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Sodium glucose transporters

Hong Kyu Lee
Cardio-renal protective effect of Sodium Glucose Co-transporter-2 (SGLT2) inhibitors is well established by three large clinical trials; Empagliflozin, Cardiovascular Outcome Events Trial in Type 2 Diabetes Patients (EMPA-REG OUTCOME), Canagliflozin Cardiovascular Assessment Study (CANVAS), and most recently Dapagliflozin Effect on Cardiovascular Events Trial 58 by the Thrombolysis in Myocardial Infarction Study Group (DECLARE-TIMI 58). Three different SGLT2 inhibitors, empagliflozin, canagliflozin and dapagliflozin, were proven effective not only for their glucose lowering effect, but in reducing deterioration of renal function and prevented hospitalization due to heart failure...
December 9, 2018: Journal of Diabetes Investigation
Brian M Inouye, Francis M Hughes, Huixia Jin, Robin Lütolf, Kunal C Potnis, Jonathan C Routh, Douglas C Rouse, Wen-Chi Foo, J Todd Purves
Purpose: Diabetes is a grave and progressive condition characterized by debilitating complications. Diabetic bladder dysfunction (DBD) is a very common complication with no specific treatments currently available. Unlike other tissues affected by this disease, the bladder is subjected to two independent insults; 1) polyuria, created by the osmotic effects of glucose in the urine, and 2) hyperglycemia itself. Based on our understanding of inflammation as a major contributor to the underlying organ damage in several other diabetic complications, its presence in the bladder during DBD and the contribution of polyuria and hyperglycemia to its development were assessed...
2018: Research and Reports in Urology
Paola Bisignano, Chiara Ghezzi, Hyunil Jo, Nicholas F Polizzi, Thorsten Althoff, Chakrapani Kalyanaraman, Rosmarie Friemann, Matthew P Jacobson, Ernest M Wright, Michael Grabe
Sodium-dependent glucose transporters (SGLTs) exploit sodium gradients to transport sugars across the plasma membrane. Due to their role in renal sugar reabsorption, SGLTs are targets for the treatment of type 2 diabetes. Current therapeutics are phlorizin derivatives that contain a sugar moiety bound to an aromatic aglycon tail. Here, we develop structural models of human SGLT1/2 in complex with inhibitors by combining computational and functional studies. Inhibitors bind with the sugar moiety in the sugar pocket and the aglycon tail in the extracellular vestibule...
December 7, 2018: Nature Communications
William G Herrington, David Preiss, Richard Haynes, Maximilian von Eynatten, Natalie Staplin, Sibylle J Hauske, Jyothis T George, Jennifer B Green, Martin J Landray, Colin Baigent, Christoph Wanner
Diabetes is a common cause of chronic kidney disease (CKD), but in aggregate, non-diabetic diseases account for a higher proportion of cases of CKD than diabetes in many parts of the world. Inhibition of the renin-angiotensin system reduces the risk of kidney disease progression and treatments that lower blood pressure (BP) or low-density lipoprotein cholesterol reduce cardiovascular (CV) risk in this population. Nevertheless, despite such interventions, considerable risks for kidney and CV complications remain...
December 2018: Clinical Kidney Journal
Raja Rezg, Anne Abot, Bessem Mornagui, Claude Knauf
Bisphenol S, an industrial chemical, has raised concerns for both human and ecosystem health. Yet, health hazards posed by bisphenol S (BPS) exposure remain poorly studied. Compared to all tissues, the intestine and the liver are among the most affected by environmental endocrine disruptors. The aim of this study was to investigate the molecular effect of BPS on gene expression implicated in the control of glucose metabolism in the intestine (apelin and its receptor APJ, SGLT1, GLUT2) and in the liver (glycogenolysis and/or gluconeogenesis key enzymes (glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK)) and pro-inflammatory cytokine expression (TNF-α and IL-1β))...
December 7, 2018: Environmental Science and Pollution Research International
Jason Powell, Scott G Garland
OBJECTIVE: The purpose of this article is to review the pharmacological aspects of ertugliflozin and its clinical trials, which led to Food and Drug Administration (FDA) approval for the treatment of type 2 diabetes mellitus (T2DM). DATA SOURCES: A MEDLINE/PubMed (May 2013 to October 2018) search was conducted using the following keywords: ertugliflozin, sodium glucose co-transporter 2 inhibitor, SGLT2 inhibitor, type 2 diabetes mellitus, hyperglycemia. Study Selection and Data Extraction Quantify: We included English-language articles evaluating ertugliflozin pharmacology, pharmacokinetics, efficacy, and safety in humans for blood glucose reduction in human subjects...
December 7, 2018: Annals of Pharmacotherapy
Tomás P Griffin, Md Nahidul Islam, Liam Blake, Marcia Bell, Matthew D Griffin, Paula M O'Shea
The aldosterone to renin ratio (ARR) is recommended for case detection of primary aldosteronism (PA). Several factors including medications can undermine its diagnostic accuracy. The objective was to explore the effect of Sodium Glucose Co-Transporter-2 Inhibition on the ARR in patients with type 2 diabetes mellitus (T2DM) who were prescribed a Sodium Glucose Co-Transporter-2 Inhibitor (SGLT-2i) as part of routine clinical care. The primary outcomes were intra-individual changes in aldosterone, renin and ARR...
December 6, 2018: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
Yui Yamazaki, Kyoko Arita, Shinichi Harada, Shogo Tokuyama
Cerebral ischemic stress increases cerebral sodium-glucose transporter type 1 (SGLT-1). However, the mechanism by which cerebral ischemia leads to the up-regulation of SGLT-1 remains unclear. In peripheral tissue, the activation of mitogen-activated protein kinases (MAPKs) increases SGLT-1. MAPK pathways [c-Jun N-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated protein kinase (ERK)] are activated by cerebral ischemic stress. Therefore, we confirmed the involvement of MAPKs in the up-regulation of cerebral SGLT-1 after cerebral ischemia...
November 7, 2018: Journal of Pharmacological Sciences
Diana Isaacs, Stephanie Yager, Marcie Parker, Lauren Wolfe, Jennifer Luxenburg, Sanela Lekic
OBJECTIVE: People with type 1 diabetes often have suboptimal glycemic control. The gold standard of treatment is basal-bolus insulin or subcutaneous insulin infusion via insulin pump. Although insulin therapy improves glycemic control, weight gain and hypoglycemia often limit achievement of hemoglobin A1C (A1C) goals. The number of people with type 1 diabetes who are overweight or obese is increasing, and there are many similarities between what was historically called type 1 and type 2 diabetes...
November 30, 2018: Annals of Pharmacotherapy
Hirotaka Watada, Masanari Shiramoto, Shinya Ueda, Weifeng Tang, Michiko Asano, Fredrik Thoren, Hyosung Kim, Toshitaka Yajima, David W Boulton, Eiichi Araki
AIMS: To assess the pharmacokinetics/pharmacodynamics (PK/PD) of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor that increases urinary glucose excretion (UGE), and its major metabolite, dapagliflozin-3-O-glucuronide (D3OG), in Japanese patients with type 1 diabetes (T1D) and inadequate glycemic control (HbA1c 7-10%). MATERIALS AND METHODS: Japanese patients (18-65 years) with inadequately controlled T1D were randomized 1:1:1 to dapagliflozin 5 mg, 10 mg, or placebo (n=14 each) once daily for seven days with adjustable insulin...
November 30, 2018: Diabetes, Obesity & Metabolism
Blythe D Shepard, Hermann Koepsell, Jennifer L Pluznick
Olfactory receptors (ORs) are G protein-coupled receptors which serve to detect odorants in the nose. Additionally, these receptors are expressed in other tissues where they have functions outside of the canonical smell response. Olfactory Receptor 1393 (Olfr1393) was recently identified as a novel regulator of sodium glucose co-transporter 1 (Sglt1) localization in the renal proximal tubule. Glucose reabsorption in the proximal tubule (via Sglt1 and Sglt2) has emerged as an important contributor to the development of diabetes...
November 28, 2018: American Journal of Physiology. Renal Physiology
Muhammad Saad, Umut Gomceli, Pranav Ravi, Andrisael G Lacoste, Neil Shah, Timothy J Vittorio
Heart failure (HF) is one of the leading causes of hospital readmissions and health care expenditures. With a vast degree of advancements in the clinical approach and diagnosis, its management protocol is limited in terms of enhancing quality of life and prognosis. Type 2 diabetes mellitus (T2DM) is considered as one of the commonly associated comorbid conditions in the HF population. The understanding of the molecular and metabolic models of HF has led to the utilization of therapeutic goals of T2DM in improving HF-related complications...
2018: Drugs in Context
Kuang-Feng Chu, Jen-Shin Song, Chiung-Tong Chen, Teng-Kuang Yeh, Tsung-Chih Hsieh, Chung-Yu Huang, Min-Hsien Wang, Szu-Huei Wu, Chun-Hsu Yao, Yu-Sheng Chao, Jinq-Chyi Lee
Sodium-dependent glucose co-transporter 2 (SGLT2) inhibition has been demonstrated to efficiently control hyperglycemia via an insulin secretion-independent pathway. The unique mode of action eliminates the risk of hypoglycemia and makes SGLT2 inhibitors an attractive option for the treatment of type 2 diabetes. In a continuation of our previous studies on SGLT2 inhibitors bearing different sugar moieties, sixteen new N-glucosyl indole derivatives were designed, synthesized, and evaluated for their inhibitory activity against hSGLT2...
November 7, 2018: Bioorganic Chemistry
Xiaomin Liu, Yanmao Wang, Xiaotian Zhang, Xinju Zhang, Jing Guo, Jinbao Zhou, Yimin Chai, Zhong-Liang Ma
BACKGROUND: Diabetic wounds are refractory and very difficult to heal. We aimed to use miRNA to identify novel and specific molecular markers for diabetes mellitus (DM) diagnosis and treatment. METHODS: The expression level of miR-296-5p was determined in tissue samples of 12 DM patients. The effect of miR-296-5p on proliferation of β-cells was examined using CCK-8 and colony formation assay. The effect of miR-296-5p on cell cycle progression was analyzed using flow cytometry...
November 22, 2018: Diabetes/metabolism Research and Reviews
Evangelia Kalaitzoglou, John L Fowlkes, Iuliana Popescu, Kathryn M Thrailkill
Persons with type 1 or type 2 diabetes (T1D, T2D) have a significantly higher fracture risk than age-matched persons without diabetes, attributed to disease-specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin-based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall-related fractures, particularly in the elderly...
November 22, 2018: Diabetes/metabolism Research and Reviews
Caroline M Apovian, Jennifer Okemah, Patrick M O'Neil
Obesity is one of the main risk factors for type 2 diabetes (T2D), representing a major worldwide health crisis. Modest weight-loss (≥ 5% but < 10%) can minimize and reduce diabetes-associated complications, and significant weight-loss can potentially resolve disease. Treatment guidelines recommend that intensive lifestyle interventions, pharmacologic therapy, and/or metabolic surgery be considered as options for patients with T2D and obesity. The benefits and risks of such interventions should be evaluated in the context of their weight-loss potential, ability to sustain weight change, side effect profile, and costs...
November 21, 2018: Advances in Therapy
Michael S Kelly, Jelena Lewis, Ashley M Huntsberry, Lauren Dea, Ivan Portillo
OBJECTIVE: To review glucose-lowering efficacy and changes in renal function associated with sodium-glucose co-transporter 2 (SGLT2) inhibitors among patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). DATA SOURCES: A literature search of MEDLINE and Cochrane databases was performed from 2000 to August 2018 using search terms: SGLT2 inhibitors, sodium glucose co-transporter 2, canagliflozin, empagliflozin, dapagliflozin, ertugliflozin, and chronic kidney disease...
November 17, 2018: Postgraduate Medicine
Yunyun Li, Xiaoxi Lu, Haiqin Wu, Mi Xia, Qihang Hou, Weiwei Hu, Tiejun Li, Li Wu, Qinghua Yu
To explore the effects of reducing the Cp levels on intestinal barrier function, low Cp (LP) and NRC standard Cp (NP) diets were fed to pigs from 45 to 160 days, and in vitro experiments were performed using monolayers of IPEC-J2 cells. The number of goblet cells, expression of proteins related to cell junction, amino acid transport, glucose transport, transepithelial electrical resistance (TEER), dextran permeability, and IL-6 secretion level were detected in pigs. The results demonstrated that a moderate reduction of Cp levels did not affect intestinal morphology, as demonstrated by a normal villi height, crypt depth and normal numbers of goblet cells...
November 12, 2018: Research in Veterinary Science
Kenneth Cusi, Fernando Bril, Diana Barb, David Polidori, Sue Sha, Atalanta Ghosh, Kristin Farrell, Nishanth E Sunny, Srilaxmi Kalavalapalli, Jeremy Pettus, Theodore P Ciaraldi, Sunder Mudaliar, Robert R Henry
AIMS: Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves glycemic control by increasing urinary glucose excretion, but its impact on intrahepatic triglyceride (IHTG) accumulation and relationship to changes in body weight and glucose metabolism remain unknown. MATERIALS AND METHODS: In this double-blind, parallel-group, placebo-controlled, 24-week trial subjects with inadequately controlled type 2 diabetes mellitus (T2DM; HbA1c=7.7±0.7%) from two centers were randomly assigned (1:1) to canagliflozin 300 mg or placebo...
November 16, 2018: Diabetes, Obesity & Metabolism
Yusuf Olgar, Belma Turan
Sodium-glucose cotransporter 2 (SGLT2)-inhibitors showed significant effect in patients with diabetes or metabolic syndrome, MetS with high cardiovascular-risk. Although the increased intracellular Zn2+ level ([Zn2+]i), oxidative stress and alterated cardiac matrix metalloproteinases (MMPs) in diabetic cardiomyopathy can intersect with different signaling pathways, the exact mechanisms are not known yet. Since either MMPs or SGLT2 have important role in cardiac-fibrosis under hyperglycemia, we aimed to examine the role of SGLT2-inhibitor dapagliflozin (DAP) on cardiac Zn2+-transporters responsible from [Zn2+]i-regulation, comparison to insulin (INS), together with MMP levels and systemic oxidative-stress-status in MetS-rats...
November 16, 2018: Canadian Journal of Physiology and Pharmacology
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