Role of ketogenic starvation sensors in mediating the renal protective effects of SGLT2 inhibitors in type 2 diabetes

2020 ◽  
Vol 34 (9) ◽  
pp. 107647 ◽  
Author(s):  
Milton Packer
Keyword(s):  
Type 2 Diabetes ◽  
Sglt2 Inhibitors ◽  
Protective Effects

scholarly journals Renal haemodynamic and protective effects of renoactive drugs in type 2 diabetes: Interaction with SGLT2 inhibitors

Nephrology ◽  
2021 ◽  
Author(s):  
Rosalie A. Scholtes ◽  
Michaël J. B. Baar ◽  
Megan D. Kok ◽  
Petter Bjornstad ◽  
David Z. I. Cherney ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Sglt2 Inhibitors ◽  
Protective Effects

scholarly journals Vascular Disease in Diabetic Women: Why Do They Miss the Female Protection?

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Ana Paula Villela Dantas ◽  
Zuleica Bruno Fortes ◽  
Maria Helena Catelli de Carvalho
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Type 2 Diabetes Mellitus ◽  
Vascular Disease ◽  
Vascular Dysfunction ◽  
Protective Effects ◽  
Vascular Protection

Gender plays a pivotal role in the onset as well as in the progression of the cardiovascular disease with a higher morbidity and mortality being detected in men with respect to women. Type 2 Diabetes Mellitus (T2DM) may reduce gender-related differences in the prevalence of cardiovascular disease by fading the vascular protective effects afforded by estrogen in females. This article will discuss the role of sex and sex hormones on the incidence and mechanisms involved in vascular dysfunction associated to T2DM, which might explain why women with T2DM lack the vascular protection.

scholarly journals SGLT2 Inhibitors for Treatment of Diabetic Nephropathy

2019 ◽  
Vol 12 (3) ◽  
Author(s):  
Nasser Mikhail
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Primary Outcome ◽  
Sglt2 Inhibitors ◽  
Drug Discontinuation ◽  
Protective Effects ◽  
Renal Protection ◽  
Ras Blockers

Background: Sodium-glucose co-transporter 2 (SGLT2) are medications approved for treatment of type 2 diabetes. Recent evidence suggests that these agents exert Reno protective effects. Methods: Review of literature (English, French, Spanish) from January 1990 to November 10, 2019. Searching terms include sodium-glucose co-transporters 2 inhibitors (SGLT2) inhibitors, chronic kidney disease (CKD), end-stage kidney disease (ESKD). Randomized trials, meta-analysis, expert opinions and guidelines are also reviewed. Results: The effects of canagliflozin on renal events were evaluated in patients with type 2 diabetes and albuminuric diabetic nephropathy already on renin-angiotensin (RAS) blockade. The primary outcome was a composite of the incidence of ESKD, doubling of serum creatinine, renal or cardiovascular (CV) death. Canagliflozin was associated with 30% reduction in the incidence of this primary outcome [hazard ratio (HR) 0.70, 95% CI 0.59-0.82, P=0.00001)]. Similar results were generally reported in large CV trials of canagliflozin, empagliflozin and dapagliflozin although renal events were secondary or post-hoc outcomes. Renoprotection by SGLT2 inhibitors was observed in patients with different degrees of renal function at baseline, with or without albuminuria, and taking or not RAS blockers. SGLT2 inhibitors were generally safe with drug discontinuation rates similar to placebo. Canagliflozin was tolerated in patients with eGFR <60 ml/min/1.73 m2. The incidence of acute renal injury was numerically less frequent with SGLT2 inhibitors compared with placebo. Conclusions: SGLT2 inhibitors slow progression of diabetic nephropathy and should be standard of care on top of RAS blockers for renal protection in patients with type 2 diabetes. Regulatory authorities should consider allowing using canagliflozin 100 mg/d in patients with estimated glomerular filtration rate (eGFR) between 30-45 ml/min/1.73 m2./p>

scholarly journals Antihyperglycemic agents as novel natriuretic therapies in diabetic kidney disease

2018 ◽  
Vol 315 (5) ◽  
pp. F1406-F1415 ◽  
Author(s):  
David León Jiménez ◽  
David Z. I. Cherney ◽  
Petter Bjornstad ◽  
Luis Castilla-Guerra ◽  
José Pablo Miramontes González
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Kidney Disease ◽  
Sglt2 Inhibitors ◽  
Tubuloglomerular Feedback ◽  
Protective Effects ◽  
Sodium Glucose Cotransporter ◽  
Sglt2 Inhibition ◽  
Clinical Benefits ◽  
Intraglomerular Pressure

While sodium-glucose cotransporter-2 (SGLT2) inhibitors have been used for the routine management of type 2 diabetes for several years, it is perhaps their natriuretic effects that are most important clinically. This natriuresis activates tubuloglomerular feedback, resulting in reduced glomerular hypertension and proteinuria, leading to renal protective effects in the EMPA-REG OUTCOME and CANVAS Program trials. In the cardiovascular system, it is likely that plasma volume contraction due to natriuresis in response to SGLT2 inhibition is at least in part responsible for the reduction in the risk of heart failure observed in these trials. We compare this mechanism of action with other antidiabetics. Importantly, other diuretic classes, including thiazide and loop diuretics, have not resulted in such robust clinical benefits in patients with type 2 diabetes, possibly because these older agents do not influence intraglomerular pressure directly. In contrast, SGLT2 inhibitors do have important physiological similarities with carbonic anhydrase inhibitors, which also act proximally, and have been shown to activate tubuloglomerular feedback.

The Role of the Kidney and SGLT2 Inhibitors in Type 2 Diabetes

2015 ◽  
Vol 39 ◽  
pp. S167-S175 ◽  
Author(s):  
Pamela M. Katz ◽  
Lawrence A. Leiter
Keyword(s):  
Type 2 Diabetes ◽  
Sglt2 Inhibitors

scholarly journals LncRNA LYPLAL1-DT in Type 2 Diabetes With Macrovascular Complication Contributes Protective Effects on Endothelial Cells via Regulating the miR-204-5p/SIRT1 Axis

2021 ◽  
Author(s):  
Xiao Zhu ◽  
Yihan Liu ◽  
Jia Cui ◽  
Jianyi Lv ◽  
Changlong Li ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Rna Sequencing ◽  
High Glucose ◽  
Metabolic Memory ◽  
Protective Effects ◽  
Macrovascular Complication ◽  
Healthy Control

Abstract Background: Long noncoding RNAs (lncRNAs) are involved in diabetes related diseases. However, the role of lncRNAs in the pathogenesis of type 2 diabetes with macrovascular complication (DMC) has seldomly been recognized. This study aimed to screen lncRNA profiles of leukocytes from DMC patients in order to explore the protective role of lncRNA LYPLAL1-DT in endothelial cells (EC) under high glucose (HG) and inflammatory conditions (IS).Methods: RNA sequencing was performed for critically pair-grouped blood samples of DMC patients and healthy control. Then the differentially expressed (DE) lncRNAs from circulating leukocytes were identified. Real-time PCR analyses were used to select the DE-lncRNAs within expanding cohorts. CCK8, transwell, Western blot, dual-luciferase system, and RIP were used to investigate the influence and molecular mechanisms of validated DE-lncRNAs in EC under HG and IS conditions. RNA sequencing was also used to identify DE-lncRNAs in exosomes isolated from the DMC serum and healthy control. Results: A total of 477 DE-lncRNAs were identified between DMC and healthy control. The enrichment and pathway analysis showed that most of them belonged to inflammatory, metabolic, and vascular diseases. A set of 12 of the 16 lncRNAs was validated as significant DE-lncRNAs in expanding cohorts. Furthermore, these DE-lncRNAs were shown to be significantly related to hypoxia, high glucose, and TNF-α stimulus (IS) in EC with an apparent metabolic memory of high glucose, especially novel lncRNA LYPLAL1-DT. LYPLAL1-DT overexpression results in the promotion of proliferation, migration of EC, as well as an elevation of autophagy under HG, and IS conditions. Overexpressed LYPLAL1-DT reduces the adhesion of monocytes to EC, boosts anti-inflammation, and suppresses inflammatory molecules secreted in the medium. Mechanistically, LYPLAL1-DT acts as ceRNA by downregulating miR-204-5p, therefore enhancing SIRT1 and protecting EC autophagy function; thus, alleviating apoptosis. Finally, exosome sequencing revealed LYPLAL1-DT expression was 4 times lower in DMC cells than in healthy samples. Conclusion: We identified 12 DE-lncRNAs related to DMC. Out of the 12 DE-lncRNAs lncRNA LYPLAL1-DT was identified to have protective effects on EC as ceRNA mediated through the miR-204-5p/SIRT1 pathway. Therefore, it inhibits the autophagy of EC as well as modulating systemic inflammation. This approach could be regarded as a new potential therapeutic target in DMC.

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