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Shakila Sabir, Ammara Saleem, Muhammad Furqan Akhtar, Muhammad Saleem, Moosa Raza
Finding a radical cure for diabetes has reached paramount importance in medicine due to the widespread prevalence of the disease. A substantial reduction in insulin-secreting beta cells is evident in diabetes. The failure of cyclin-dependent kinases (CDKs) and cyclins to access the nucleus is responsible for quiescence or senescence in human and rodent beta cells. The augmentation of beta cell proliferation is supposed to reverse diabetes. This concept has inspired the discovery of newer drugs that encourage the proliferation of beta cells...
June 18, 2018: Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University
Ying-Ying Cai, Shao-Zhou Zou, Cun-Xia Fan, Chun-Yan Wu, Shu Fang, Ping Li, Yao-Ming Xue, Mei-Ping Guan
OBJECTIVE: To investigate the protective effect of exendin-4 against diabetic cardiomyopathy in mice and explore the underlying mechanism. METHODS: C57BL/6J mice were randomly divided into normal control group with normal diet and diabetic group with high-fat diet for 4 weeks before streptozotocin injection. The successfully established diabetic mouse models were divided into diabetic group with exendin-4 treatment and diabetic control group for daily treatment with intraperitoneal injection of 1 nmol/kg exendin-4 and saline of equivalent volume for 8 weeks, respectively...
May 20, 2018: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
Andreas Evers, Martin Bossart, Stefania Pfeiffer-Marek, Ralf Elvert, Herman A Schreuder, Michael Kurz, Siegfried Stengelin, Martin Lorenz, Andreas Herling, Anish Ashok Konkar, Ulrike Lukasczyk, Anja Pfenninger, Katrin Lorenz, Torsten Haack, Dieter Kadereit, Michael Wagner
Novel peptidic dual agonists of the glucagon-like peptide 1 (GLP-1) and glucagon receptor are reported to have enhanced efficacy over pure GLP-1 receptor agonists with regard to treatment of obesity and diabetes. We describe novel exendin-4 based dual agonists designed with an activity ratio favoring the GLP-1 versus the glucagon receptor. As result of an iterative optimization procedure that included molecular modeling, structural biological studies (X-ray, NMR), peptide design & synthesis, experimental activity and solubility profiling, a candidate molecule was identified...
June 7, 2018: Journal of Medicinal Chemistry
Ashwin Singh Parihar, Shelvin Kumar Vadi, Rajender Kumar, Bhagwant Rai Mittal, Harmandeep Singh, Amanjit Bal, Rama Walia, Jaya Shukla, Saroj Kumar Sinha
Insulinomas are the most common functioning pancreatic neuroendocrine tumors and the leading cause of persistent hypoglycemia with hyperinsulinemia in adults. Glucagon-like-peptide-1 (GLP) receptor analogs are the latest agents being used in the detection of insulinomas, with initial reports suggesting high sensitivity due to universal GLP1 receptor expression on these tumors. PET/CT imaging in this patient using Ga DOTA-Exendin, a GLP receptor analog, proved useful for accurate localization of the culprit lesion, aiding in the definitive management of the patient...
June 5, 2018: Clinical Nuclear Medicine
Alberto Oddo, Sofia Mortensen, Henning Thøgersen, Leonardo De Maria, Stephanie Hennen, James McGuire, Jacob Kofoed, Lars Linderoth, Steffen Reedtz-Runge
Peptide agonists acting on the glucagon-like peptide 1 receptor (GLP-1R) promote glucose-dependent insulin release and therefore represent important therapeutic agents for Type 2 diabetes (T2D). Previous data indicated that an N-terminal type II beta-turn motif might be an important feature for agonists acting on GLP-1R. In contrast, recent publications reporting the structure of full-length GLP-1R have shown the N-terminus of receptor-bound agonists in an alpha-helical conformation. In order to reconcile these conflicting results we prepared N-terminally constrained analogs of glucagon-like peptide 1 (GLP-1) and exendin-4 and evaluated their receptor affinity and functionality in vitro; we then examined their crystal structures in complex with the ECD of GLP-1R and used molecular modeling and molecular dynamics simulations for further investigations...
June 7, 2018: Biochemistry
Andrej Babic, Laurent Vinet, Vineetha Chellakudam, Karolina Janikowska, Eric Allemann, Norbert Lange
Novel drug delivery systems targeting native, transplanted or cancerous beta-cells are of utmost importance. Herein, we present new exendin-4 derivatives with modified unnatural amino acids at strategic positions within the polypeptide sequence. The modified peptides allowed modular orthogonal chemical modifications to attach imaging agents and amphiphilic squalene-PEG groups. The resulting conjugates, SQ-PEG-ExC1-Cy5 and SQ-PEG-ExC40-Cy5 fluorescence probes display low nM affinity to GLP-1R in fluorescence-based binding assays with EC50 at 1...
June 5, 2018: Bioconjugate Chemistry
Rania G Abdel-Latif, Gehan H Heeba, Ashraf Taye, Mohamed M A Khalifa
Ischemic stroke is a major cause of neurological damage and brain dysfunction with consequent strong cerebral oxidative imbalance, inflammatory and apoptotic responses. Lixisenatide is a new potent glucagon-like peptide -1 (GLP-1) analogue that has been used clinically in the treatment of type II diabetes. Recent studies suggested the beneficial central effects of GLP-1-based therapies on different neurodegenerative diseases. This study aimed to investigate the ameliorative effect of lixisenatide in global cerebral ischemia-reperfusion (I/R) rat model and elaborate the underline mechanisms that could mediate the proposed activity...
June 1, 2018: European Journal of Pharmacology
Rasmus Hytting-Andreasen, Emilie Balk-Møller, Bolette Hartmann, Jens Pedersen, Johanne Agerlin Windeløv, Jens Juul Holst, Hannelouise Kissow
OBJECTIVE: Mucositis is a side effect of chemotherapy seen in the digestive tract, with symptoms including pain, diarrhoea, inflammation and ulcerations. Our aim was to investigate whether endogenous glucagon-like peptide -1 and -2 (GLP-1 and GLP-2) are implicated in intestinal healing after chemotherapy-induced mucositis. DESIGN: We used a transgenic mouse model Tg(GCG.DTR)(Tg) expressing the human diphtheria toxin receptor in the proglucagon-producing cells. Injections with diphtheria toxin ablated the GLP-1 and GLP-2 producing L-cells in Tg mice with no effect in wild-type (WT) mice...
2018: PloS One
Wei Yu, Wenliang Zha, Jun Ren
Mitochondrial injury and defective autophagy are common in diabetic cardiomyopathy. Recent evidence supports benefits of glucagon-like peptide-1 (GLP-1) agonists exendin-4 (Exe) and liraglutide (LIRA) against diabetic cardiomyopathy. This study was designed to examine the effect of Exe and LIRA on glucose-induced cardiomyocyte and mitochondrial injury, oxidative stress, apoptosis, and autophagy change. Cardiomyocytes isolated from adult mice and H9c2 myoblast cells were exposed to high glucose (HG, 33 mM) with or without Exe or LIRA...
2018: Oxidative Medicine and Cellular Longevity
Jean-Philippe Krieger, Ellen Paula Santos da Conceição, Graciela Sanchez-Watts, Myrtha Arnold, Klaus G Pettersen, Mazher Mohammed, Salvatore Modica, Pius Lossel, Shaun F Morrison, Christopher J Madden, Alan G Watts, Wolfgang Langhans, Shin J Lee
Endogenous intestinal glucagon-like peptide-1 (GLP-1) controls satiation and glucose metabolism via vagal afferent neurons (VAN). Recently, VAN have received increasing attention for their role in brown adipose tissue (BAT) thermogenesis. It is however unclear whether VAN GLP-1 receptor (GLP-1R) signaling affects BAT thermogenesis and energy expenditure (EE), and whether this VAN mechanism contributes to energy balance. First, we tested the effect of the GLP-1R agonist Exendin-4 (Ex4, 0.3 μg/kg IP) on EE and BAT thermogenesis, and whether these effects require VAN GLP-1R signaling, using a rat model with a selective Glp1r knockdown (kd) in VAN...
May 30, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Uma Anand, Yiangos Yiangou, Ayesha Akbar, Tom Quick, Anthony MacQuillan, Mike Fox, Marco Sinisi, Yuri E Korchev, Ben Jones, Steve R Bloom, Praveen Anand
INTRODUCTION: Glucagon like-peptide 1 receptor (GLP-1R) agonists diminish appetite and may contribute to the weight loss in inflammatory bowel disease (IBD). OBJECTIVES: The aim of this study was to determine, for the first time, the expression of GLP-1R by colon nerve fibres in patients with IBD, and functional effects of its agonists in cultured rat and human sensory neurons. METHODS: GLP-1R and other nerve markers were studied by immunohistochemistry in colon biopsies from patients with IBD (n = 16) and controls (n = 8), human dorsal root ganglia (DRG) tissue, and in GLP-1R transfected HEK293 cells...
2018: PloS One
Zhonglei Sun, Yingfu Liu, Xianbin Kong, Renjie Wang, Yunqiang Xu, Chongzhi Shang, Jingrui Huo, Mengqiang Huang, Fei Zhao, Kefeng Bian, Sai Zhang, Yue Tu, Xuyi Chen
BACKGROUND/AIMS: Current therapies for spinal cord injury (SCI) have limited efficacy, and identifying a therapeutic target is a pressing need. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) plays an important role in regulating calcium homeostasis, which has been shown to inhibit apoptosis. Exendin-4 has been shown to inhibit the apoptosis of nerve cells in SCI, which can also improve SERCA2 expression. In this study, we sought to determine whether exendin-4 plays a protective role in a rat model of SCI via SERCA2...
May 22, 2018: Cellular Physiology and Biochemistry
Selvinaz Dalaklioglu, Arda Tasatargil, Nilay Kuscu, Soner Celik, Ciler Celik-Ozenci, Sebahat Ozdem, Ayse Barutcigil, Ikbal Kucukcetin
OBJECTIVE: The aim of this study was to investigate the effect of chronic exendin-4 (Ex-4) treatment on corpus cavernosum (CC) dysfunction in methylglyoxal (MGO) administered rats. METHODS: Male rats were divided into four groups as control, MGO (75 mg/kg/day in drinking water for 12 weeks), MGO + low-dose Ex-4 (0.1 μg/kg twice daily subcutaneously for 12 weeks concomitant with MGO), and MGO + high-dose Ex-4 (1 μg/kg twice daily subcutaneously for 12 weeks concomitant with MGO)...
May 21, 2018: Peptides
Ke Lu, Xiaoyan Chen, Jianhua Yan, Xinchun Li, Chen Huang, Qi Wan, Xuelian Deng, Qiao Zou
OBJECTIVE: To investigate the utility of intravoxel incoherent motion-diffusion weighted imaging (IVIM-DWI) derived parameters in hypothalamus for monitoring the effect of Exendin-4 (Ex-4) intervention on the feeding behavior in obese diabetic rats within early feeding. METHODS: 21 obese and 19 non-obese rats which were treated with streptozotocin injections were initially divided into an obese diabetes group (OD, n = 10), a non-obese diabetes group (D, n = 8), an obese group (O, n = 9) and a non-obese group (N, n = 9)...
May 23, 2018: Obesity Facts
David C Hornigold, Emma Roth, Victor Howard, Sarah Will, Stephanie Oldham, Matthew P Coghlan, Clemence Blouet, James L Trevaskis
Combination approaches for the treatment of metabolic diseases such as obesity and diabetes are becoming increasingly relevant. Co-administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist with a cholecystokinin receptor-1 (CCKR1) agonist exert synergistic effects on weight loss in obese rodents. Here, we report on the effects of a novel fusion peptide (C2816) comprised of a stabilized GLP-1R agonist, AC3174, and a CCKR1-selective agonist, AC170222. C2816 was constructed such that AC3174 was linked to the N-terminus of AC170222, thus preserving the C-terminal amide of the CCK moiety...
May 18, 2018: Appetite
Yoshio Fujitani
The incidence of type 2 diabetes increases with age. The age-dependent decline in functional β-cell mass contributes to the increased risk of onset of diabetes, reflecting the central role of pancreatic β cells in glucose homeostasis. Indeed, the replication rate of human and rodent β cells is known to decline sharply with age, and such a characteristic of β cells may explain the increased onset of type 2 diabetes in the older population. The molecular mechanism involved in the age-dependent decline of β-cell proliferation has been extensively studied, mainly using rodents and in vitro culture systems, but its molecular basis is still largely unknown...
May 16, 2018: Journal of Diabetes Investigation
Moritaka Goto, Shinji Furuta, Satoko Yamashita, Hiroyuki Hashimoto, Wataru Yano, Noriyuki Inoue, Noriaki Kato, Kohei Kaku
AIMS/INTRODUCTION: Recent data showed that DPP-4 inhibitors exert a lipid-lowering effect in diabetic patients. However, the mechanism of action is not yet clearly understood. We investigated the effect of anagliptin on cholesterol metabolism and transport in the small intestine using non-diabetic hyperlipidemic animals, to clarify the mechanisms underlying the cholesterol-lowering action. MATERIALS AND METHODS: Male ApoE-deficient mice were orally administered anagliptin in the normal chow...
May 13, 2018: Journal of Diabetes Investigation
Hayden J L McEwen, Emmanuelle Cognard, Sharon R Ladyman, Zin Khant-Aung, Alexander Tups, Peter R Shepherd, David R Grattan
β-catenin is a multifunctional protein that can act in the canonical Wnt/β-catenin pathway to regulate gene expression but can also bind to cadherin proteins in adherens junctions where it plays a key role in regulating cytoskeleton linked with these junctions. Recently, evidence has been presented indicating an essential role for β-catenin in regulating trafficking of insulin vesicles in β-cells and showing that changes in nutrient levels rapidly alter levels of β-catenin in these cells. Given the importance of neuroendocrine hormone secretion in the regulation of whole body glucose homeostasis, the objective of this study was to investigate whether β-catenin signalling is regulated in the hypothalamus during the normal physiological response to food intake...
May 11, 2018: Journal of Neuroendocrinology
Feng Ye, Yi Liu, Shiying Li, Jiande D Z Chen
PURPOSE: To find out the best location for intestinal electrical stimulation (IES) to decrease hyperglycemia, and mechanisms involving intraluminal nutrients and plasma glucagon-like peptide-1 (GLP-1) MATERIALS AND METHODS: Eight rats had electrodes implanted at the duodenum and ileums for IES. The oral glucose tolerance test (OGTT) was performed with IES and sham-IES and with/without GLP-1 antagonist, exendin. To study the role of intraluminal nutrients, the experiment was repeated using intraperitoneal glucose tolerance test (IPGTT)...
May 4, 2018: Obesity Surgery
Wei-Ren Shen, Keisuke Kimura, Masahiko Ishida, Haruki Sugisawa, Akiko Kishikawa, Kazuhiro Shima, Saika Ogawa, Jiawei Qi, Hideki Kitaura
Glucagon-like peptide-1 (GLP-1) receptor agonists are an effective treatment approach for type 2 diabetes. Recently, anti-inflammatory effects of GLP-1 receptor agonists have also been reported. Lipopolysaccharide (LPS) induces inflammation and osteoclast formation. In this study, we investigated the effect of exendin-4, a widely used GLP-1 receptor agonist, in LPS-induced osteoclast formation and bone resorption. LPS with or without exendin-4 was administered on mouse calvariae by daily subcutaneous injection...
2018: Journal of Immunology Research
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