root and aortic arch both showing a 67% decrease; p<0.05) and plaque MMP-9 levels (aortic root showing a 69% and aortic arch a 58% reduction; both p<0.01) compared with controls. Moreover, sitagliptin significantly increased plaque collagen content more than twofold (aortic root showing an increase of 58% and aortic arch an increase of 73%; both p<0.05) compared with controls but did not change overall lesion size (8.1 ± 3.5% vs 5.1 ± 2.5% for sitagliptin vs controls; p0NS). In vitro, pretreatment of isolated human monocytes with GLP-1 significantly decreased cell migration induced by both monocyte chemotactic protein-1 and by the protein known as regulated on activation, normal T cell expressed and secreted (RANTES) in a concentration-dependent manner. Furthermore, GLP-1 significantly decreased MMP-9 release from isolated human monocyte-derived macrophages. Conclusions/interpretation Sitagliptin reduces plaque inflammation and increases plaque stability, potentially by GLP-1-mediated inhibition of chemokine-induced monocyte migration and macrophage MMP-9 release. The effects observed may provide potential mechanisms for how DPP-IV inhibitors could modulate vascular disease in high-risk patients with type 2 diabetes mellitus.

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Glucagon-like peptide-1 protects mesenteric endothelium from injury during inflammation

Cited by 50 publications

References 41 publications

GLP-1 Secretion Is Increased by Inflammatory Stimuli in an IL-6–Dependent Manner, Leading to Hyperinsulinemia and Blood Glucose Lowering

GLP-1 Secretion Is Increased by Inflammatory Stimuli in an IL-6–Dependent Manner, Leading to Hyperinsulinemia and Blood Glucose Lowering

Sitagliptin reduces albuminuria in patients with type 2 diabetes [Rapid Communication]

Sitagliptin reduces plaque macrophage content and stabilises arteriosclerotic lesions in Apoe −/− mice

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