scholarly journals Pharmacodynamic Model of Sodium–Glucose Transporter 2 (SGLT2) Inhibition: Implications for Quantitative Translational Pharmacology

2011 ◽  
Vol 13 (4) ◽  
pp. 576-584 ◽  
Author(s):  
Tristan S. Maurer ◽  
Avijit Ghosh ◽  
Nahor Haddish-Berhane ◽  
Aarti Sawant-Basak ◽  
Carine M. Boustany-Kari ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Pharmacodynamic Model ◽  
Glucose Transporter 2 ◽  
Translational Pharmacology ◽  
Sglt2 Inhibition

scholarly journals SGLT2 inhibition requires reconsideration of fundamental paradigms in chronic kidney disease, ‘diabetic nephropathy’, IgA nephropathy and podocytopathies with FSGS lesions

2020 ◽  
Author(s):  
Hans-Joachim Anders ◽  
Anna Julie Peired ◽  
Paola Romagnani
Keyword(s):  
Chronic Kidney Disease ◽  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Glucose Transporter ◽  
Immunoglobulin A ◽  
Adverse Outcomes ◽  
Glucose Transporter 2 ◽  
Research Activities ◽  
Background Therapy ◽  
Sglt2 Inhibition

Abstract In 2020, the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial first demonstrated that inhibition of the sodium–glucose transporter-2 (SGLT2) with dapagliflozin attenuates the progression of chronic kidney disease (CKD) with proteinuria in patients with or without diabetes at an unprecedented effect size. These results have far-reaching implications for a series of traditional concepts in Nephrology. It now became obvious that CKD with and without diabetes involves a predominant SGLT2-driven pathophysiology compared with the other pathogenic pathways currently under consideration. As SGLT2 inhibition is similarly efficacious in diabetic and non-diabetic CKD with proteinuria, treating CKD rather than ‘diabetic nephropathy’ becomes the central paradigm. Indeed, in older adults with type 2 diabetes, CKD is rather of multifactorial origin. As the DAPA-CKD trial included more patients with immunoglobulin A nephropathy (IgAN) than any of the previous IgAN trials, dual renin-angiotensin/SGLT2 inhibition may become the new standard. The same applies for patients with podocytopathy-related focal segmental glomerulosclerosis lesions. From now on, IgAN and podocytopathy trials without SGLT2 inhibition as background therapy and without glomerular filtration rate decline as primary outcome criterion will be of limited value. These and other potential implications will trigger broad discussions and secondary research activities with conclusions difficult to predict today. However, one is for sure: Nephrology after the DAPA-CKD trial will be not the same as it was before. Finally!

Efficacy and cardiovascular safety of Thiazolidinediones

2020 ◽  
Vol 15 ◽  
Author(s):  
Raveendran Arkiath Veettil ◽  
Cornelius James Fernandez ◽  
Koshy Jacob
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Glucose Transporter ◽  
Cell Function ◽  
Cardiovascular Safety ◽  
Cardiovascular Outcome Trials ◽  
Glucose Transporter 2 ◽  
Insulin Sensitizers

: Type 2 diabetes mellitus (T2DM) is characterized by a progressive beta cell dysfunction in the setting of peripheral insulin resistance. Insulin resistance in subjects with type 2 diabetes and metabolic syndrome is primarily caused by an ectopic fat accumulation in liver and skeletal muscle. Insulin sensitizers are particularly important in the management of T2DM. Though, thiazolidinediones (TZDs) are principally insulin sensitizers, they possess an ability to preserve pancreatic β-cell function and thereby exhibit durable glycemic control. Cardiovascular outcome trials (CVOTs) have shown that Glucagon-like-peptide 1 receptor agonists (GLP-1 RAs) and sodium glucose transporter-2 inhibitors (SGLT2i) have proven cardiovascular safety. In this era of CVOTs, drugs with proven cardiovascular (CV) safety are often preferred in patients with preexisting cardiovascular disease or at risk of cardiovascular disease. In this review, we will describe the three available drugs belonging to the TZD family, with special emphasis on their efficacy and CV safety.

SGLT-2 inhibitors: Ideal Remedy for Cardioprotection in Diabetes Mellitus.

2020 ◽  
Vol 13 ◽  
Author(s):  
Keshav Kumar ◽  
Tapan Behl ◽  
Arun Kumar ◽  
Sandeep Arora
Keyword(s):  
Diabetes Mellitus ◽  
Glucose Transporter ◽  
Clinical Trial Data ◽  
Cardiac Complications ◽  
Cardiac Inflammation ◽  
First Line Therapy ◽  
Glucose Transporter 2 ◽  
Specific Medication ◽  
Hba1c Levels

Background: A chronic metabolic disease, diabetes mellitus (DM), is associated with various comorbidity due to cardiac complications that considerably decreasing the quality of life, but there is no specific medication for this. The recent developed drugs Sodium glucose transporter 2 inhibitors (SGLT2-Is), have action on diabetes as well as on kidney. Current research and studies have shown that SGLT2-Is attenuated the risk of cardiac complication associated with morbidity and hospitalization in diabetes patients. Introduction: Sodium glucose linked transporter 2 (SGLT2) receptors are mainly situated in proximal tubule of nephron. About 90% of glucose concentration is reabsorbed by these receptors in the nephron. The advanced remedy for the management of DM is SGLT2-Is which inhibit or lower the reabsorption of glucose. Objectives: The present review explores the mechanistic principle and the clinical trial data of SGLT2-Is which further support cardioprotective effects associated with these medications. Methods: The review collaborates PUBMED, Google Scholar and Research gate databases, which were explored using keywords and their combinations such as sodium glucose co-transporter 2 inhibitors, diabetes mellitus, cardioprotective effect, empagliflozin, canagliflozin, dapagliflozin and several others, to create an eclectic manuscript. Results: SGLT2-Is showed improvement in diabetes as well as in cardiac complications. These medications decreased HbA1c levels to control hyperglycemia. The mechanism of action of these drugs showed reduction in cardiac oxidative stress, cardiac apoptosis and cardiac inflammation. Besides, SGLT-2-Is showed improvement in cardiac structure and cardiac function. Conclusion: Anti-diabetic drugs, SGLT2-Is have a protective effect against cardiac complications. This indicates that these medication could become first line therapy for cardiac patients with DM.

scholarly journals High Carbohydrate Diet Increased Glucose Transporter Protein Levels in Jejunum but Did Not Lead to Enhanced Post-Exercise Skeletal Muscle Glycogen Recovery

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2140
Author(s):  
Yumiko Takahashi ◽  
Yutaka Matsunaga ◽  
Hiroki Yoshida ◽  
Terunaga Shinya ◽  
Ryo Sakaguchi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Transporter ◽  
High Carbohydrate Diet ◽  
Oral Glucose ◽  
Carbohydrate Diet ◽  
Post Exercise ◽  
Glucose Administration ◽  
Protein Levels ◽  
High Carbohydrate ◽  
Glucose Transporter 2

We examined the effect of dietary carbohydrate intake on post-exercise glycogen recovery. Male Institute of Cancer Research (ICR) mice were fed moderate-carbohydrate chow (MCHO, 50%cal from carbohydrate) or high-carbohydrate chow (HCHO, 70%cal from carbohydrate) for 10 days. They then ran on a treadmill at 25 m/min for 60 min and administered an oral glucose solution (1.5 mg/g body weight). Compared to the MCHO group, the HCHO group showed significantly higher sodium-D-glucose co-transporter 1 protein levels in the brush border membrane fraction (p = 0.003) and the glucose transporter 2 level in the mucosa of jejunum (p = 0.004). At 30 min after the post-exercise glucose administration, the skeletal muscle and liver glycogen levels were not significantly different between the two diet groups. The blood glucose concentration from the portal vein (which is the entry site of nutrients from the gastrointestinal tract) was not significantly different between the groups at 15 min after the post-exercise glucose administration. There was no difference in the total or phosphorylated states of proteins related to glucose uptake and glycogen synthesis in skeletal muscle. Although the high-carbohydrate diet significantly increased glucose transporters in the jejunum, this adaptation stimulated neither glycogen recovery nor glucose absorption after the ingestion of post-exercise glucose.

scholarly journals Impact of SGLT2 Inhibitors on Heart Failure: From Pathophysiology to Clinical Effects

2021 ◽  
Vol 22 (11) ◽  
pp. 5863
Author(s):  
Giuseppe Palmiero ◽  
Arturo Cesaro ◽  
Erica Vetrano ◽  
Pia Clara Pafundi ◽  
Raffaele Galiero ◽  
...  
Keyword(s):  
Heart Failure ◽  
Glucose Transporter ◽  
The Elderly ◽  
Intracellular Sodium ◽  
Clinical Effects ◽  
Glucose Lowering ◽  
Beneficial Effects ◽  
Glucose Transporter 2 ◽  
Function Impairment

Heart failure (HF) affects up to over 20% of patients with type 2 diabetes (T2DM), even more in the elderly. Although, in T2DM, both hyperglycemia and the proinflammatory status induced by insulin resistance are crucial in cardiac function impairment, SGLT2i cardioprotective mechanisms against HF are several. In particular, these beneficial effects seem attributable to the significant reduction of intracellular sodium levels, well-known to exert a cardioprotective role in the prevention of oxidative stress and consequent cardiomyocyte death. From a molecular perspective, patients’ exposure to gliflozins’ treatment mimics nutrient and oxygen deprivation, with consequent autophagy stimulation. This allows to maintain the cellular homeostasis through different degradative pathways. Thus, since their introduction in the clinical practice, the hypotheses on SGLT2i mechanisms of action have changed: from simple glycosuric drugs, with consequent glucose lowering, erythropoiesis enhancing and ketogenesis stimulating, to intracellular sodium-lowering molecules. This provides their consequent cardioprotective effect, which justifies its significant reduction in CV events, especially in populations at higher risk. Finally, the updated clinical evidence of SGLT2i benefits on HF was summarized. Thus, this review aimed to analyze the cardioprotective mechanisms of sodium glucose transporter 2 inhibitors (SGLT2i) in patients with HF, as well as their clinical impact on cardiovascular events.

scholarly journals Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with β-cell mass

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Brenda Strutt ◽  
Sandra Szlapinski ◽  
Thineesha Gnaneswaran ◽  
Sarah Donegan ◽  
Jessica Hill ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Glucose Transporter ◽  
Cell Mass ◽  
Elevated Serum ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Transporter 2 ◽  
Glucose Stimulated Insulin Secretion

AbstractThe apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9–12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.

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