Glucagon-Like Peptide 1 Recruits Microvasculature and Increases Glucose Use in Muscle via a Nitric Oxide–Dependent Mechanism

Chai, Weidong; Dong, Zheng; Wang, Nasui; Wang, Wenhui; Tao, Ling; Cao, Wenhong; Liu, Zhenqi

doi:10.2337/db11-1073

Cited by 166 publications

(182 citation statements)

References 46 publications

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“…Improved vascular function has been reported following native GLP-1 infusion in preclinical studies 25,26 and also in clinical trials in both healthy subjects 12 and patients with type 2 diabetes. 13 However, it is not yet clear whether native GLP-1 exerts this beneficial effect through direct actions by the GLP-1 receptor 27 or through indirect actions of its dipeptidyl peptidase (DPP)-4-mediated cleavage product, GLP-1(9-36), known to mediate important mitochondrial and other, as yet unidentified, GLP-1 receptor-independent signalling pathways.…”

Section: Discussionmentioning

confidence: 99%

The effect of liraglutide on endothelial function in patients with type 2 diabetes

Nandy

Johnson

Basu

et al. 2014

Diabetes and Vascular Disease Research

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This single-centre, 12-week, double-blind, placebo-controlled trial assessed how the human glucagon-like-peptide 1 analogue liraglutide impacted endothelial function in adult patients (n = 49) with type 2 diabetes and no overt cardiovascular disease. Patients were randomized to liraglutide, placebo or glimepiride. At baseline and Week 12, venous occlusion plethysmography was used to measure forearm blood flow (FBF) in response to acetylcholine (ACh) and sodium nitroprusside (SNP) before and after l-N G -monomethyl arginine (L-NMMA) infusion. At Week 12, AChmediated FBF increased with liraglutide and decreased with placebo; however, the between-treatment difference was not significant (p = 0.055). Inhibition of ACh-mediated FBF after L-NMMA infusion increased with liraglutide and decreased with placebo; this between-treatment difference was also not significant (p = 0.149). No change in FBF was observed with SNP. Liraglutide did not significantly impact endothelium-dependent vasodilation after 12 weeks; however, additional investigations looking at the effect of liraglutide on endothelial function in alternative vasculature and during the postprandial period are warranted.

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Section: Discussionmentioning

confidence: 99%

The effect of liraglutide on endothelial function in patients with type 2 diabetes

Nandy

Johnson

Basu

et al. 2014

Diabetes and Vascular Disease Research

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“…Moreover, GLP-1 also increases insulin sensitivity in liver, muscle and adipocyte models (14)(15)(16) (17). Boc5 (a GLP-1R agonist) also significantly reduced fat mass and adipocyte hypertrophy in an animal model of obesity (18).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, GLP-1 also increases insulin sensitivity in liver, muscle and adipocyte models (14)(15)(16) …”

Section: Introductionmentioning

confidence: 99%

Glucagon-like peptide 1 regulates adipogenesis in 3T3-L1 preadipocytes

Yang

Ren

Song

et al. 2013

International Journal of Molecular Medicine

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Abstract. Glucagon-like peptide 1 (GLP-1), a gut-derived peptide, has been reported to have profound effects on metabolism and to reduce insulin resistance. Adipocyte hyperplasia stimulated by preadipocyte differentiation has a positive effect on adipose tissue insulin sensitivity. However, it remains less clear whether GLP-1 plays a role in adipogenesis. In this study, we examined the effect of GLP-1 on preadipocyte differentiation and investigated the mechanisms that may be involved in this effect. In our 3T3-L1 cell study, we tested the levels of adipocyte-specific markers and signaling pathways during preadipocyte differentiation. In addition, Oil Red O staining was used to examine lipid accumulation. Image Pro Plus 5.02 was used to analyze the size and number of lipid droplets. We found that GLP-1 elevated the protein expression levels of free fatty acid-binding protein 4 (aP2) and the transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ) in a dose-dependent manner during 3T3-L1 preadipocyte differentiation. Furthermore, RT-PCR results showed that GLP-1 promoted CCAAT/enhancer-binding protein α (C/EBPα) and lipoprotein lipase (LPL) expression at the transcriptional level. These data suggest that GLP-1 promotes preadipocyte differentiation. Our study also found that treatment of the cells with 100 nM GLP-1 enhanced the phosphorylation of Akt signaling during the first 24 h of differentiation. Although Oil Red O staining showed that GLP-1 had no significant effect on lipid accumulation, there were increased numbers of small adipocytes in the cells treated with 100 nM GLP-1. Taken together, these results indicate that GLP-1 regulates 3T3-L1 adipogenesis and the Akt signaling pathway may be involved in this process. The differentiated small adipocytes may have a positive effect against insulin resistance and obesity. IntroductionThe growing prevalence of obesity constitutes a major health problem worldwide (1). Obesity, particularly abdominal obesity, has a strong relationship with insulin resistance and is a major risk factor for type 2 diabetes and cardiovascular disease (2,3). The imbalance between energy intake and expenditure contributes to the development of obesity (1,4); the cellular mechanisms for which include the expansion of white adipose tissue via the hypertrophy of preexisting adipocytes and hyperplasia resulting from the adipogenesis of preadipocytes (4,5). When animals are maintained on a highfat diet, adipo cyte cell size initially increases, followed by an increase in fat cell number upon prolonged over-nutrition (6). In adults, ~10% of fat cells are renewed from preadipocytes annually (7). One study in adults demonstrated that short-term overfeeding increases the adipocyte cell numbers (8). Thus, adipogenesis probably has a role in the pathology of obesity in human adults. However, there are significant differences in lipid and glucose metabolism between adipocyte hypertrophy and hyperplasia (9-11). Recent studies have shown that adipocyte hypertrophy is negatively corre...

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“…Indeed, GLP-1 increases coronary blood flow and myocardial uptake of glucose in the Langendorff-perfused rat heart during low-flow ischemia (49) and myocardial glucose uptake in dogs with cardiomyopathy (31) and regulates muscle glucose uptake independent of its ability to enhance insulin secretion (3). Recently, we have shown that acute GLP-1 infusion increases muscle microvascular recruitment and glucose use independent of insulin secretion (10,40), likely via protein kinase A-mediated endothelial nitric oxide synthase (eNOS) activation (10,15). Importantly, GLP-1's microvascular action is preserved in both acute and chronic insulinresistant states (13).…”

mentioning

confidence: 99%

Liraglutide prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats

Chai

Aylor

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats. Am J Physiol Endocrinol Metab 311: E640 -E648, 2016. First published July 19, 2016 doi:10.1152/ajpendo.00205.2016.-Muscle microvasculature critically regulates endothelial exchange surface area to facilitate transendothelial delivery of insulin, nutrients, and oxygen to myocytes. Insulin resistance blunts insulin-mediated microvascular recruitment and decreases muscle capillary density; both contribute to lower microvascular blood volume. Glucagon-like peptide 1 (GLP-1) and its analogs are able to dilate blood vessels and stimulate endothelial cell proliferation. In this study, we aim to determine the effects of sustained stimulation of the GLP-1 receptors on insulin-mediated capillary recruitment and metabolic insulin responses, small arterial endothelial function, and muscle capillary density. Rats were fed a high-fat diet (HFD) for 4 wk with or without simultaneous administration of liraglutide and subjected to a euglycemic hyperinsulinemic clamp for 120 min after an overnight fast. Insulin-mediated muscle microvascular recruitment and muscle oxygenation were determined before and during insulin infusion. Muscle capillary density was determined and distal saphenous artery used for determination of endothelial function and insulin-mediated vasodilation. HFD induced muscle microvascular insulin resistance and small arterial vessel endothelial dysfunction and decreased muscle capillary density. Simultaneous treatment of HFD-fed rats with liraglutide prevented all of these changes and improved insulin-stimulated glucose disposal. These were associated with a significantly increased AMPK phosphorylation and the expressions of VEGF and its receptors. We conclude that GLP-1 receptor agonists may exert their salutary glycemic effect via improving microvascular insulin sensitivity and muscle capillary density during the development of insulin resistance, and early use of GLP-1 receptor agonists may attenuate metabolic insulin resistance as well as prevent cardiovascular complications of diabetes.

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Glucagon-Like Peptide 1 Recruits Microvasculature and Increases Glucose Use in Muscle via a Nitric Oxide–Dependent Mechanism

Cited by 166 publications

References 46 publications

The effect of liraglutide on endothelial function in patients with type 2 diabetes

The effect of liraglutide on endothelial function in patients with type 2 diabetes

Glucagon-like peptide 1 regulates adipogenesis in 3T3-L1 preadipocytes

Liraglutide prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats

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