The NIHR CRN trials database is accessible to the public at no charge, open to all prospective registrants, managed by a not-for-profit organization, has a mechanism to ensure the validity of the registration data, and is electronically searchable

The NIHR CRN trials database is accessible to the public at no charge, open to all prospective registrants, managed by a not-for-profit organization, has a mechanism to ensure the validity of the registration data, and is electronically searchable. studying the effect of chronic glucagon-like peptide-1 receptor activation on exercise-induced ischaemia in patients with chronic stable angina managed conservatively or awaiting revascularisation. The hypothesis being liraglutide, a subcutaneously injectable glucagon-like peptide-1 receptor agonist, is able to improve exercise haemodynamics in patients with obstructive coronary artery disease when compared with saline placebo. Methods and design The Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) trial is an investigator-initiated single-centre randomised double-blinded placebo-controlled crossover proof-of-principle physiological study. Primary endpoints are change in rate pressure product at 0.1?mV ST-segment depression and change in degree of ST-segment depression at peak exercise during sequential exercise tolerance testing performed over a 6-week study period (R)-ADX-47273 in which 26 patients will be randomised to either liraglutide or saline with crossover to the opposing regimen at week 3. Discussion The study will be conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The local Research Ethics Committee and Medicines and Healthcare Products Regulatory Agency have approved the study. Trial registration National Institute of Health Research Clinical Research Network (NIHR CRN) Portfolio ID 11112 and ClinicalTrials.gov Identifier “type”:”clinical-trial”,”attrs”:”text”:”NCT02315001″,”term_id”:”NCT02315001″NCT02315001. strong class=”kwd-title” Keywords: Glucagon-like peptide-1 receptor agonist, Incretin hormone, Liraglutide, Chronic stable angina, (R)-ADX-47273 Exercise-induced ischaemia, Type 2 diabetes mellitus Background The incretin concept was borne from the observation that an oral load of glucose can provoke a two to three times more potent insulinotropic stimulus than an isoglycaemic intravenous glucose infusion [1,2]. This effect has been attributed to the action of incretin (INtestinal seCRETion of INsulin) hormones, which constitute part of the glucagon superfamily. Glucose-dependent insulinotropic polypeptide (GIP), a 42-amino acid peptide made by duodenal and jejunal enteroendocrine K cells in the proximal small bowel, was the first incretin hormone to be isolated from purified porcine intestinal extracts [3]. More than a decade later, glucagon-like peptide-1 (GLP-1) was identified, a 30-amino acid cleavage product of proglucagon, synthesised predominantly by the enteroendocrine L cells of the distal ileum and colon [4,5]. Despite their site of production, plasma levels of GIP and GLP-1 rise within minutes of enteral nutrition, indicating a combined neural and endocrine signalling axis prompting their secretion [6]. Together, GIP and GLP-1 are fundamental to maintaining normal glucose homeostasis in man. They contribute almost equally to, and have an additive effect on, enhancing glucose-dependent insulin exocytosis after meal ingestion, although GLP-1-mediated effects appear to predominate at higher glucose levels [7]. There is a defective incretin effect in Type 2 diabetes mellitus (T2DM) [8]. Levels of GIP can increase after enteral nutrition but the ability to potentiate postprandial insulin secretion is significantly impaired [9,10]. In contrast, meal-stimulated levels of GLP-1 are severely depressed. A continuous infusion of exogenous GLP-1 can, however, result in a near normal insulin-mediated response to an oral glucose load, suggesting preservation of insulinotropic activity [11-14]. Furthermore the risk of hypoglycaemia with GLP-1 is minimal, as both its stimulatory effect on insulin secretion and its inhibitory action on glucagon release switch off when ambient glucose levels are 4?mmol/L [5,14,15]. Despite these properties, the pharmaco-therapeutic utility of native GLP-1 in T2DM is profoundly limited by its rapid inactivation by the enzyme dipeptidyl dipeptidase-4 (DPP-4), which cleaves 2 amino terminal peptides from GLP-1(7-36) to form the GLP-1(9-36) metabolite [5]. GLP-1 has a half-life of 2?minutes which means only 10-20% of total plasma GLP-1 is biologically active [16]. Novel treatment strategies for T2DM, based on the incretin effect, have been developed to overcome this endogenous cul-de-sac. Subcutaneously injectable.Patients will be asked to store these in a refrigerator and to dispose of their used syringes in a sharps bin. ischaemia in patients with chronic stable angina managed conservatively or awaiting revascularisation. The hypothesis being liraglutide, a subcutaneously injectable glucagon-like peptide-1 receptor agonist, is able to improve exercise haemodynamics in patients with obstructive coronary artery disease when compared with saline placebo. Methods and design The Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) trial is an investigator-initiated single-centre randomised double-blinded placebo-controlled crossover proof-of-principle physiological study. Primary endpoints are change in rate pressure product at 0.1?mV ST-segment depression and change in degree of ST-segment depression at peak exercise during sequential exercise tolerance testing performed over a 6-week study period in which 26 patients will be randomised to either liraglutide or saline with crossover to the opposing regimen at week 3. Discussion The study will be conducted in accordance with the concepts of Great Clinical Practice as well as the Declaration of Helsinki. The neighborhood Study Ethics Committee and Medications and Healthcare Items Regulatory Agency possess approved the analysis. Trial registration Country wide Institute of Wellness Research Clinical Study Network (NIHR CRN) Collection Identification 11112 and ClinicalTrials.gov Identifier “type”:”clinical-trial”,”attrs”:”text”:”NCT02315001″,”term_id”:”NCT02315001″NCT02315001. strong course=”kwd-title” Keywords: Glucagon-like peptide-1 receptor agonist, Incretin hormone, Liraglutide, Chronic steady angina, Exercise-induced ischaemia, Type 2 diabetes mellitus Background The incretin concept was borne through the observation an dental load of blood sugar can provoke a 2-3 times stronger insulinotropic stimulus than an isoglycaemic intravenous blood sugar infusion [1,2]. This impact has been related to the actions of incretin (INtestinal seCRETion of INsulin) human hormones, which constitute area of the glucagon superfamily. Glucose-dependent insulinotropic polypeptide (GIP), a 42-amino acidity peptide created by duodenal and jejunal enteroendocrine K cells in the proximal little colon, was the 1st incretin hormone to become isolated from purified porcine intestinal components [3]. Greater than a 10 years later on, glucagon-like peptide-1 (GLP-1) was determined, a 30-amino acidity cleavage item of proglucagon, synthesised mainly from the enteroendocrine L cells from the distal ileum and digestive tract [4,5]. Despite their site of creation, plasma degrees of GIP and GLP-1 rise within a few minutes of enteral nourishment, indicating a mixed neural and endocrine signalling axis prompting their secretion [6]. Collectively, GIP and GLP-1 are key to maintaining regular blood sugar homeostasis in guy. They contribute nearly equally to, and also have an additive influence on, improving glucose-dependent insulin exocytosis after food ingestion, although GLP-1-mediated results may actually predominate at higher sugar levels [7]. There’s a faulty incretin impact in Type 2 diabetes mellitus (T2DM) [8]. Degrees of GIP can boost after enteral nourishment however the capability to potentiate postprandial insulin secretion can be considerably impaired [9,10]. On the other hand, meal-stimulated degrees of GLP-1 are seriously frustrated. A continuing infusion of exogenous GLP-1 can, nevertheless, create a near regular insulin-mediated response for an dental glucose load, recommending preservation of insulinotropic activity [11-14]. Furthermore the chance of hypoglycaemia with GLP-1 can be minimal, as both its stimulatory influence on insulin secretion and its own inhibitory actions on glucagon launch pull the plug on when ambient sugar levels are 4?mmol/L [5,14,15]. Despite these properties, the pharmaco-therapeutic energy of indigenous GLP-1 in T2DM can be profoundly tied to its fast inactivation from the enzyme dipeptidyl dipeptidase-4 (DPP-4), which cleaves 2 amino terminal peptides from GLP-1(7-36) to create the GLP-1(9-36) metabolite [5]. GLP-1 includes a half-life of 2?mins this means only 10-20% of total plasma GLP-1 is biologically dynamic [16]. Book treatment approaches for T2DM, predicated on the incretin impact, have been created to conquer this endogenous cul-de-sac. Subcutaneously injectable GLP-1 receptor (GLP-1R) agonists (DPP-4 mediated degradation-resistant peptides with improved pharmacokinetics that work via the human being GLP-1R) and dental DPP-4 inhibitors (little molecules with medically useful dental bioavailability that shield the endogenous peptide from DPP-4 rate of metabolism and therefore enhance its innate insulinotropic activity) are actually licensed and also have become area of the regular of look after the administration of T2DM [17-19]. Essentially GLP-1R agonists offer pharmacologic degrees of a GLP-1R stimulus whereas DPP-4 inhibitors protect physiologic degrees of endogenous GLP-1 [6]. The GLP-1R can be a heptahelical G-protein combined receptor within many extra-pancreatic cells mattresses broadly, including lung, kidney, central, peripheral and enteric anxious systems, lymphocytes, smooth muscle tissue cells and atrial cardiomyocytes [20-23]. It really is this expression from the GLP-1R in the myocardium, and the entire ubiquity from the receptor, which has fuelled developing fascination with the immediate and indirect cardiovascular (CV) ramifications of.Medications that require to become withheld will end up being identified as of this check out and withdrawn cautiously (see Desk?7). to increase this developing body of proof by studying the result of chronic glucagon-like peptide-1 receptor activation on exercise-induced ischaemia in individuals with chronic steady angina handled conservatively or awaiting revascularisation. The hypothesis becoming liraglutide, a subcutaneously injectable glucagon-like peptide-1 receptor agonist, can improve workout haemodynamics in individuals with obstructive coronary artery disease in comparison to saline placebo. Strategies and style The Liraglutide to boost corONary haemodynamics during Workout Plat tension (LIONESS) trial can be an investigator-initiated single-centre randomised double-blinded placebo-controlled crossover proof-of-principle physiological research. Major endpoints are modification in price pressure item at 0.1?mV ST-segment melancholy and modification in amount of ST-segment melancholy at peak workout during sequential workout tolerance tests performed more than a 6-week research period where 26 individuals will become randomised to either liraglutide or saline with crossover towards the opposing routine in week 3. Dialogue The analysis will be carried out relative to the concepts of Great Clinical Practice as well as the Declaration of Helsinki. The neighborhood Study Ethics Committee and Medications and Healthcare Items Regulatory Agency possess approved the analysis. Trial registration Country wide Institute of Wellness Research Clinical Analysis Network (NIHR CRN) Stock portfolio Identification 11112 and ClinicalTrials.gov Identifier “type”:”clinical-trial”,”attrs”:”text”:”NCT02315001″,”term_id”:”NCT02315001″NCT02315001. strong course=”kwd-title” Keywords: Glucagon-like peptide-1 receptor agonist, Incretin hormone, Liraglutide, Chronic steady angina, Exercise-induced ischaemia, Type 2 diabetes mellitus Background The incretin concept was borne in the observation an dental load of blood sugar can provoke a 2-3 times stronger insulinotropic stimulus than an isoglycaemic intravenous blood sugar infusion [1,2]. This impact has been related to the actions of incretin (INtestinal seCRETion of INsulin) human hormones, which constitute area of the glucagon superfamily. Glucose-dependent insulinotropic polypeptide (GIP), a 42-amino acidity peptide created by duodenal and jejunal enteroendocrine K cells in the proximal little colon, was the initial incretin hormone to become isolated from purified porcine intestinal ingredients [3]. Greater than a 10 years afterwards, glucagon-like peptide-1 (GLP-1) was discovered, a 30-amino acidity cleavage item of proglucagon, synthesised mostly with the enteroendocrine L cells from the distal ileum and digestive tract [4,5]. Despite their site of creation, plasma degrees of GIP and GLP-1 rise within a few minutes of enteral diet, indicating a mixed neural and endocrine signalling axis prompting their secretion [6]. Jointly, GIP and GLP-1 are key to maintaining regular blood sugar homeostasis in guy. They contribute nearly equally to, and also have an additive influence on, improving glucose-dependent insulin exocytosis after food ingestion, although GLP-1-mediated results may actually predominate at higher sugar levels [7]. There’s a faulty incretin impact in Type 2 diabetes mellitus (T2DM) [8]. Degrees of GIP can boost after enteral diet however the capability to potentiate postprandial insulin secretion is normally considerably impaired [9,10]. On the other hand, meal-stimulated degrees of GLP-1 are significantly despondent. A continuing infusion of exogenous GLP-1 can, nevertheless, create a near regular insulin-mediated response for an dental glucose load, recommending preservation of insulinotropic activity [11-14]. Furthermore the chance of hypoglycaemia with GLP-1 is normally minimal, as both its stimulatory influence on insulin secretion and its own inhibitory actions on glucagon discharge turn off when ambient sugar levels are 4?mmol/L [5,14,15]. Despite these properties, the pharmaco-therapeutic tool of indigenous GLP-1 in T2DM is normally profoundly tied to its speedy inactivation with the enzyme dipeptidyl dipeptidase-4 (DPP-4), which cleaves 2 amino terminal peptides from GLP-1(7-36) to create the GLP-1(9-36) metabolite [5]. GLP-1 includes a half-life of 2?a few minutes this means only 10-20% of total plasma GLP-1 is biologically dynamic [16]. Book treatment approaches for T2DM, predicated on the incretin impact, have been created to get over this endogenous cul-de-sac. Subcutaneously injectable GLP-1 receptor (GLP-1R) agonists (DPP-4 mediated degradation-resistant peptides with improved pharmacokinetics that action via the individual GLP-1R) and dental DPP-4.Sufferers can end up being randomised to enter a GLP-1 treatment matched-volume or arm saline placebo arm. Methods and style The Liraglutide to boost corONary haemodynamics during Workout tension (LIONESS) trial can be an investigator-initiated single-centre randomised double-blinded placebo-controlled crossover proof-of-principle physiological research. Principal endpoints are transformation in price pressure item at 0.1?mV ST-segment unhappiness and transformation in amount of ST-segment unhappiness at peak workout during sequential workout tolerance assessment performed more than a 6-week research period where 26 sufferers will end up being randomised to either liraglutide or saline with crossover towards the opposing program in week 3. Debate The analysis will be executed relative to the concepts of Great Clinical Practice as well as the Declaration of Helsinki. The neighborhood Analysis Ethics Committee and Medications and Healthcare Items Regulatory Agency have got approved the analysis. Trial registration Country wide Institute of (R)-ADX-47273 Wellness Research Clinical Analysis Network (NIHR CRN) Stock portfolio Identification 11112 and ClinicalTrials.gov Identifier “type”:”clinical-trial”,”attrs”:”text”:”NCT02315001″,”term_id”:”NCT02315001″NCT02315001. strong course=”kwd-title” Keywords: Glucagon-like peptide-1 receptor agonist, Incretin hormone, Liraglutide, Chronic steady angina, Exercise-induced ischaemia, Type 2 diabetes mellitus Background The incretin concept was borne in the observation an dental load of blood sugar can provoke a 2-3 times stronger insulinotropic stimulus than an (R)-ADX-47273 isoglycaemic intravenous blood sugar infusion [1,2]. This impact has been related to the actions of incretin (INtestinal seCRETion of INsulin) human hormones, which constitute area of the glucagon superfamily. Glucose-dependent insulinotropic polypeptide (GIP), a 42-amino acidity peptide created by duodenal and jejunal enteroendocrine K cells in the proximal little colon, was the initial incretin hormone to become isolated from purified porcine intestinal ingredients [3]. Greater than a 10 years afterwards, glucagon-like peptide-1 (GLP-1) was determined, a 30-amino acidity cleavage item of proglucagon, synthesised mostly with the enteroendocrine L cells from the distal ileum and digestive tract [4,5]. Despite their site of creation, plasma degrees of GIP and GLP-1 rise within a few minutes of enteral diet, indicating a mixed neural and endocrine signalling axis prompting their secretion [6]. Jointly, GIP and GLP-1 are key to maintaining regular blood sugar homeostasis in guy. They contribute nearly equally to, and also have an additive influence on, improving glucose-dependent insulin exocytosis after food ingestion, although GLP-1-mediated results may actually predominate at higher sugar levels [7]. There’s a faulty incretin impact in Type 2 diabetes mellitus (T2DM) [8]. Degrees of GIP can boost after enteral diet however the capability to potentiate postprandial insulin secretion is certainly considerably impaired [9,10]. On the other hand, meal-stimulated degrees of GLP-1 are significantly frustrated. A continuing infusion of exogenous GLP-1 can, nevertheless, create a near regular insulin-mediated response for an dental glucose load, recommending preservation of insulinotropic activity [11-14]. Furthermore the chance of hypoglycaemia with GLP-1 is certainly minimal, as both its stimulatory influence on insulin secretion and its own inhibitory actions on glucagon discharge turn off when ambient sugar levels are 4?mmol/L [5,14,15]. Despite these properties, the pharmaco-therapeutic electricity of indigenous GLP-1 in T2DM is certainly profoundly tied to its fast inactivation with the enzyme dipeptidyl dipeptidase-4 (DPP-4), which cleaves 2 amino terminal peptides from GLP-1(7-36) to create the GLP-1(9-36) metabolite [5]. GLP-1 includes a half-life of 2?mins this means only 10-20% of total plasma GLP-1 is biologically dynamic [16]. Book treatment approaches for T2DM, predicated on the incretin impact, have been created to get over this endogenous cul-de-sac. Subcutaneously injectable GLP-1 receptor (GLP-1R) agonists (DPP-4 mediated degradation-resistant peptides with improved pharmacokinetics that work via the individual GLP-1R) and dental DPP-4 inhibitors (little molecules with medically useful dental bioavailability that shield the endogenous peptide from DPP-4 fat burning capacity and thus enhance its innate insulinotropic activity) are actually licensed and also have become area of the regular of look after the administration of T2DM [17-19]. Essentially GLP-1R agonists offer pharmacologic degrees of a GLP-1R stimulus whereas DPP-4 inhibitors protect physiologic degrees of endogenous GLP-1 [6]. The GLP-1R is certainly a heptahelical G-protein combined receptor found broadly in a number of extra-pancreatic tissue bedrooms, including lung, kidney, central, enteric and peripheral anxious systems, lymphocytes, simple muscle tissue cells and atrial cardiomyocytes [20-23]. It really is this expression from the GLP-1R in the myocardium, and the entire ubiquity from the receptor, which has fuelled developing fascination with the immediate and indirect cardiovascular (CV).