scholarly journals The Effects of Glucagon-Like Peptide-1 Receptor Agonists and Dipeptydilpeptidase-4 Inhibitors on Blood Pressure and Cardiovascular Complications in Diabetes

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Habib Yaribeygi ◽  
Farin Rashid Farrokhi ◽  
Mohammed Altigani Abdalla ◽  
Thozhukat Sathyapalan ◽  
Maciej Banach ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Molecular Mechanisms ◽  
Cardiovascular Disorder ◽  
Cardiovascular Complications ◽  
Activity Levels ◽  
Beneficial Effects ◽  
Conflicting Evidence ◽  
Patients With Diabetes ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 receptor (GLP-1R) agonists are a class of newly introduced antidiabetic medications that potentially lower blood glucose by several molecular pathways. DPP-4 inhibitors are the other type of novel antidiabetic medications which act by preventing GLP-1 inactivation and thereby increasing the activity levels of GLP-1, leading to more glucose-induced insulin release from islet β-cells and suppression of glucagon release. Most patients with diabetes have concurrent hypertension and cardiovascular disorder. If antihyperglycemic agents can attenuate the risk of hypertension and cardiovascular disease, they will amplify their overall beneficial effects. There is conflicting evidence on the cardiovascular benefits of GLP-1R induction in laboratory studies and clinical trials. In this study, we have reviewed the main molecular mechanisms by which GLP-1R induction may modulate the cardiovascular function and the results of cardiovascular outcome clinical trials.

Efficacy and cardiovascular safety of SGLT2 Inhibitors

2020 ◽  
Vol 15 ◽  
Author(s):  
Cornelius James Fernandez ◽  
Abisha Graciano Nevins ◽  
Shasta Nawaz ◽  
Tahir Nazir ◽  
Fahmy W F Hanna
Keyword(s):  
Decision Process ◽  
Cardiovascular Events ◽  
Unmet Need ◽  
Clinical Decision ◽  
Sglt2 Inhibitors ◽  
Renal Protection ◽  
Sodium Glucose Cotransporter ◽  
Patients With Diabetes ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

: Patients with diabetes continued to exhibit a high risk for cardiovascular and renal events despite achieving satisfactory glycemic, blood pressure and lipid targets. Studies evaluating new diabetes medications focused on cardiovascular events, largely overlooking heart failure (HF). The latter has recently been recognised as a major cause of morbidity and mortality in patients with diabetes mellitus. There had been an unmet need for drugs with cardiovascular (including HF) and renal protection, with an expectation that an ideal diabetic drug should improve these end points. Moreover, an ideal drug should have weight lowering benefits. Recently published outcome trials have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) can reduce cardiovascular and renal events, together with statistically significant weight reduction. As a result, many recently published international guidelines have recommended SGLT2 inhibitors and GLP-1RAs in patients with diabetes and pre-existing cardiovascular disease (CVD). In this review we will critically analyse the efficacy and cardiovascular (CV) safety of SGLT2 inhibitors, based on the available literature to help position them in the clinical decision process.

The Physiology of Glucagon-like Peptide 1

2007 ◽  
Vol 87 (4) ◽  
pp. 1409-1439 ◽  
Author(s):  
Jens Juul Holst
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Glucagon Secretion ◽  
Peptide Hormone ◽  
Postprandial Glucose ◽  
Cell Secretion ◽  
Amino Acid Peptide ◽  
Reactive Hypoglycemia ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the “ileal brake” mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.

scholarly journals Glucagon-like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review

2020 ◽  
Vol 41 (1) ◽  
pp. 14-30 ◽  
Author(s):  
Mark P Maskery ◽  
Christian Holscher ◽  
Stephanie P Jones ◽  
Christopher I Price ◽  
W David Strain ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Scoping Review ◽  
Clinical Studies ◽  
Neuroprotective Agents ◽  
Receptor Agonists ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Retrospective Database

Stroke mortality and morbidity is expected to rise. Despite considerable recent advances within acute ischemic stroke treatment, scope remains for development of widely applicable neuroprotective agents. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally licensed for the management of Type 2 Diabetes Mellitus, have demonstrated pre-clinical neuroprotective efficacy in a range of neurodegenerative conditions. This systematic scoping review reports the pre-clinical basis of GLP-1RAs as neuroprotective agents in acute ischemic stroke and their translation into clinical trials. We included 35 pre-clinical studies, 11 retrospective database studies, 7 cardiovascular outcome trials and 4 prospective clinical studies. Pre-clinical neuroprotection was demonstrated in normoglycemic models when administration was delayed by up to 24 h following stroke induction. Outcomes included reduced infarct volume, apoptosis, oxidative stress and inflammation alongside increased neurogenesis, angiogenesis and cerebral blood flow. Improved neurological function and a trend towards increased survival were also reported. Cardiovascular outcomes trials reported a significant reduction in stroke incidence with semaglutide and dulaglutide. Retrospective database studies show a trend towards neuroprotection. Prospective interventional clinical trials are on-going, but initial indicators of safety and tolerability are favourable. Ultimately, we propose that repurposing GLP-1RAs is potentially advantageous but appropriately designed trials are needed to determine clinical efficacy and cost-effectiveness.

Molecular mechanisms underlying nutrient-stimulated incretin secretion

2010 ◽  
Vol 12 ◽  
Author(s):  
Helen E. Parker ◽  
Frank Reimann ◽  
Fiona M. Gribble
Keyword(s):  
Drug Discovery ◽  
Molecular Mechanisms ◽  
Fat Metabolism ◽  
Potential Range ◽  
Incretin Hormones ◽  
Appetite Control ◽  
K Cells ◽  
Incretin Secretion ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells in the intestinal epithelium in response to nutrient ingestion. The actions of GLP-1 and GIP – not only on local gut physiology but also on glucose homeostasis, appetite control and fat metabolism – have made these hormones an attractive area for drug discovery programmes. The potential range of strategies to target the secretion of these hormones therapeutically has been limited by an incomplete understanding of the mechanisms underlying their release. The use of organ and whole-animal perfusion techniques, cell line models and primary L- and K-cells has led to the identification of a variety of pathways involved in the sensing of carbohydrate, fat and protein in the gut lumen. This review focuses on our current understanding of these signalling mechanisms that might underlie nutrient responsiveness of L- and K-cells.

scholarly journals Glucagon-Like Peptide-1 Receptor Agonist Protects Dorsal Root Ganglion Neurons against Oxidative Insult

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Mohammad Sarif Mohiuddin ◽  
Tatsuhito Himeno ◽  
Rieko Inoue ◽  
Emiri Miura-Yura ◽  
Yuichiro Yamada ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Dorsal Root Ganglion ◽  
Dorsal Root ◽  
Receptor Agonist ◽  
Drg Neurons ◽  
Beneficial Effects ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Ganglion Neurons ◽  
Oxidative Insult

Objective. Diabetic polyneuropathy (DPN) is one of the most prevalent diabetic complications. We previously demonstrated that exendin-4 (Ex4), a glucagon-like peptide-1 receptor agonist (GLP-1RA), has beneficial effects in animal models of DPN. We hypothesized that GLP-1 signaling would protect neurons of the peripheral nervous system from oxidative insult in DPN. Here, the therapeutic potential of GLP-1RAs on DPN was investigated in depth using the cellular oxidative insult model applied to the dorsal root ganglion (DRG) neuronal cell line. Research Design and Methods. Immortalized DRG neuronal 50B11 cells were cultured with and without hydrogen peroxide in the presence or absence of Ex4 or GLP-1(7-37). Cytotoxicity and viability were determined using a lactate dehydrogenase assay and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt), respectively. Antioxidant enzyme activity was evaluated using a superoxide dismutase assay. Alteration of neuronal characteristics of 50B11 cells induced by GLP-1RAs was evaluated with immunocytochemistry utilizing antibodies for transient receptor potential vanilloid subfamily member 1, substance P, and calcitonin gene-related peptide. Cell proliferation and apoptosis were also examined by ethynyl deoxyuridine incorporation assay and APOPercentage dye, respectively. The neurite projection ratio induced by treatment with GLP-1RAs was counted. Intracellular activation of adenylate cyclase/cyclic adenosine monophosphate (cAMP) signaling was also quantified after treatment with GLP-1RAs. Results. Neither Ex4 nor GLP-1(7-37) demonstrated cytotoxicity in the cells. An MTS assay revealed that GLP-1RAs amended impaired cell viability induced by oxidative insult in 50B11 cells. GLP-1RAs activated superoxide dismutase. GLP-1RAs induced no alteration of the distribution pattern in neuronal markers. Ex4 rescued the cells from oxidative insult-induced apoptosis. GLP-1RAs suppressed proliferation and promoted neurite projections. No GLP-1RAs induced an accumulation of cAMP. Conclusions. Our findings indicate that GLP-1RAs have neuroprotective potential which is achieved by their direct actions on DRG neurons. Beneficial effects of GLP-1RAs on DPN could be related to these direct actions on DRG neurons.

scholarly journals A Review on the Association between Glucagon-Like Peptide-1 Receptor Agonists and Thyroid Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Wei-Yih Chiu ◽  
Shyang-Rong Shih ◽  
Chin-Hsiao Tseng
Keyword(s):  
Clinical Trials ◽  
Thyroid Cancer ◽  
Cell Cancer ◽  
Adverse Event Reporting System ◽  
C Cells ◽  
C Cell ◽  
Increased Risk ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The Impact

There is a concern on the risk of thyroid cancer associated with glucagon-like peptide-1 (GLP-1) analogs including liraglutide and exenatide. In this article, we review related experimental studies, clinical trials and observational human studies currently available. In rodents, liraglutide activated the GLP-1 receptors on C-cells, causing an increased incidence of C-cell neoplasia. Animal experiments with monkeys demonstrated no increase in calcitonin release and no C-cell proliferation after long-term liraglutide administration. Longitudinal 2-year data from clinical trials do not support any significant risk for the activation or growth of C-cell cancer in humans in response to liraglutide. However, an analysis of the FDA adverse event reporting system database suggested an increased risk for thyroid cancer associated with exenatide after its marketing. Noticeably, a recent study discovered that GLP-1 receptor could also be expressed in human papillary thyroid carcinomas (PTC), but the impact of GLP-1 analogs on PTC is not known. Therefore, GLP-1 analogs might increase the risk of thyroid C-cell pathology in rodents, but its risk in humans awaits confirmation. Since GLP-1 receptor is also expressed in PTC besides C-cells, it is important to investigate the actions of GLP-1 on different subtypes of thyroid cancer in the future.

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