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

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.

Diabetes Mellitus, Mitochondrial Dysfunction and Ca2+-Dependent Permeability Transition Pore

“…In rodent models of type 2 diabetes induced by a high-fat diet and low doses of streptozotocin treatment, autophagy was shown to be activated in pancreatic β-cells [ 21 , 70 ]. With the progression of diabetes mellitus in humans and laboratory animals, the mitochondrial-specific autophagy is suppressed in many tissues and organs (pancreas, heart, skeletal muscle, eyes) [ 20 , 22 , 23 , 24 , 25 , 28 , 71 ], which may be associated with a decrease in the activation of AMPK and SIRT1 [ 72 , 73 , 74 ]. Some studies revealed that the chronically elevated level of glucose upon type I diabetes induces the accumulation of p53 protein in the cytoplasm of β-cells of the pancreas.…”

Mitochondrial dysfunction in cardiovascular disease: Current status of translational research/clinical and therapeutic implications

“…161,162 Interestingly, metformin and SGLT2 inhibitors have been reported to activate SIRT1 that may partly be contributing to their cardioprotective and HF-ameliorating effects. 88…”

“…154 Furthermore, metformin and SGLT2 inhibitors activate SIRT1 and/or AMP-activated protein kinase and variably promote autophagic flux in cardiomyocytes, which may partially explain their benefits in HF. 88 On the other hand, inhibition of autophagy/mitophagy, for example, by administering 3-methyladenine targeting several variants of phosphatidylinositol 3-kinase (PI3K), and bafilomycin A1 suppressing functions of lysosome, may lead to CVD progression. 173,186 In an animal study, the antihypertrophic and antiapoptotic effects of puerarin, an isoflavone that activates autophagy, were blocked after suppression of autophagy by pretreatment with 3-methyladenine.…”

<p>SGLT2 Inhibitors: A Novel Player in the Treatment and Prevention of Diabetic Cardiomyopathy</p>

“…12 In addition, they cannot be ascribed to natriuretic effect, since diuretic therapy has been associated with increased risk of CVD and mortality in patients with HF. [13][14][15][16] As a consequence, accumulating evidence has been gathered in an attempt to figure out the possible underlying mechanisms of cardioprotection. In view of the rapid decline in risk of HHF, it can be speculated that the benefits of SGLT2Is are due to the direct effects on the heart itself, namely improved DCM, instead of metabolic improvement.…”