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https://www.readbyqxmd.com/read/28639755/-the-combination-of-glp-1-analogs-and-sglt2-inhibitors-new-perspectives
#1
Claire Ritz, Jaafar Jaafar, Jacques Philippe
Type 2 diabetes therapy has expanded considerably over the last decade. Two anti-diabetic therapeutic groups, which are GLP-1 (glucagon-like peptide-1) receptor agonists and SGLT2 inhibitors (sodium-glucose co-transporter-2), have shown efficacy not only on glycemic control but also on weight and other parameters that will be detailed in this article. Cardiovascular safety studies for two of these molecules were shown for the first time to decrease overall and cardiovascular mortality. The combination of these two therapeutic classes provides a logical solution due to their different mechanisms of action...
May 31, 2017: Revue Médicale Suisse
https://www.readbyqxmd.com/read/28637887/mitigating-cardiovascular-risk-in-type-2-diabetes-with-antidiabetes-drugs-a-review-of-principal-cardiovascular-outcome-results-of-empa-reg-outcome-leader-and-sustain-6-trials
#2
Sanjay Kaul
The U.S. Food and Drug Administration (FDA) issued a diabetes guidance in 2008 mandating that all new antidiabetes drugs rule out excess cardiovascular (CV) risk, defined as an upper bound of the two-sided 95% CI for major adverse CV events (MACE) of less than 1.80 preapproval and 1.30 postapproval. Over 25 large, prospective, randomized, controlled clinical trials involving nearly 195,000 subjects thus far have been completed or are ongoing in accordance with this guidance. The results of seven trials have been presented so far-three with dipeptidyl peptidase 4 inhibitors, one with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and three with glucagon-like peptide 1 receptor agonists (GLP-1 RA)...
July 2017: Diabetes Care
https://www.readbyqxmd.com/read/28630133/dual-regulation-of-gluconeogenesis-by-insulin-and-glucose-in-the-proximal-tubules-of-the-kidney
#3
Motohiro Sasaki, Takayoshi Sasako, Naoto Kubota, Yoshitaka Sakurai, Iseki Takamoto, Tetsuya Kubota, Reiko Inagi, George Seki, Moritaka Goto, Kohjiro Ueki, Masaomi Nangaku, Takahito Jomori, Takashi Kadowaki
Growing attention has been focused on the roles of the proximal tubules (PTs) of the kidney in glucose metabolism, including the mechanism of regulation of gluconeogenesis. Here, we found that PT-specific IRS1/2 double-knockout mice, established by using the newly generated sodium-glucose cotransporter-2 (SGLT2)-Cre transgenic mice, exhibited impaired insulin signaling and upregulated gluconeogenic gene expression and renal gluconeogenesis, resulting in systemic insulin resistance. On the other hand, in streptozotocin-treated mice, although insulin action was impaired in the PTs, the gluconeogenic gene expression was unexpectedly downregulated in the renal cortex, which was restored by administration of an SGLT1/2 inhibitor...
June 19, 2017: Diabetes
https://www.readbyqxmd.com/read/28584109/dapagliflozin-suppresses-glucagon-signaling-in-rodent-models-of-diabetes
#4
May-Yun Wang, Xinxin Yu, Young Lee, Sara Kay McCorkle, Shiuhwei Chen, Jianping Li, Zhao V Wang, Jaime A Davidson, Philipp E Scherer, William L Holland, Roger H Unger, Michael G Roth
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of antidiabetic drug used for the treatment of diabetes. These drugs are thought to lower blood glucose by blocking reabsorption of glucose by SGLT2 in the proximal convoluted tubules of the kidney. To investigate the effect of inhibiting SGLT2 on pancreatic hormones, we treated perfused pancreata from rats with chemically induced diabetes with dapagliflozin and measured the response of glucagon secretion by alpha cells in response to elevated glucose...
June 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28522196/impact-of-glucose-lowering-therapies-on-risk-of-stroke-in-type-2-diabetes
#5
REVIEW
F Bonnet, A J Scheen
Patients with type 2 diabetes (T2D) have an increased risk of stroke compared with people without diabetes. However, the effects of glucose-lowering drugs on risk of ischaemic stroke in T2D have been less extensively investigated than in coronary heart disease. Some evidence, including the UKPDS, has suggested a reduced risk of stroke with metformin, although the number of studies is limited. Inhibition of the KATP channels increases ischaemic brain lesions in animals. This is in agreement with a recent meta-analysis showing an increased risk of stroke with sulphonylureas vs...
May 15, 2017: Diabetes & Metabolism
https://www.readbyqxmd.com/read/28511711/sglt2-inhibitors-a-novel-choice-for-the-combination-therapy-in-diabetic-kidney-disease
#6
REVIEW
Honghong Zou, Baoqin Zhou, Gaosi Xu
Diabetic kidney disease (DKD) is the most common cause of end stage renal disease. The comprehensive management of DKD depends on combined target-therapies for hyperglycemia, hypertension, albuminuria, and hyperlipaemia, etc. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, the most recently developed oral hypoglycemic agents acted on renal proximal tubules, suppress glucose reabsorption and increase urinary glucose excretion. Besides improvements in glycemic control, they presented excellent performances in direct renoprotective effects and the cardiovascular (CV) safety by decreasing albuminuria and the independent CV risk factors such as body weight and blood pressure, etc...
May 16, 2017: Cardiovascular Diabetology
https://www.readbyqxmd.com/read/28502112/sglt2-inhibitor-luseogliflozin-added-to-glucagon-like-peptide-1-receptor-agonist-liraglutide-improves-glycemic-control-with-bodyweight-and-fat-mass-reductions-in-japanese-patients-with-type-2-diabetes-a-52-week-open-label-single-arm-study
#7
Yutaka Seino, Daisuke Yabe, Takashi Sasaki, Atsushi Fukatsu, Hisae Imazeki, Hidekazu Ochiai, Soichi Sakai
AIMS/INTRODUCTION: To evaluate the safety and efficacy of luseogliflozin added to liraglutide monotherapy in Japanese individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: This 52-week, multicenter, open-label, single-arm clinical study enrolled Japanese patients who had inadequate glycemic control with diet/exercise and liraglutide monotherapy. Major efficacy endpoints included the changes from baseline in HbA1c, fasting plasma glucose (FPG), and bodyweight...
May 14, 2017: Journal of Diabetes Investigation
https://www.readbyqxmd.com/read/28499695/dapagliflozin-modulates-glucagon-secretion-in-an-sglt2-independent-manner-in-murine-alpha-cells
#8
A Solini, G Sebastiani, L Nigi, E Santini, C Rossi, F Dotta
AIM: SGLT2 inhibitors reduce renal glucose uptake through an insulin-independent mechanism. They also increase glucagon concentration, although the extent to which this is due to a direct effect on pancreatic alpha cells remains unclear. METHODS: In the present work, αTC1 cells treated with the SGLT2 inhibitor dapagliflozin (Dapa) were analyzed for glucose transporters, molecular mediators of hormone secretion, glucagon and GLP-1 release, and the effects of somatostatin...
May 9, 2017: Diabetes & Metabolism
https://www.readbyqxmd.com/read/28482281/ace-and-sglt2-inhibitors-the-future-for-non-diabetic-and-diabetic-proteinuric-renal-disease
#9
REVIEW
Norberto Perico, Piero Ruggenenti, Giuseppe Remuzzi
Most chronic nephropathies progress relentlessly to end-stage kidney disease. Research in animals and humans has helped our understanding of the mechanisms of chronic kidney disease progression. Current therapeutic strategies to prevent or revert renal disease progression focus on reduction of urinary protein excretion and blood pressure control. Blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors and/or angiotensin II type 1 receptor blockers is the most effective treatment to achieve these purposes in non-diabetic and diabetic proteinuric renal diseases...
May 5, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28432726/combination-therapy-with-glp-1-receptor-agonist-and-sglt2-inhibitor
#10
REVIEW
Ralph A DeFronzo
The SGLT2 inhibitors (SGLTi) and glucagon-like-1 receptor agonists (GLP-1 RAs) effectively reduce HbA1c, but via very different mechanisms, making them an effective duet for combination therapy. Recently, drugs in both of these antidiabetic classes have been shown to reduce cardiovascular events, most probably by different mechanisms. SGLT2i appear to exert their CV protective actions by haemodynamic effects, while GLP-1 RAs work via anti-atherogenic/anti-inflammatory mechanisms, raising the possibility that combined therapy with these 2 classes may produce additive CV benefits...
April 22, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28431667/the-potential-and-pitfalls-of-glp-1-receptor-agonists-for-renal-protection-in-type-2-diabetes
#11
Merlin C Thomas
Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RA) offer substantial benefits for the management of glucose levels in type 2 diabetes. In addition, recent data from clinical trials have demonstrated that treatment with Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RA) are also able to reduce new onset macroalbuminuria. These benefits may be consistent with the known effects of GLP-1 RA on traditional risk factors for progressive kidney disease including glucose lowering, blood pressure lowering, reduced insulin levels and weight reduction...
April 2017: Diabetes & Metabolism
https://www.readbyqxmd.com/read/28431666/glp-1-receptor-agonists-and-heart-failure-in-diabetes
#12
André J Scheen
The prevalence of heart failure (HF) is increasing in patients with type 2 diabetes (T2D), and glucose-lowering agents have distinctive effects on the risk of developing HF that requires hospitalization. Such an increased risk has been consistently reported with thiazolidinediones (glitazones) and perhaps also with the dipeptidyl peptidase (DPP)-4 inhibitor saxagliptin (at least in SAVOR - TIMI 53), whereas a markedly decreased risk was highlighted with the sodium - glucose cotransporter type 2 (SGLT2) inhibitor empagliflozin in EMPA-REG OUTCOME...
April 2017: Diabetes & Metabolism
https://www.readbyqxmd.com/read/28391584/the-effect-of-ppar%C3%AE-agonist-on-sglt2-and-glucagon-expressions-in-alpha-cells-under-hyperglycemia
#13
M Kim, E J Lee, H M Shin, H S Jung, T K Kim, T N Kim, M J Kwon, S H Lee, B D Rhee, J H Park
BACKGROUND: Although sodium glucose cotransporter 2 (SGLT2) inhibitors have many beneficial effects for type 2 diabetes, including decreased cardiovascular death, recent reports that they increased glucagon through SGLT2 inhibition raised some concern. Troglitazone, Peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, was reported to increase SGLT2 in renal proximal tubule cells, but its role on pancreatic alpha cells have not been reported. We investigated the effect of troglitazone on SGLT2 expression in alpha cells and subsequent glucagon regulation in hyperglycemia...
April 8, 2017: Journal of Endocrinological Investigation
https://www.readbyqxmd.com/read/28383832/-cardiovascular-and-renal-protection-of-patients-with-type-2-diabetes-focus-after-empa-reg-outcome-and-leader
#14
REVIEW
A J Scheen, L Piérard, J-M Krzesinski, N Paquot
Type 2 diabetes (T2D), often associated with arterial hypertension, represents a high risk of cardiovascular disease and nephropathy. Two clinical trials demonstrate the superiority versus a placebo of two antidiabetic drugs in patients with T2D and high cardiovascular risk : empagliflozin, an inhibitor of sodium-glucose type 2 (SGLT2) cotransporters, in EMPA-REG OUTCOME and liraglutide, an agonist of glucagon-like peptide-1 (GLP-1) receptors, in LEADER. Both medications showed a significant reduction in major cardiovascular events (-14 and -13 %, respectively), cardiovascular mortality (-38 and -22%), all-cause mortality (-32 and -15 %) and renal events (-39 et -22 %)...
September 2016: Revue Médicale de Liège
https://www.readbyqxmd.com/read/28338019/ghrelin-facilitates-glut2-sglt1-and-sglt2-mediated-intestinal-glucose-transport-in-goldfish-carassius-auratus
#15
Ayelén Melisa Blanco, Juan Ignacio Bertucci, Naresh Ramesh, María Jesús Delgado, Ana Isabel Valenciano, Suraj Unniappan
Glucose homeostasis is an important biological process that involves a variety of regulatory mechanisms. This study aimed to determine whether ghrelin, a multifunctional gut-brain hormone, modulates intestinal glucose transport in goldfish (Carassius auratus). Three intestinal glucose transporters, the facilitative glucose transporter 2 (GLUT2), and the sodium/glucose co-transporters 1 (SGLT1) and 2 (SGLT2), were studied. Immunostaining of intestinal sections found colocalization of ghrelin and GLUT2 and SGLT2 in mucosal cells...
March 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28276972/pharmacotherapy-of-treatment-resistant-type-2-diabetes
#16
REVIEW
André J Scheen
Despite type 2 diabetes (T2D) management offers a variety of pharmacological interventions targeting different defects, numerous patients remain with persistent hyperglycaemia responsible for severe complications. Unlike resistant hypertension, treatment resistant T2D is not a classical concept although it is a rather common observation in clinical practice. Areas covered: This article proposes a definition for 'treatment resistant diabetes', analyses the causes of poor glucose control despite standard therapy, briefly considers the alternative approaches to glucose-lowering pharmacotherapy and finally describes how to overcome poor glycaemic control, using innovative oral or injectable combination therapies...
April 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28251513/intensifying-treatment-beyond-monotherapy-in-type-2-diabetes-mellitus-where-do-newer-therapies-fit
#17
REVIEW
Alexander Kuhn, Jean Park, Adline Ghazi, Vanita R Aroda
PURPOSE OF REVIEW: Guidelines for a standard second diabetes medication for the treatment of type 2 diabetes (T2DM) have yet to be established. The rapid increase in the number of newer therapies available makes the choice more difficult. Thus, we reviewed clinical trial evidence evaluating newer therapies available for treatment intensification beyond monotherapy. RECENT FINDINGS: Head-to-head studies comparing newer therapies versus traditional (i.e., sulfonylurea) approaches consistently find lower incidence of hypoglycemia and weight gain with newer therapies...
March 2017: Current Cardiology Reports
https://www.readbyqxmd.com/read/28151518/-type-2-diabetes-treatment-and-cardiovascular-risk-what-can-we-learn-from-trials
#18
Agostino Consoli, Fabrizio Febo
Diabetes treatment should include drugs with absolutely no adverse effects toward cardiovascular risk. Indeed, it would be advisable to use drugs with intrinsic protective effect against the risk of cardiovascular events. Intervention trials aiming at demonstrating a protective cardiovascular effect of very tight glucose control have produced controversial results. It is commonly perceived, however, that early intervention with safe treatment strategies is likely to be beneficial. In regard to safety, in the attempt to firmly establish cardiovascular safety of new drugs for diabetes, Government Authorities have mandated that cardiovascular safety trials need to be performed for all new drugs registered for diabetes treatment...
December 2016: Giornale Italiano di Cardiologia
https://www.readbyqxmd.com/read/28151517/-effects-of-glucagon-like-peptide-1-receptor-agonists-on-cardiovascular-risk-factors-and-the-cardiovascular-system
#19
Teresa Vanessa Fiorentino, Giorgio Sesti
The results of the cardiovascular outcome trials comparing the SGLT2 inhibitor empagliflozin and the glucagon-like peptide-1 receptor agonist liraglutide to placebo have been recently published. Interestingly, empagliflozin and liraglutide treatments significantly reduce cardiovascular events in subjects with type 2 diabetes. The mechanisms underlying the observed cardioprotective effects of empagliflozin and liraglutide are speculative and future studies are needed to better understand these results. However, since reduction in the primary outcome was evident 3 months after starting empagliflozin and 24 months after starting liraglutide, it is tempting to hypothesize that the cardiovascular benefits observed in diabetic patients treated with empagliflozin are due to its hemodynamic effects and to metabolic substrate shift induced by the mild and persistent hyperketonemia, while the positive effects of liraglutide treatment may be attributable to biologic changes of atherosclerotic lesions...
December 2016: Giornale Italiano di Cardiologia
https://www.readbyqxmd.com/read/28092375/postprandial-macrophage-derived-il-1%C3%AE-stimulates-insulin-and-both-synergistically-promote-glucose-disposal-and-inflammation
#20
Erez Dror, Elise Dalmas, Daniel T Meier, Stephan Wueest, Julien Thévenet, Constanze Thienel, Katharina Timper, Thierry M Nordmann, Shuyang Traub, Friederike Schulze, Flurin Item, David Vallois, Francois Pattou, Julie Kerr-Conte, Vanessa Lavallard, Thierry Berney, Bernard Thorens, Daniel Konrad, Marianne Böni-Schnetzler, Marc Y Donath
The deleterious effect of chronic activation of the IL-1β system on type 2 diabetes and other metabolic diseases is well documented. However, a possible physiological role for IL-1β in glucose metabolism has remained unexplored. Here we found that feeding induced a physiological increase in the number of peritoneal macrophages that secreted IL-1β, in a glucose-dependent manner. Subsequently, IL-1β contributed to the postprandial stimulation of insulin secretion. Accordingly, lack of endogenous IL-1β signaling in mice during refeeding and obesity diminished the concentration of insulin in plasma...
March 2017: Nature Immunology
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