The GLP-1 Analogs Liraglutide and Semaglutide Reduce Atherosclerosis in ApoE−/− and LDLr−/− Mice by a Mechanism That Includes Inflammatory Pathways

JACC Basic to Translational Science, Journal Year: 2018, Volume and Issue: 3(6), P. 844 - 857

Published: Nov. 21, 2018

The glucagon-like peptide-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide reduce cardiovascular risk in type 2 diabetes patients. mode of action is suggested to occur through modified atherosclerotic progression. In this study, both the compounds significantly attenuated plaque lesion development apolipoprotein E-deficient (ApoE-/-) mice low-density lipoprotein receptor-deficient (LDLr-/-) mice. This attenuation was partly independent weight cholesterol lowering. aortic tissue, exposure a Western diet alters expression genes pathways relevant pathogenesis atherosclerosis, including leukocyte recruitment, rolling, adhesion/extravasation, metabolism, lipid-mediated signaling, extracellular matrix protein turnover, hemorrhage. Treatment with reversed these changes. These data suggest GLP-1RAs affect atherosclerosis an anti-inflammatory mechanism.

Language: Английский

---

Glucagon-Like Peptide-1 and Its Class B G Protein–Coupled Receptors: A Long March to Therapeutic Successes

Pharmacological Reviews, Journal Year: 2016, Volume and Issue: 68(4), P. 954 - 1013

Published: Sept. 14, 2016

The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein–coupled (GPCR) that mediates the action of GLP-1, hormone secreted from three major tissues in humans, enteroendocrine L cells distal intestine, α pancreas, and central nervous system, which exerts important actions useful management type 2 diabetes mellitus obesity, including glucose homeostasis regulation gastric motility food intake. Peptidic analogs GLP-1 have been successfully developed with enhanced bioavailability pharmacological activity. Physiologic biochemical studies truncated, chimeric, mutated peptides GLP-1R variants, together ligand-bound crystal structures extracellular domain first three-dimensional 7-helical transmembrane GPCRs, provided basis for two-domain–binding mechanism its cognate receptor. Although efforts discovering therapeutically viable nonpeptidic agonists hampered, small-molecule modulators offer complementary chemical tools to investigate ligand-directed biased cellular signaling GLP-1R. integrated structural information different homologous receptors give new insights into molecular determinants ligand selectivity functional activity, thereby providing novel opportunities design development more efficacious agents treat metabolic disorders.

Language: Английский

---

Cardiovascular Actions of Incretin-Based Therapies

Circulation Research, Journal Year: 2014, Volume and Issue: 114(11), P. 1788 - 1803

Published: May 22, 2014

Glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors represent 2 distinct classes of incretin-based therapies used for the treatment type diabetes mellitus. Activation GLP-1R signaling or inhibition DPP-4 activity produces a broad range overlapping unique cardiovascular actions. Native GLP-1 regulates biology via activation classical GLP-1R, through GLP-1(9-36), cardioactive metabolite generated by DPP-4-mediated cleavage. In contrast, clinically approved are not cleaved to GLP-1(9-36) produce majority their actions GLP-1R. The mechanisms engaged more complex, encompassing increased levels intact GLP-1, reduced changes in numerous peptides. Herein we review recent experimental clinical advances that reveal how affect normal diabetic heart coronary vasculature, often independent blood glucose. Improved understanding complex science is required optimize selection these therapeutic agents patients with disease.

Language: Английский

---

GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes

Nature Reviews Nephrology, Journal Year: 2017, Volume and Issue: 13(10), P. 605 - 628

Published: Sept. 4, 2017

Language: Английский

---

Novel targets and future strategies for acute cardioprotection: Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart

Cardiovascular Research, Journal Year: 2017, Volume and Issue: 113(6), P. 564 - 585

Published: March 15, 2017

Ischaemic heart disease and the failure that often results, remain leading causes of death disability in Europe worldwide. As such, order to prevent improve clinical outcomes patients presenting with an acute ST-segment elevation myocardial infarction undergoing coronary artery bypass graft surgery, novel therapies are required protect against detrimental effects ischaemia/reperfusion injury (IRI). During last three decades, a wide variety ischaemic conditioning strategies pharmacological treatments have been tested clinic—however, their translation from experimental studies for improving patient has both challenging disappointing. Therefore, this Position Paper European Society Cardiology Working Group on Cellular Biology Heart, we critically analyse current state settings, provide recommendations its into setting, highlight therapeutic targets new treatment reducing IRI.

Language: Английский

---

Review of head‐to‐head comparisons of glucagon‐like peptide‐1 receptor agonists

Diabetes Obesity and Metabolism, Journal Year: 2015, Volume and Issue: 18(4), P. 317 - 332

Published: Oct. 29, 2015

Currently, six glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for treating type 2 diabetes. These fall into two classes based on their activation: short-acting exenatide twice daily and lixisenatide once daily; longer-acting liraglutide daily, weekly, albiglutide weekly dulaglutide weekly. The phase III trial of a seventh GLP-1RA, taspoglutide was stopped because unacceptable adverse events (AEs). Nine head-to-head trials one large II study have compared the efficacy safety these seven GLP-1RAs. All were associated with notable reductions in glycated haemoglobin (HbA1c) levels, although led to greater decreases than formulations albiglutide, HbA1c did not differ between dulaglutide. As GLP-1RAs delay gastric emptying, they effects postprandial glucose levels agents, whereas compounds reduced plasma throughout 24-h period studied. Liraglutide weight similar those but most frequently observed AEs gastrointestinal disorders, particularly nausea, vomiting diarrhoea. Nauseaoccurred less frequently, however, liraglutide. Both may be higher incidences injection-site reactions GLP-1RA use clinical practice should customized individual patients, profile patient preference. Ongoing assessments novel delivery methods further expand future treatment options.

Language: Английский

---

GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects

Frontiers in Endocrinology, Journal Year: 2021, Volume and Issue: 12

Published: Aug. 23, 2021

Glucagon like peptide-1 (GLP-1) is an incretin secretory molecule. GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes (T2DM) due to their attributes such as body weight loss, protection islet β cells, promotion cell proliferation and minimal side effects. Studies have found that GLP-1R distributed on pancreatic other tissues has multiple biological effects, reducing neuroinflammation, promoting nerve growth, improving heart function, suppressing appetite, delaying gastric emptying, regulating blood lipid metabolism fat deposition. Moreover, GLP-1RAs neuroprotective, anti-infectious, cardiovascular protective, metabolic regulatory exhibiting good application prospects. Growing attention been paid relationship between tumorigenesis, development prognosis patient with T2DM. Here, we reviewed therapeutic effects possible mechanisms action nervous, cardiovascular, endocrine systems correlation metabolism, tumours diseases.

Language: Английский

---

Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes

European Heart Journal, Journal Year: 2015, Volume and Issue: 36(34), P. 2288 - 2296

Published: June 10, 2015

Type 2 diabetes mellitus (T2DM) is characterized by multiple pathophysiologic abnormalities. With time, glucose-lowering medications are commonly required to reduce and maintain plasma glucose concentrations within the normal range. individuals also at a very high risk for microvascular complications incidence of heart attack stroke increased two- three-fold compared with non-diabetic individuals. Therefore, when selecting normalize levels in T2DM patients, it important that agent not aggravate, ideally even improve, cardiovascular factors (CVRFs) morbidity mortality. In this review, we examine effect oral (metformin, sulfonylureas, meglitinides, thiazolidinediones, DPP4 inhibitors, SGLT2 α-glucosidase inhibitors) injectable (glucagon-like peptide-1 receptor agonists insulin) drugs on established CVRFs long-term studies outcomes. Firm evidence disease can be reversed or prevented improving glycaemic control still incomplete must await large, clinical trials patients low using modern treatment strategies, i.e. drug combinations designed maximize HbA1c reduction while minimizing hypoglycaemia excessive weight gain.

Language: Английский

---

Islet α cells and glucagon—critical regulators of energy homeostasis

Nature Reviews Endocrinology, Journal Year: 2015, Volume and Issue: 11(6), P. 329 - 338

Published: April 7, 2015

Language: Английский

---

Pleiotropic Effects of GLP-1 and Analogs on Cell Signaling, Metabolism, and Function

Frontiers in Endocrinology, Journal Year: 2018, Volume and Issue: 9

Published: Nov. 23, 2018

The incretin hormone Glucagon-Like Peptide-1 (GLP-1) is best known for its 'incretin effect' in restoring glucose homeostasis diabetics, however, it now apparent that has a broader range of physiological effects the body. Both vitro and vivo studies have demonstrated GLP-1 mimetics alleviate endoplasmic reticulum stress, regulate autophagy, promote metabolic reprogramming, stimulate anti-inflammatory signaling, alter gene expression influence neuroprotective pathways. A substantial body evidence accumulated with respect to how analogues act restore maintain normal cellular functions. These findings prompted several clinical trials which reported improve cardiac function, lung function reduce mortality patients obstructive disease, blood pressure lipid storage, even prevent synaptic loss neurodegeneration. Mechanistically, elicits via acute elevation cAMP levels, subsequent protein kinase(s) activation, pathways well defined pancreatic β-cells insulin secretion conjunction elevated Ca2+ ATP. More recently, new shed light on additional downstream stimulated by chronic exposure, direct relevance our understanding potential therapeutic longer lasting recently developed use. In this review, we provide comprehensive description diverse roles across multiple tissues, describe discuss novel pleiotropic applications treatment human disease.

Language: Английский

---