Sitagliptin Protects Cardiac Function by Reducing Nitroxidative Stress and Promoting Autophagy in Zucker Diabetic Fatty (ZDF) Rats

Zhang, Yi; Wang, Huanyuan; Man, Fuli; Guo, Zhiying; Xu, Jiahui; Yan, Wenjing; Pan, Qi; Wang, Wen

doi:10.1007/s10557-018-6831-9

Cited by 29 publications

(9 citation statements)

References 37 publications

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“…Enhanced levels of TG, TC, HDLC, and LDL cholesterol (LDLC) were recorded in our diabetic control group versus the lean one, thus supporting the findings of Pang et al [30] and Zhou et al [31]. Our results revealed that a higher dose of BB reduces TG and TC levels, presumably due to hypotriglyceridaemic and hypocholesterolemic properties of BB.…”

Section: Discussionsupporting

confidence: 91%

Bee Bread Can Alleviate Lipid Abnormalities and Impaired Bone Morphology in Obese Zucker Diabetic Rats

et al. 2021

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This study examined for the first time whether bee bread (BB, consisting of monofloral rape bee pollen) could alleviate lipid derangements and reduced bone quality in Zucker diabetic fatty (ZDF) rats, which are considered an appropriate animal model for type 2 diabetes mellitus (T2DM) investigation. Adult ZDF rats were segregated into four groups: lean non-diabetic rats (L group), obese diabetic rats untreated (C group), and those treated with the BB at two doses (500 and 700 mg/kg body weight, respectively, B1 and B2 groups) for 10 weeks. Significantly reduced levels of total cholesterol and triglyceride were recorded in the B2 group versus the C group. In both BB-treated groups, significantly increased relative volume of trabecular bone and trabecular thickness, enhanced density of secondary osteons, accelerated periosteal bone apposition, and improved blood flow were observed. A positive effect of higher dose of BB on femoral weight and cortical bone thickness was also demonstrated. Our results suggest a promising potential of BB to ameliorate T2DM-related complications associated with lipid and bone damages.

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Section: Discussionsupporting

confidence: 91%

Bee Bread Can Alleviate Lipid Abnormalities and Impaired Bone Morphology in Obese Zucker Diabetic Rats

et al. 2021

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“…Theoretically, any antihyperglycemic drug might increase the activity of low-energy sensors and promote autophagy simply by lowering blood glucose; however, the magnitude of the effect may be modest and be offset by other actions. Incretins and thiazolidinediones have been reported to enhance autophagy in experimental models [68][69][70], but they potentiate the release and/ or response to insulin, which acts to suppress autophagy [71]. These effects may help to explain why enhanced insulin signaling adversely affects the course of heart failure [72].…”

Section: Effect Of Antihyperglycemic Drugs On Autophagic Flux Nutrient Deprivation Signaling and Cellular Stressmentioning

confidence: 99%

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

Packer

2020

Cardiovasc Diabetol

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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.

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“…Canagliflozin, another SGLT2 inhibitor, activated autophagy in immune cells [29]. A negative correlation between beclin-1 and DPP4 activity was observed in patients with coronary heart disease [59]. The DPP4 inhibitors vildagliptin and sitagliptin improved cardiac function after myocardial infarction through activation of autophagy in the rodent models of diabetes [60,61].…”

Section: Reactivation Of Autophagy: a Missing Link In The Mechanism Omentioning

confidence: 99%

“…The DPP4 inhibitors vildagliptin and sitagliptin improved cardiac function after myocardial infarction through activation of autophagy in the rodent models of diabetes [60,61]. Sitagliptin activated autophagy in cardiac muscle in Zucker diabetic fatty rats, in high-glucose cultured embryonic heart myoblastic (H9c2) cells [59] and in the liver of ob/ob mice, a mouse model of genetic obesity and diabetes [62].…”

Section: Reactivation Of Autophagy: a Missing Link In The Mechanism Omentioning

confidence: 99%

SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

Korbut

Taskaeva

Bgatova

et al. 2020

IJMS

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Recent data have indicated the emerging role of glomerular autophagy in diabetic kidney disease. We aimed to assess the effect of the SGLT2 inhibitor empagliflozin, the DPP4 inhibitor linagliptin, and their combination, on glomerular autophagy in a model of type 2 diabetes. Eight-week-old male db/db mice were randomly assigned to treatment with empagliflozin, linagliptin, empagliflozin-linagliptin or vehicle for 8 weeks. Age-matched non-diabetic db/+ mice acted as controls. To estimate glomerular autophagy, immunohistochemistry for beclin-1 and LAMP-1 was performed. Podocyte autophagy was assessed by counting the volume density (Vv) of autophagosomes, lysosomes and autolysosomes by transmission electron microscopy. LC3B and LAMP-1, autophagy markers, and caspase-3 and Bcl-2, apoptotic markers, were evaluated in renal cortex by western blot. Vehicle-treated db/db mice had weak glomerular staining for beclin-1 and LAMP-1 and reduced Vv of autophagosomes, autolysosomes and lysosomes in podocytes. Empagliflozin and linagliptin, both as monotherapy and in combination, enhanced the areas of glomerular staining for beclin-1 and LAMP-1 and increased Vv of autophagosomes and autolysosomes in podocytes. Renal LC3B and Bcl-2 were restored in actively treated animals. LAMP-1 expression was enhanced in the empagliflozin group; caspase-3 expression decreased in the empagliflozin-linagliptin group only. Mesangial expansion, podocyte foot process effacement and urinary albumin excretion were mitigated by both agents. The data provide further explanation for the mechanism of the renoprotective effect of SGLT2 inhibitors and DPP4 inhibitors in diabetes.Int. J. Mol. Sci. 2020, 21, 2987 2 of 22 dedifferentiation. In its turn, the loss or damage of podocytes causes dysfunction of the filtration barrier and increases albuminuria [2]. Some recent studies have indicated an emerging role of autophagy downregulation in diabetic podocytopathy [4][5][6]. Autophagy is a cellular recycling process involving self-degradation and reconstruction of damaged organelles and proteins [6]. The process is vital for highly differentiated post-mitotic cells, such as neurons and podocytes [7]. A growing body of evidence indicates a critical role of autophagy in maintaining podocyte integrity and renal function [6]. Mice with podocyte-specific deletion of autophagic regulators, such as class III PI3K vacuolar protein sorting 34 (Vps34) and the Atg5 gene, develop early proteinuria, progressive glomerulosclerosis, and renal failure [6]. Accordingly, autophagy is considered a potential therapeutic target for renal protection [8,9].Sodium-glucose cotransporter-2 (SGLT2) inhibitors and dipeptidylpeptidase-4 (DPP4) inhibitors are promising antidiabetic agents introduced into clinical practice in the last decade. The antihyperglycemic effect of SGLT2 inhibitors is mediated by increment of glucosuria, while DPP4 inhibitors realize their activity through an increase in the half-life of incretin hormones. Both SGLT2 and DPP4 inhibitors demonstrated renal protective...

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Sitagliptin Protects Cardiac Function by Reducing Nitroxidative Stress and Promoting Autophagy in Zucker Diabetic Fatty (ZDF) Rats

Cited by 29 publications

References 37 publications

Bee Bread Can Alleviate Lipid Abnormalities and Impaired Bone Morphology in Obese Zucker Diabetic Rats

Bee Bread Can Alleviate Lipid Abnormalities and Impaired Bone Morphology in Obese Zucker Diabetic Rats

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

SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

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