NDLI: Autophagy-dependent and -independent modulation of oxidative and organellar stress in the diabetic heart by glucose-lowering drugs

Content Provider	Springer Nature : BioMed Central
Author	Packer, Milton
Abstract	Autophagy is a lysosome-dependent intracellular degradative pathway, which mediates the cellular adaptation to nutrient and oxygen depletion as well as to oxidative and endoplasmic reticulum stress. The molecular mechanisms that stimulate autophagy include the activation of energy deprivation sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). These enzymes not only promote organellar integrity directly, but they also enhance autophagic flux, which leads to the removal of dysfunctional mitochondria and peroxisomes. Type 2 diabetes is characterized by suppression of SIRT1 and AMPK signaling as well as an impairment of autophagy; these derangements contribute to an increase in oxidative stress and the development of cardiomyopathy. Antihyperglycemic drugs that signal through insulin may further suppress autophagy and worsen heart failure. In contrast, metformin and SGLT2 inhibitors activate SIRT1 and/or AMPK and promote autophagic flux to varying degrees in cardiomyocytes, which may explain their benefits in experimental cardiomyopathy. However, metformin and SGLT2 inhibitors differ meaningfully in the molecular mechanisms that underlie their effects on the heart. Whereas metformin primarily acts as an agonist of AMPK, SGLT2 inhibitors induce a fasting-like state that is accompanied by ketogenesis, a biomarker of enhanced SIRT1 signaling. Preferential SIRT1 activation may also explain the ability of SGLT2 inhibitors to stimulate erythropoiesis and reduce uric acid (a biomarker of oxidative stress)—effects that are not seen with metformin. Changes in both hematocrit and serum urate are the most important predictors of the ability of SGLT2 inhibitors to reduce the risk of cardiovascular death and hospitalization for heart failure in large-scale trials. Metformin and SGLT2 inhibitors may also differ in their ability to mitigate diabetes-related increases in intracellular sodium concentration and its adverse effects on mitochondrial functional integrity. Differences in the actions of SGLT2 inhibitors and metformin may reflect the distinctive molecular pathways that explain differences in the cardioprotective effects of these drugs.
Related Links	https://cardiab.biomedcentral.com/counter/pdf/10.1186/s12933-020-01041-4.pdf
Ending Page	11
Page Count	11
Starting Page	1
File Format	HTM / HTML
ISSN	14752840
DOI	10.1186/s12933-020-01041-4
Journal	Cardiovascular Diabetology
Issue Number	1
Volume Number	19
Language	English
Publisher	BioMed Central
Publisher Date	2020-05-13
Access Restriction	Open
Subject Keyword	Diabetes Angiology Cardiology Autophagy SGLT2 inhibitors Metformin Sirtuin-1 Uric acid
Content Type	Text
Resource Type	Review
Subject	Cardiology and Cardiovascular Medicine Internal Medicine Endocrinology, Diabetes and Metabolism
Journal Impact Factor	8.5/2023
5-Year Journal Impact Factor	8.9/2023

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart

Direct cardiac effects of SGLT2 inhibitors

The impact of metformin on kidney disease progression and mortality in diabetic patients using SGLT2 inhibitors: a real-world cohort study

Different effects of SGLT2 inhibitors according to the presence and types of heart failure in type 2 diabetic patients

Differences in outcomes of hospitalizations for heart failure after SGLT2 inhibitor treatment: effect modification by atherosclerotic cardiovascular disease

SGLT2 inhibitors and lower limb complications: an updated meta‐analysis

Cardiovascular outcomes with sodium–glucose cotransporter-2 inhibitors vs other glucose-lowering drugs in 13 countries across three continents: analysis of CVD-REAL data

The protective role of SGLT2 inhibitors on aortic aneurysm mediated by oxidative stress and inflammation in type 2 diabetes mellitus

The potential anti-arrhythmic effect of SGLT2 inhibitors

Autophagy-dependent and -independent modulation of oxidative and organellar stress in the diabetic heart by glucose-lowering drugs

Similar Documents

SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart

Direct cardiac effects of SGLT2 inhibitors

The impact of metformin on kidney disease progression and mortality in diabetic patients using SGLT2 inhibitors: a real-world cohort study

Different effects of SGLT2 inhibitors according to the presence and types of heart failure in type 2 diabetic patients

Differences in outcomes of hospitalizations for heart failure after SGLT2 inhibitor treatment: effect modification by atherosclerotic cardiovascular disease

SGLT2 inhibitors and lower limb complications: an updated meta‐analysis

Cardiovascular outcomes with sodium–glucose cotransporter-2 inhibitors vs other glucose-lowering drugs in 13 countries across three continents: analysis of CVD-REAL data

The protective role of SGLT2 inhibitors on aortic aneurysm mediated by oxidative stress and inflammation in type 2 diabetes mellitus

The potential anti-arrhythmic effect of SGLT2 inhibitors

Autophagy-dependent and -independent modulation of oxidative and organellar stress in the diabetic heart by glucose-lowering drugs