scholarly journals Sodium–Glucose Cotransporter 2 Inhibitors Work as a “Regulator” of Autophagic Activity in Overnutrition Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Kazuhiko Fukushima ◽  
Shinji Kitamura ◽  
Kenji Tsuji ◽  
Jun Wada
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Sglt2 Inhibitors ◽  
Sirtuin 1 ◽  
Therapeutic Interventions ◽  
Autophagy Flux ◽  
Protective Mechanisms ◽  
Multiple Organs ◽  
Sodium Glucose Cotransporter ◽  
Autophagic Activity

Several large clinical trials have shown renal and cardioprotective effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors in diabetes patients, and the protective mechanisms need to be elucidated. There have been accumulating studies which report that SGLT2 inhibitors ameliorate autophagy deficiency of multiple organs. In overnutrition diseases, SGLT2 inhibitors affect the autophagy via various signaling pathways, including mammalian target of rapamycin (mTOR), sirtuin 1 (SIRT1), and hypoxia-inducible factor (HIF) pathways. Recently, it turned out that not only stagnation but also overactivation of autophagy causes cellular damages, indicating that therapeutic interventions which simply enhance or stagnate autophagy activity might be a “double-edged sword” in some situations. A small number of studies suggest that SGLT2 inhibitors not only activate but also suppress the autophagy flux depending on the situation, indicating that SGLT2 inhibitors can “regulate” autophagic activity and help achieve the appropriate autophagy flux in each organ. Considering the complicated control and bilateral characteristics of autophagy, the potential of SGLT2 inhibitors as the regulator of autophagic activity would be beneficial in the treatment of autophagy deficiency.

scholarly journals Mitigation of the Adverse Consequences of Nutrient Excess on the Kidney: A Unified Hypothesis to Explain the Renoprotective Effects of Sodium-Glucose Cotransporter 2 Inhibitors

2020 ◽  
Vol 51 (4) ◽  
pp. 289-293 ◽  
Author(s):  
Milton Packer
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Renin Angiotensin System ◽  
Tissue Expansion ◽  
Adenosine Monophosphate ◽  
Sglt2 Inhibitors ◽  
Sirtuin 1 ◽  
Glomerular Hyperfiltration ◽  
Sodium Glucose Cotransporter

The 2 most common causes of chronic kidney disease worldwide (type 2 diabetes and obesity) are states of nutrient excess, suggesting that fuel overabundance leads to deleterious effects on the structure and function of the kidneys. Three pathophysiological pathways may potentially explain this linkage. First, both obesity and type 2 diabetes are characterized by glomerular hyperfiltration, which may result from increased proximal tubular reabsorption of sodium (due to enhanced glucose and sodium transport) coupled with activation of the renin-angiotensin system. Second, both obesity and type 2 diabetes are characterized by adipose tissue expansion and inflammation, followed by the augmented synthesis and release of lipid intermediates and proinflammatory adipocytokines that can have deleterious effects on the kidney. Third, states of nutrient excess cause a diminution in the activation of the energy sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). The result is a suppression of autophagy, a lysosomal degradative pathway that is responsible for the clearance of damaged organelles that are an important source of oxidative and endoplasmic reticulum stress and inflammation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors induces a transcriptional paradigm that mimics fasting, which leads to the amelioration of glomerular hyperfiltration and adipose tissue inflammation as well as augmentation of AMPK/SIRT1 signaling and autophagy, thereby acting to mute organellar and cellular stress in the kidney. Therefore, SGLT2 inhibitors are positioned to antagonize all 3 pathways by which nutrient excess can lead to nephropathy.

scholarly journals Cardioprotective Effects of Sirtuin-1 and Its Downstream Effectors

2020 ◽  
Vol 13 (9) ◽  
Author(s):  
Milton Packer
Keyword(s):  
Heart Failure ◽  
Experimental Models ◽  
Sglt2 Inhibitors ◽  
Sirtuin 1 ◽  
Nutrient Deprivation ◽  
Fibroblast Growth Factor 21 ◽  
Downstream Effectors ◽  
Sodium Glucose Cotransporter ◽  
Cardioprotective Effects ◽  
Amp Activated Protein Kinase

The cardioprotective effects of SGLT2 (sodium-glucose cotransporter 2) inhibitors may be related to their ability to induce a fasting-like paradigm, which triggers the activation of nutrient deprivation pathways to promote cellular homeostasis. The most distinctive metabolic manifestations of this fasting mimicry are enhanced gluconeogenesis and ketogenesis, which are not seen with other antihyperglycemic drugs. The principal molecular stimulus to gluconeogenesis and ketogenesis is activation of SIRT1 (sirtuin-1) and its downstream mediators: PGC-1α (proliferator-activated receptor gamma coactivator 1-alpha) and FGF21 (fibroblast growth factor 21). These three nutrient deprivation sensors exert striking cardioprotective effects in a broad range of experimental models. This benefit appears to be related to their actions to alleviate oxidative stress and promote autophagy—a lysosome-dependent degradative pathway that disposes of dysfunctional organelles that are major sources of cellular injury. Nutrient deprivation sensors are suppressed in states of perceived energy surplus (ie, type 2 diabetes mellitus and chronic heart failure), but SGLT2 inhibitors activate SIRT1/PGC-1α/FGF21 signaling and promote autophagy. This effect may be related to their action to trigger the perception of a system-wide decrease in environmental nutrients, but SGLT2 inhibitors may also upregulate SIRT1, PGC-1α, and FGF21 by a direct effect on the heart. Interestingly, metformin-induced stimulation of AMP-activated protein kinase (a nutrient deprivation sensor that does not promote ketogenesis) has not been shown to reduce heart failure events in clinical trials. Therefore, promotion of ketogenic nutrient deprivation signaling by SGLT2 inhibitors may explain their cardioprotective effects, even though SGLT2 is not expressed in the heart.

Mechanisms of Protective Effects of SGLT2 Inhibitors in Cardiovascular Disease and Renal Dysfunction

2019 ◽  
Vol 19 (20) ◽  
pp. 1818-1849 ◽  
Author(s):  
Ban Liu ◽  
Yuliang Wang ◽  
Yangyang Zhang ◽  
Biao Yan
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Renal Dysfunction ◽  
Sglt2 Inhibitors ◽  
Sodium Glucose Cotransporter ◽  
Glucose Reabsorption ◽  
Renal Glucose Reabsorption

: Type 2 diabetes mellitus is one of the most common forms of the disease worldwide. Hyperglycemia and insulin resistance play key roles in type 2 diabetes mellitus. Renal glucose reabsorption is an essential feature in glycaemic control. Kidneys filter 160 g of glucose daily in healthy subjects under euglycaemic conditions. The expanding epidemic of diabetes leads to a prevalence of diabetes-related cardiovascular disorders, in particular, heart failure and renal dysfunction. Cellular glucose uptake is a fundamental process for homeostasis, growth, and metabolism. In humans, three families of glucose transporters have been identified, including the glucose facilitators GLUTs, the sodium-glucose cotransporter SGLTs, and the recently identified SWEETs. Structures of the major isoforms of all three families were studied. Sodium-glucose cotransporter (SGLT2) provides most of the capacity for renal glucose reabsorption in the early proximal tubule. A number of cardiovascular outcome trials in patients with type 2 diabetes have been studied with SGLT2 inhibitors reducing cardiovascular morbidity and mortality. : The current review article summarises these aspects and discusses possible mechanisms with SGLT2 inhibitors in protecting heart failure and renal dysfunction in diabetic patients. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed down the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.

Efficacy and cardiovascular safety of SGLT2 Inhibitors

2020 ◽  
Vol 15 ◽  
Author(s):  
Cornelius James Fernandez ◽  
Abisha Graciano Nevins ◽  
Shasta Nawaz ◽  
Tahir Nazir ◽  
Fahmy W F Hanna
Keyword(s):  
Decision Process ◽  
Cardiovascular Events ◽  
Unmet Need ◽  
Clinical Decision ◽  
Sglt2 Inhibitors ◽  
Renal Protection ◽  
Sodium Glucose Cotransporter ◽  
Patients With Diabetes ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

: Patients with diabetes continued to exhibit a high risk for cardiovascular and renal events despite achieving satisfactory glycemic, blood pressure and lipid targets. Studies evaluating new diabetes medications focused on cardiovascular events, largely overlooking heart failure (HF). The latter has recently been recognised as a major cause of morbidity and mortality in patients with diabetes mellitus. There had been an unmet need for drugs with cardiovascular (including HF) and renal protection, with an expectation that an ideal diabetic drug should improve these end points. Moreover, an ideal drug should have weight lowering benefits. Recently published outcome trials have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) can reduce cardiovascular and renal events, together with statistically significant weight reduction. As a result, many recently published international guidelines have recommended SGLT2 inhibitors and GLP-1RAs in patients with diabetes and pre-existing cardiovascular disease (CVD). In this review we will critically analyse the efficacy and cardiovascular (CV) safety of SGLT2 inhibitors, based on the available literature to help position them in the clinical decision process.

scholarly journals Central administration of sodium-glucose cotransporter-2 inhibitors increases food intake involving adenosine monophosphate-activated protein kinase phosphorylation in the lateral hypothalamus in healthy rats

2021 ◽  
Vol 9 (1) ◽  
pp. e002104
Author(s):  
Kenji Takeda ◽  
Hiraku Ono ◽  
Ko Ishikawa ◽  
Tomohiro Ohno ◽  
Jin Kumagai ◽  
...  
Keyword(s):  
Food Intake ◽  
Lateral Hypothalamus ◽  
Molecular Mechanisms ◽  
Intraperitoneal Administration ◽  
Adenosine Monophosphate ◽  
Sglt2 Inhibitors ◽  
Central Administration ◽  
Hypothalamic Area ◽  
Sodium Glucose Cotransporter ◽  
Increase Food Intake

IntroductionSodium glucose cotransporter-2 (SGLT2) inhibitors are widely used for diabetes treatment. Although SGLT2 inhibitors have been clinically observed to increase food intake, roles or even the presence of SGLT2 in the central nervous system (CNS) has not been established. We aimed to elucidate potential functions of SGLT2 in the CNS, and the effects of CNS-targeted SGLT2 inhibitors on food intake.Research design and methodsWe administered three kinds of SGLT2 inhibitors, tofogliflozin, dapagliflozin, and empagliflozin, into the lateral ventricle (LV) in rats and evaluated their effects on food intake. We also evaluated the effects of tofogliflozin administration in the third (3V) and fourth ventricle (4V). Intraperitoneal administration of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist known to suppress food intake, was combined with central tofogliflozin to elucidate whether GLP-1 signaling antagonizes the effect of central SGLT2 inhibitors on food intake. To elucidate potential molecular mechanisms mediating changes in feeding, hypothalamic areas associated with food intake regulation were harvested and analyzed after intracerebroventricular administration (ICV) of tofogliflozin.ResultsBolus ICV injection of tofogliflozin induced a robust increase in food intake starting at 1.5 hours postinjection, and lasting for 5 days. No effect was observed when the same dose of tofogliflozin was administered intraperitoneally. ICV dapagliflozin and empagliflozin significantly enhanced food intake, although the strength of these effects varied among drugs. Food intake was most markedly enhanced when tofogliflozin was infused into the LV. Fewer or no effects were observed with infusion into the 3V or 4V, respectively. Systemic administration of liraglutide suppressed the effect of ICV tofogliflozin on food intake. ICV tofogliflozin increased phosphorylation of AMPK and c-fos expression in the lateral hypothalamus.ConclusionsSGLT2 inhibitors in the CNS increase food intake. SGLT2 activity in the CNS may regulate food intake through AMPK phosphorylation in the lateral hypothalamic area.

α-Oxoaldehyde metabolism and diabetic complications

2003 ◽  
Vol 31 (6) ◽  
pp. 1358-1363 ◽  
Author(s):  
P.J. Beisswenger ◽  
S.K. Howell ◽  
R.G. Nelson ◽  
M. Mauer ◽  
B.S. Szwergold
Keyword(s):  
Diabetic Complications ◽  
Complex Mixture ◽  
Therapeutic Interventions ◽  
Diabetic Patients ◽  
Human Populations ◽  
Control Mechanisms ◽  
Protective Mechanisms ◽  
Glycation End Products ◽  
End Products

The factors responsible for variable susceptibility to diabetic nephropathy are not clear. According to the non-enzymatic glycation hypothesis, diabetes-related tissue damage occurs due to a complex mixture of toxic products, including α-oxoaldehydes, which are inherently toxic as well as serving as presursors for advanced glycation end-products. Protective mechanisms exist to control this unavoidable glycation, and these are determined by genetic or environmental factors that can regulate the concentrations of the reactive sugars or end-products. In diabetes these protective mechanisms become more important, since glycation stress increases, and less efficient defence systems against this stress could lead to diabetic complications. Some of these enzymatic control mechanisms, including those that regulate α-oxoaldehydes, have been identified. We have observed significant increases in production of the α-oxoaldehydes methylglyoxal and 3-deoxyglucosone in three human populations with biopsy-proven progression of nephropathy. The increase in methylglyoxal could be secondary to defects in downstream glycolytic enzymes (such as glyceraldehyde-3-phosphate dehydrogenase) that regulate its production, or in detoxification mechanisms such as glyoxalase. Other mechanisms, however, appear to be responsible for the observed increase in 3-deoxyglucosone levels. We present results of our studies on the mechanisms responsible for variable production of α-oxoaldehydes by measuring the activity and characteristics of these enzymes in cells from complication-prone and -resistant diabetic patients. New therapeutic interventions designed to control these endogenous mechanisms could potentially enhance protection against excessive glycation and prevent or reverse complications of long-term diabetes.

scholarly journals Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors: Renoprotective Mechanisms beyond Glycemic Control

2021 ◽  
Vol 22 (9) ◽  
pp. 4374
Author(s):  
Tomoaki Takata ◽  
Hajime Isomoto
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Glycemic Control ◽  
Kidney Injury ◽  
Sglt2 Inhibitors ◽  
Pleiotropic Effects ◽  
Future Research ◽  
Diabetic Patients ◽  
Sodium Glucose Cotransporter ◽  
Stage Renal Disease

Diabetes mellitus is a major cause of chronic kidney disease and end-stage renal disease. However, the management of chronic kidney disease, particularly diabetes, requires vast improvements. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for the treatment of diabetes, have been shown to protect against kidney injury via glycemic control, as well as various other mechanisms, including blood pressure and hemodynamic regulation, protection from lipotoxicity, and uric acid control. As such, regulation of these mechanisms is recommended as an effective multidisciplinary approach for the treatment of diabetic patients with kidney disease. Thus, SGLT2 inhibitors are expected to become key drugs for treating diabetic kidney disease. This review summarizes the recent clinical evidence pertaining to SGLT2 inhibitors as well as the mechanisms underlying their renoprotective effects. Hence, the information contained herein will advance the current understanding regarding the pleiotropic effects of SGLT2 inhibitors, while promoting future research in the field.

scholarly journals Pharmacovigilance of Sodium-Glucose Cotransporter-2 Inhibitors for Genital Fungal Infections and Urinary Tract Infections: A Review of the Food and Drug Administration Adverse Event Reporting System Database

2018 ◽  
Vol 34 (4) ◽  
pp. 144-148
Author(s):  
Hannah Mohammad ◽  
Nancy Borja-Hart
Keyword(s):  
Urinary Tract ◽  
Tract Infection ◽  
Adverse Events ◽  
Fungal Infections ◽  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
Sglt2 Inhibitors ◽  
Postmarketing Surveillance ◽  
Sodium Glucose Cotransporter ◽  
Tract Infections

Background: Postmarketing surveillance had previously identified the need for revisions in the labeling of the sodium-glucose cotransporter-2 (SGLT2) inhibitors drug class related to the risk of diabetic ketoacidosis. Other adverse events have been reported. Objective: To examine postmarketing surveillance data of the SGLT2 inhibitors, using the Food and Drug Administration Adverse Event Reporting System (FAERS) database, specifically to assess prevalence of urinary tract infections (UTIs) and genital fungal infections. Methods: FAERS case reports submitted between March 2013 and November 2015 were reviewed for 6 SGLT2 inhibitors (mono and combo therapies). The Medical Dictionary for Regulatory Activities (MedDRA) was used to define preferred terms (genital fungal infections: vulvovaginal mycotic infection, vulvovaginal candidiasis, urinary tract infection fungal, and genital candidiasis; UTI: urinary tract infection, genitourinary tract infection, kidney infection, cystitis, and pyelonephritis). Word frequencies were queried using the qualitative data analysis software NVivo 11 (QSR International), and results were then individually reviewed. Results: A total of 12 581 cases were received, but 466 were excluded (total n = 12 115). A total of 348 cases related to genital fungal infections were reported (2.9% of reports submitted): dapagliflozin = 53, empagliflozin/linagliptin = 6, canagliflozin = 267, canagliflozin/metformin = 3, empagliflozin = 17, and dapagliflozin/metformin HCl ER = 2. A total of 727 cases related to UTIs were reported (6% of reports submitted): dapagliflozin = 168, empagliflozin/linagliptin = 5, canagliflozin/metformin = 8, canagliflozin = 503, empagliflozin = 38, and dapagliflozin/metformin HCl ER = 5. Conclusions: A causal relationship between SGLT2 inhibitors and the adverse events reported cannot be established due to the nature of postmarketing surveillance. However, health care providers should counsel patients about these potential adverse events.

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