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GLP-1 Analogues

Rui-Fang Wang, Guo-Fang Xue, Christian Hölscher, Miao-Jing Tian, Peng Feng, Ji-Ying Zheng, Dong-Fang Li
Glucagon-like peptide-1(GLP-1) is a growth factor that has neuroprotective and anti-inflammatory properties. The protease resistant GLP-1 analogue liraglutide has been shown to be neuroprotective in previous studies in animal models of Alzheimer's disease or Parkinson's disease. Status epilepticus (SE) is a complex disorder, involving many underlying pathological processes, including excitotoxic and chronic inflammatory events. The present pilot study aims to investigate whether liraglutide alleviates the chronic inflammation response and mitochondrial stress induced by SE in the lithium-pilocarpine animal model...
March 9, 2018: Epilepsy Research
Martin M Grajower
Hypoglycemia is the major side effect of insulin therapy. The elderly are especially vulnerable to episodes of hypoglycemia, and with greater risks of complications such as falls. Two new long-acting basal insulins, glargine-300 (Gla-300) and degludec, are associated with lower incidences of hypoglycemia than previously available basal insulins. One of them, Gla-300, was studied in the elderly and has a lower incidence of hypoglycemia in patients over 65 years old. These new data should be incorporated into decision making when treating the elderly patient with insulin, whether they have type 1 or 2 diabetes...
March 2018: Endocrine Practice
Pernille Wismann, Søren L Pedersen, Gitte Hansen, Karin Mannerstedt, Philip J Pedersen, Palle B Jeppesen, Niels Vrang, Keld Fosgerau, Jacob Jelsing
AIM: Analogues of several gastrointestinal peptide hormones have been developed into effective medicines for treatment of diseases such as type 2 diabetes mellitus (T2DM), obesity and short bowel syndrome (SBS). In this study, we aimed to explore whether the combination of glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) into a potent co-agonist could provide additional benefits compared to existing monotherapies. METHODS: A short-acting (GUB09-123) and a half-life extended (GUB09-145) GLP-1/GLP-2 co-agonist were generated using solid-phase peptide synthesis and tested for effects on food intake, body weight, glucose homeostasis, and gut proliferation in lean mice and in diabetic db/db mice...
March 11, 2018: Physiology & Behavior
Katerina Kapodistria, Effie-Photini Tsilibary, Eleni Kotsopoulou, Petros Moustardas, Paraskevi Kitsiou
Liraglutide, a human long-lasting GLP-1 analogue, is currently regarded as a powerful treatment option for type 2 diabetes. Apart from glucoregulatory and insulinotropic actions, liraglutide increases β-cell mass through stimulation of β-cell proliferation and islet neogenesis, as well as inhibition of β-cell apoptosis. However, the underline molecular mechanisms have not been fully characterized. In this study, we investigated the mechanism by which liraglutide preserves islet β-cells in an animal model of overt diabetes, the obese db/db mice, and protects a mouse pancreatic β-cell line (βTC-6 cells) against apoptosis...
March 10, 2018: Journal of Cellular and Molecular Medicine
A H Heald, A A Fryer, S G Anderson, M Livingston, M Lunt, M Davies, Gyc Moreno, R Gadsby, R J Young, M Stedman
AIMS: Despite increasing spend on new Type 2 diabetes mellitus (T2DM) therapies, the proportion of people with T2DM achieving target glycaemia outcomes is declining. Our aim was to determine, using published General Practice level data, how differences in T2DM prescribing patterns relate to glycaemic target achievement levels. METHODS: Multiple linear regression modelling was used to link practice characteristics and defined daily dose (DDD) of class of medication in 2015/16 and changes to 2014/15 in medication to proportions achieving target glycaemic control (TGC; glycated haemoglobin A1c (HbA1c) ≤7...
March 8, 2018: Diabetes, Obesity & Metabolism
Bahendeka Silver, Kaushik Ramaiya, Swai Babu Andrew, Otieno Fredrick, Sarita Bajaj, Sanjay Kalra, Bavuma M Charlotte, Karigire Claudine, Anthony Makhoba
A diagnosis of diabetes or hyperglycemia should be confirmed prior to ordering, dispensing, or administering insulin (A). Insulin is the primary treatment in all patients with type 1 diabetes mellitus (T1DM) (A). Typically, patients with T1DM will require initiation with multiple daily injections at the time of diagnosis. This is usually short-acting insulin or rapid-acting insulin analogue given 0 to 15 min before meals together with one or more daily separate injections of intermediate or long-acting insulin...
March 5, 2018: Diabetes Therapy: Research, Treatment and Education of Diabetes and related Disorders
Gitanjali Srivastava, Caroline Apovian
PURPOSE OF REVIEW: Obesity is a global health crisis with detrimental effects on all organ systems leading to worsening disease state and rising costs of care. Persons with obesity failing lifestyle therapies need to be escalated to appropriate pharmacological treatment modalities, medical devices, and/or bariatric surgery if criteria are met and more aggressive intervention is needed. The progression of severe obesity in the patient population coupled with related co-morbidities necessitates the development of novel therapies for the treatment of obesity...
March 5, 2018: Current Obesity Reports
Lukas O Dialer, Andreas Jodal, Roger Schibli, Simon M Ametamey, Martin Béhé
Background: Analogues of exendin-4 have been radiolabeled for imaging the glucagon-like peptide type 1 receptors (GLP-1R) which are overexpressed in insulinoma. The aim of this research was to synthesize an18 F-labeled silicon containing exendin-4 peptide (18 F- 2 ) and to evaluate its in vitro and in vivo behavior in CHL-GLP-1 receptor positive tumor-bearing mice.18 F-labeled silicon containing exendin-4 peptide (18 F- 2 ) was prepared via one-step nucleophilic substitution of a silane precursor with18 F-fluoride in the presence of acetic acid and K222...
2018: EJNMMI Radiopharm Chem
Zekrayat J H Medras, Norhan M El-Sayed, Sawsan A Zaitone, Eman A Toraih, Manal M Sami, Yasser M Moustafa
BACKGROUND: Glutamine aminoacid regulates insulin exocytosis from pancreatic β-cells. Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has fascinated function in inhibiting β-cell apoptosis and preserving pancreatic β-cell mass. The present study investigated the benefit of adding glutamine to a regimen of liraglutide in diabetic rats focusing on their role in increasing insulin production and upregulation of the expression of sodium-dependent neutral aminoacid transporter-2 (SNAT2)...
October 25, 2017: Pharmacological Reports: PR
Peng Feng, Xiangjian Zhang, Dongfang Li, Chenhui Ji, Ziyue Yuan, Ruifang Wang, Guofang Xue, Guanglai Li, Christian Hölscher
Type 2 diabetes mellitus (T2DM) is a risk factors for developing Parkinson's disease (PD). Insulin desensitization is observed in the brains of PD patients, which may be an underlying mechanism that promotes neurodegeneration. Incretin hormones are growth factors that can re-sensitize insulin signalling. We have previously shown that analogues of the incretins GLP-1 or GIP have neuroprotective effects in the MPTP mouse model of PD. Novel dual GLP-1/GIP receptor agonists have been developed as treatments for T2DM...
February 17, 2018: Neuropharmacology
O M Abdelwahed, O M Tork, M M Gamal El Din, L Rashed, M Zickri
BACKGROUND: Brain derived neurotrophic factor (BDNF) is one of the most essential neurotrophic factors in the brain. BDNF is involved in learning, memory and locomotion suggesting it as a target in type 2 diabetes mellitus (T2DM) associated cognitive changes. Visfatin; an adipokine discovered to be expressed in the brain; was found to have multiple effects including its participation in keeping energy supply to the cell and is consequentially involved in cell survival. Its role in cognitive functions in T2DM was not studied before...
February 5, 2018: Brain Research Bulletin
Enrique Gallego-Colon, Agnieszka Klych-Ratuszny, Agnieszka Kosowska, Wojciech Garczorz, Mohammad Reza F Aghdam, Michal Wozniak, Tomasz Francuz
BACKGROUND: Incretin analogue drugs, a FDA-approved treatment in diabetes, has been tested for its therapeutic properties as modulators of atherosclerosis. We investigated the effects of incretin drugs on the modulation of gene expression and protein levels of matrix metalloproteinases (MMPs) as well as their inhibitors - tissue inhibitors of metalloproteinases (TIMPs) in coronary artery smooth muscle cells (hCASMC) in the context of atherosclerotic plaque formation and inflammation. METHODS: TNFα-stimulated hCASMC were treated with Glucagon-like Peptide 1 (GLP-1) (10 nM and 100 nM) and Exendin-4 (1 nM and 10 nM)...
October 4, 2017: Pharmacological Reports: PR
Ben Jones, Stephen R Bloom, Teresa Buenaventura, Alejandra Tomas, Guy A Rutter
Stimulation of insulin secretion by glucagon-like peptide-1 (GLP-1) and other gut-derived peptides is central to the incretin response to ingesting nutriments. Analogues of GLP-1, and inhibitors of its breakdown, have found widespread clinical use for the treatment of type 2 diabetes (T2D) and obesity. The release of these peptides underlies the improvements in glycaemic control and disease remission after bariatric surgery. Given therapeutically, GLP-1 analogues can lead to side effects including nausea, which limit dosage...
February 2018: Peptides
Varun Pathak, Peter R Flatt, Nigel Irwin
Cholecystokinin (CCK) is a hormone secreted from I-cells of the gut, as well as neurons in the enteric and central nervous system, that binds and activates CCK-1 and CCK-2 receptors to mediate its biological actions. To date knowledge relating to the physiological significance of CCK has predominantly focused around induction of short-term satiety. However, CCK has also been highlighted to possess important actions in relation to the regulation of insulin secretion, as well as overall beta-cell function and survival...
February 2018: Peptides
F P M O'Harte, V Parthsarathy, C Hogg, P R Flatt
Nine structurally modified apelin-13 analogues were assessed for their in vitro and acute in vivo antidiabetic potential. Stability was assessed in mouse plasma and insulinotropic efficacy tested in cultured pancreatic BRIN-BD11 cells and isolated mouse pancreatic islets. Intracellular Ca2+ and cAMP production in BRIN-BD11 cells was determined, as was glucose uptake in 3T3-L1 adipocytes. Acute antihyperglycemic effects of apelin analogues were assessed following i.p. glucose tolerance tests (ipGGT, 18 mmol/kg) in normal and diet-induced-obese (DIO) mice and on food intake in normal mice...
February 2018: Peptides
Jordan Rowlands, Vinicius Cruzat, Rodrigo Carlessi, Philip Newsholme
Pharmacological long lasting Glucagon-like peptide-1 (GLP-1) analogues, such as Exendin-4, have become widely used diabetes therapies. Chronic GLP-1R stimulation has been linked to β-cell protection and these pro-survival actions of GLP-1 are dependent on the activation of the mammalian target of rapamycin (mTOR) leading to accumulation of Hypoxia inducible factor 1 alpha (HIF-1α). Recent studies from our lab indicate that prolonged GLP-1R stimulation promotes metabolic reprograming of β-cells towards a highly glycolytic phenotype and activation of the mTOR/HIF-1α pathway was required for this action...
February 2018: Peptides
Murad H Kheder, Simon R Bailey, Kevin J Dudley, Martin N Sillence, Melody A de Laat
Background: Equine metabolic syndrome (EMS) is associated with insulin dysregulation, which often manifests as post-prandial hyperinsulinemia. Circulating concentrations of the incretin hormone, glucagon-like peptide-1 (GLP-1) correlate with an increased insulin response to carbohydrate intake in animals with EMS. However, little is known about the equine GLP-1 receptor (eGLP-1R), or whether GLP-1 concentrations can be manipulated. The objectives were to determine (1) the tissue localisation of the eGLP-1R, (2) the GLP-1 secretory capacity of equine intestine in response to glucose and (3) whether GLP-1 stimulated insulin secretion from isolated pancreatic islets can be attenuated...
2018: PeerJ
Christian Hölscher
Type 2 diabetes is a risk factor for several chronic neurodegenerative disorders such as Alzheimer's or Parkinson's disease. The link appears to be insulin de-sensitisation in the brain. Insulin is an important neuroprotective growth factor. GLP-1 and GIP are growth factors that re-sensitise insulin and GLP-1 mimetics are used in the clinic to treat diabetes. GLP-1 and GIP mimetics initially designed to treat diabetes show good protective effects in animal models of Alzheimer's and Parkinson's disease. Based on these results, several clinical trials have shown first encouraging effects in patients with Alzheimer's or Parkinson' disease...
January 31, 2018: Neuropharmacology
Sohita Dhillon
Novo Nordisk has developed a subcutaneous formulation of semaglutide (Ozempic® ), a modified human glucagon-like peptide-1 (GLP-1) analogue, for the treatment of type 2 diabetes mellitus. It has been developed using Novo Nordisk's proprietary protein-acylation technology, and is administered using an injection device. Semaglutide lowers blood glucose by stimulating the release of insulin and also lowers body weight. Once-weekly subcutaneous semaglutide has recently been approved in the US, Puerto Rico and Canada, and has received a positive opinion in the EU for the treatment of patients with type 2 diabetes...
February 2018: Drugs
Caroline Giezenaar, Yonta van der Burgh, Kylie Lange, Seva Hatzinikolas, Trygve Hausken, Karen L Jones, Michael Horowitz, Ian Chapman, Stijn Soenen
Protein-rich supplements are used widely for the management of malnutrition in the elderly. We reported previously that the suppression of energy intake by whey protein is less in older than younger adults. The aim was to determine the effects of substitution, and adding of carbohydrate and fat to whey protein, on ad libitum energy intake from a buffet meal (180-210 min), gastric emptying (3D-ultrasonography), plasma gut hormone concentrations (0-180 min) and appetite (visual analogue scales), in healthy older men...
January 23, 2018: Nutrients
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