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GLP-1 diabetes obesity

Daniela Guarino, Diego Moriconi, Andrea Mari, Eleni Rebelos, Daria Colligiani, Simona Baldi, Marco Anselmino, Ele Ferrannini, Monica Nannipieri
AIMS/HYPOTHESIS: Postprandial hypoglycaemia (PPHG) is a complication of Roux-en-Y gastric bypass (RYGB) surgery in normoglycaemic individuals. In type 2 diabetes, RYGB improves glucose metabolism, but whether this improvement is related to the later development of PPHG is not known. We investigated the presence and mechanisms of PPHG in individuals with type 2 diabetes undergoing RYGB. METHODS: A total of 35 obese individuals with type 2 diabetes underwent an OGTT before and 24 months after surgery...
October 12, 2018: Diabetologia
Brandon B Boland, Charles Brown, Michelle L Boland, Jennifer Cann, Michael Sulikowski, Gitte Hansen, Rikke V Grønlund, Wanda King, Cristina Rondinone, James Trevaskis, Christopher J Rhodes, Joseph S Grimsby
The onset of common obesity-linked type 2 diabetes (T2D) is marked by exhaustive failure of pancreatic β-cell functional mass to compensate for insulin resistance and increased metabolic demand, leading to uncontrolled hyperglycemia. Here, the β-cell deficient obese hyperglycemic/hyperinsulinemic KS db/db mouse model was used to assess consequential effects on β-cell functional recovery by lowering glucose homeostasis and/or improving insulin sensitivity following treatment with thiazolidinedione (TZD) therapy or glucagon-like-peptide-1 receptor (GLP-1R) agonism alone, or in combination with sodium/glucose cotransporter-2 inhibition (SGLT-2i)...
October 10, 2018: Diabetes
Khyati Girdhar, Budheswar Dehury, Mahender Kumar Singh, Vineeth P Daniel, Abhinav Choubey, Surbhi Dogra, Sunil Kumar, Prosenjit Mondal
The glucagon-like peptide-1 receptor (GLP-1R) is a well-known target of therapeutics industries for the treatment of various metabolic diseases like Type2 Diabetes and Obesity. The structural-functional relationships of small molecule agonists and GLP-1R are yet to be understood. Therefore, an attempt was made on structurally known GLP-1R agonists (Compound 1, Compound 2, Compound A, Compound B, and (S)-8) to study their interaction with the extracellular domain of GLP-1R. In this study, we explored the dynamics, intrinsic stability and binding mechanisms of these molecules through computational modeling, docking, molecular dynamics (MD) simulations and MM/PBSA binding free energy estimation...
October 8, 2018: Journal of Biomolecular Structure & Dynamics
Melanie J Davies, David A D'Alessio, Judith Fradkin, Walter N Kernan, Chantal Mathieu, Geltrude Mingrone, Peter Rossing, Apostolos Tsapas, Deborah J Wexler, John B Buse
The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the prior position statements, published in 2012 and 2015, on the management of type 2 diabetes in adults. A systematic evaluation of the literature since 2014 informed new recommendations. These include additional focus on lifestyle management and diabetes self-management education and support. For those with obesity, efforts targeting weight loss, including lifestyle, medication, and surgical interventions, are recommended...
October 4, 2018: Diabetes Care
Melanie J Davies, David A D'Alessio, Judith Fradkin, Walter N Kernan, Chantal Mathieu, Geltrude Mingrone, Peter Rossing, Apostolos Tsapas, Deborah J Wexler, John B Buse
The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the prior position statements, published in 2012 and 2015, on the management of type 2 diabetes in adults. A systematic evaluation of the literature since 2014 informed new recommendations. These include additional focus on lifestyle management and diabetes self-management education and support. For those with obesity, efforts targeting weight loss, including lifestyle, medication and surgical interventions, are recommended...
October 5, 2018: Diabetologia
Yongning Sun, Chenxi Jin, Xiaoying Zhang, Weiping Jia, Jiamei Le, Jianping Ye
OBJECTIVE: L-cell dysfunction is reported for GLP-1 reduction in type 2 diabetes. However, the mechanism of dysfunction remains unknown. In this study, we examined mitochondrial function in the mechanistic study in diet-induced obese (DIO) mice. SUBJECTS: C57BL/6 mice were fed a high-fat diet (HFD) for 16 weeks to establish the DIO model for GLP-1 reduction. The mice were then treated with berberine (BBR) (100 mg/kg/day) for 8 weeks to test the impact on GLP-1 expression...
September 24, 2018: Nutrition & Diabetes
Sara J Brandt, Timo D Müller, Richard D DiMarchi, Matthias H Tschöp, Kerstin Stemmer
Obesity and its comorbidities, such as type 2 diabetes, are pressing worldwide health concerns. Available anti-obesity treatments include weight loss pharmacotherapies and bariatric surgery. While surgical interventions typically result in significant and sustained weight loss, available pharmacotherapies are far less effective, typically decreasing body weight by no more than 5 - 10%. An emerging class of multiagonist drugs may eventually bridge this gap. This new class of specially-tailored drugs hybridizes the amino acid sequences of key metabolic hormones into one single entity with enhanced potency and sustained action...
September 19, 2018: Journal of Internal Medicine
Yi-Chun Chen, Austin J Taylor, C Bruce Verchere
Biosynthesis of peptide hormones by pancreatic islet endocrine cells is a tightly orchestrated process that is critical for metabolic homeostasis. Like neuroendocrine peptides, insulin and other islet hormones are first synthesized as larger precursor molecules that are processed to their mature secreted products through a series of proteolytic cleavages, mediated by the prohormone convertases Pc1/3 and Pc2, and carboxypeptidase E. Additional posttranslational modifications including C-terminal amidation of the β-cell peptide islet amyloid polypeptide (IAPP) by peptidyl-glycine α-amidating monooxygenase (Pam) may also occur...
September 2018: Diabetes, Obesity & Metabolism
Ipek Acar, Alper Cetinkaya, Incilay Lay, Esin Ileri-Gurel
OBJECTIVES: The calcium-sensing receptor (CaSR), the major sensor of extracellular Ca2+ , is expressed in various tissues, including the gastrointestinal tract. Although the essential ligand of CaSR is calcium, its activity can be regulated by aromatic L-amino acids. The expression of CaSR on enteroendocrine cells suggests that CaSR functions as a physiological amino acid sensor for gut hormone release. Here, we investigated the effects of L-tryptophan (L-Trp) on rat glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and insulin secretion, and the role of CaSR in this mechanism in vivo...
September 17, 2018: Nutritional Neuroscience
Martin B Whyte, Fariba Shojaee-Moradie, Sharaf E Sharaf, Nicola C Jackson, Barbara Fielding, Roman Hovorka, Jeewaka Mendis, David Russell-Jones, A Margot Umpleby
Context: GLP-1 agonists control postprandial glucose and lipid excursion in type 2 diabetes; however the mechanism(s) are unclear. Objective: To determine the mechanism(s) of postprandial lipid and glucose control with lixisenatide (GLP-1 analogue) in type 2 diabetes. Design: Randomised, double-blind, cross-over study. Setting: Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, UK...
September 11, 2018: Journal of Clinical Endocrinology and Metabolism
Beata Matyjaszek-Matuszek, Aneta Szafraniec, Dominik Porada
Obesity, which affects about 13% of the world population, results in significant deterioration of health and serious clinical, mainly meta-bolic and cardiovascular complications. Although the basis of therapeutic treatment is behavioural treatment, often non-pharmacological effects do not produce the desired effect. Currently there are several drugs with a safe action profile that improve the effect of treatment (5-10% weight reduction). The aim of the paper is to present the potential of modern pharmacotherapy in the treatment of obesity, in terms of mechanism of action, efficacy, and side effects, in order to individualise therapy...
2018: Endokrynologia Polska
Junichi Namekawa, Sayaka Nemoto, Gaku Sunada, Yuki Takanashi, Sakurako Fujio, Mitsuyuki Shirai, Fumitoshi Asai
The incidence of metabolic syndrome is rapidly increasing worldwide, and adequate animal models are crucial for studies on its pathogenesis and therapy. In the search of an adequate experimental model to simulate human metabolic syndrome, the present study was performed to examine the pharmacological response of WBN/Kob-Leprfa (WBKDF) rats supplemented with a fructose-rich diet (FRD) to liraglutide, a GLP-1 receptor agonist. Male WBKDF rats fed FRD at 7 weeks of age were divided into 3 groups, and administered liraglutide (75, 300 μg/kg subcutaneously) or saline (control group), once daily for 4 weeks...
August 31, 2018: Journal of Veterinary Medical Science
Sri N Batchu, Karina Thieme, Farigol H Zadeh, Tamadher A Alghamdi, Veera Ganesh Yerra, Mitchell J Hadden, Syamantak Majumder, M Golam Kabir, Bridgit B Bowskill, Danyal Ladha, Anthony O Gramolini, Kim A Connelly, Andrew Advani
Blood glucose lowering therapies can positively or negatively affect heart function in Type 2 diabetes, or they can have neutral effects. Dipeptidyl peptidase-4 (DPP-4) inhibitors lower blood glucose by preventing the proteolytic inactivation of glucagon-like peptide-1 (GLP-1). However, GLP-1 is not the only peptide substrate of DPP-4. Here, we investigated the GLP-1 independent cardiac effects of DPP-4 substrates. Pointing to GLP-1 receptor (GLP-1R) independent actions, DPP-4 inhibition prevented systolic dysfunction equally in pressure overloaded wildtype and GLP-1R knockout mice...
August 27, 2018: Diabetes
Hidetaka Hamasaki
Recently, glucagon-like peptide-1 (GLP-1) receptor agonists have become a cornerstone for the treatment of obese patients with type 2 diabetes (T2D), exhibiting favorable effects on the cardiovascular outcome. In T2D, impaired GLP-1 secretion/function is observed, and gut microbiota dysbiosis is related to the GLP-1 resistance. Prior research has revealed that exercise increases GLP-1 levels in healthy and obese individuals; however, the efficacy of exercise on GLP-1 levels in patients with T2D remains unclear...
August 15, 2018: World Journal of Diabetes
Gian Paolo Fadini, Anna Solini, Maria Laura Manca, Giuseppe Penno, Adriano Gatti, Roberto Anichini, Stefano Del Prato, Angelo Avogaro
AIM: To evaluate the changes in renal endpoints in type 2 diabetes patients treated with dapagliflozin versus other glucose-lowering medications in routine clinical practice. MATERIALS AND METHODS: DARWIN-T2D was a retrospective study conducted at 46 outpatient diabetes clinics in Italy. An automated software collected data on 17 285 patients who received dapagliflozin, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, or gliclazide, 6751 of whom had a follow-up visit...
August 23, 2018: Diabetes, Obesity & Metabolism
Patrick M O'Neil, Andreas L Birkenfeld, Barbara McGowan, Ofri Mosenzon, Sue D Pedersen, Sean Wharton, Charlotte Giwercman Carson, Cecilie Heerdegen Jepsen, Maria Kabisch, John P H Wilding
BACKGROUND: Obesity is a major public health issue, and new pharmaceuticals for weight management are needed. Therefore, we evaluated the efficacy and safety of the glucagon-like peptide-1 (GLP-1) analogue semaglutide in comparison with liraglutide and a placebo in promoting weight loss. METHODS: We did a randomised, double-blind, placebo and active controlled, multicentre, dose-ranging, phase 2 trial. The study was done in eight countries involving 71 clinical sites...
August 25, 2018: Lancet
Abhinav Sharma, Andrew P Ambrosy, Adam D DeVore, Kenneth B Margulies, Steven E McNulty, Robert J Mentz, Adrian F Hernandez, Gary Michael Felker, Lauren B Cooper, Anuradha Lala, Justin Vader, John D Groake, Barry A Borlaug, Eric J Velazquez
AIMS: Obesity is present in up to 45% of patients with heart failure (HF). Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor antagonist, facilitates weight loss in obese patients. The efficacy of liraglutide as a weight loss agent among patients with HF and reduced ejection fraction (HFrEF) and a recent acute HF hospitalization remains unknown. METHODS AND RESULTS: The Functional Impact of GLP-1 for Heart Failure Treatment study randomized 300 patients with HFrEF (ejection fraction ≤ 40%), both with and without diabetes and a recent HF hospitalization to liraglutide or placebo...
August 17, 2018: ESC Heart Failure
Bernard P Kok, Andrea Galmozzi, Nicole K Littlejohn, Verena Albert, Cristina Godio, Woojoo Kim, Sean M Kim, Jeffrey S Bland, Neile Grayson, Mingliang Fang, Wolfgang Meyerhof, Gary Siuzdak, Supriya Srinivasan, Maik Behrens, Enrique Saez
OBJECTIVES: Extracts of the hops plant have been shown to reduce weight and insulin resistance in rodents and humans, but elucidation of the mechanisms responsible for these benefits has been hindered by the use of heterogeneous hops-derived mixtures. Because hop extracts are used as flavoring agents for their bitter properties, we hypothesized that bitter taste receptors (Tas2rs) could be mediating their beneficial effects in metabolic disease. Studies have shown that exposure of cultured enteroendocrine cells to bitter tastants can stimulate release of hormones, including glucagon-like peptide 1 (GLP-1)...
August 4, 2018: Molecular Metabolism
Xuejing Li, Suhui Qie, Xianying Wang, Yingying Zheng, Yang Liu, Guoqiang Liu
OBJECTIVES: To investigate the safety and efficacy of once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide as monotherapy or add-on to other antihyperglycaemic agents (AHAs) in patients with type 2 diabetes mellitus (T2DM). METHODS: PubMed, Embase, Cochrane library and were searched from the inception to January 18, 2018. Randomised controlled trials (RCTs) comparing semaglutide with placebo or other AHAs in T2DM patients were included in our meta-analysis...
August 12, 2018: Endocrine
Joachim Tillner, Maximilian G Posch, Frank Wagner, Lenore Teichert, Youssef Hijazi, Christine Einig, Stefanie Keil, Torsten Haack, Michael Wagner, Martin Bossart, Philip J Larsen
AIMS: To evaluate the safety, pharmacokinetics and pharmacodynamics of SAR425899, a novel polypeptide, active as an agonist at both the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCR), in healthy volunteers and in overweight/obese patients with type 2 diabetes (T2D). METHODS: Subcutaneous administrations of SAR425899 were tested in two randomized, placebo-controlled, double-blind clinical trials. In the first trial, healthy overweight volunteers (body mass index [BMI] 25-30 kg/m2 ; n = 32) received single-ascending doses (0...
August 8, 2018: Diabetes, Obesity & Metabolism
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