Empagliflozin prevents cardiomyopathy via sGC-cGMP-PKG pathway in type 2 diabetes mice

Abstract Cardiovascular complications contribute to the major mortality and morbidity in type 2 diabetes. Diabetic cardiomyopathy (DCM) is increasingly recognized as an important cause of heart failure. EMPA-REG OUTCOME trial has reported that empagliflozin, the sodium-glucose cotransporter 2 inhibitor, exerts cardiovascular benefits on diabetic population. However, the mechanism by which empagliflozin alleviates DCM still remains unclear. In the current study, we investigated the cardiac protective effects of empagliflozin on spontaneous type 2 diabetic db/db mice and its potential mechanism. Eight weeks of empagliflozin treatment (10 mg/kg/day) decreased body weight and blood glucose level, and increased urinary glucose excretion (UGE) in diabetic mice. Echocardiography revealed that both systolic and diastolic functions of db/db mice were also obviously improved by empagliflozin. Furthermore, empagliflozin-treated diabetic mice presented with amelioration of cardiac hypertrophy and fibrosis. In addition, diabetic hearts exhibited the deterioration of oxidative stress, apoptosis and pyroptosis, while these effects were significantly counteracted after empagliflozin treatment. Moreover, empagliflozin rescued diabetes-induced suppression of sGC (soluble guanylate cyclase enzyme)-cGMP (cyclic guanosine monophosphate)-PKG (cGMP-dependent protein kinase) pathway. However, when sGC-β expression of hearts was inhibited by transvascular delivery of small interfering RNA, cardiac dysfunction was aggravated and the advantages of empagliflozin were reversed through inhibiting sGC-cGMP-PKG pathway. Collectively, these findings indicate that empagliflozin improves cardiac function involving the inhibition of oxidative stress-induced injury via sGC-cGMP-PKG pathway and may be a promising therapeutic option for DCM.

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Decreased glycolytic and tricarboxylic acid cycle intermediates coincide with peripheral nervous system oxidative stress in a murine model of type 2 diabetes

Journal of Endocrinology ◽

10.1530/joe-12-0356 ◽

2012 ◽

Vol 216 (1) ◽

pp. 1-11 ◽

Cited By ~ 46

Author(s):

Lucy M Hinder ◽

Anuradha Vivekanandan-Giri ◽

Lisa L McLean ◽

Subramaniam Pennathur ◽

Eva L Feldman

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Sciatic Nerve ◽

Peripheral Nerves ◽

Sural Nerve ◽

Tca Cycle ◽

Tricarboxylic Acid ◽

Diabetic Mice ◽

Type 2 Diabetic

Diabetic neuropathy (DN) is the most common complication of diabetes and is characterized by distal-to-proximal loss of peripheral nerve axons. The idea of tissue-specific pathological alterations in energy metabolism in diabetic complications-prone tissues is emerging. Altered nerve metabolism in type 1 diabetes models is observed; however, therapeutic strategies based on these models offer limited efficacy to type 2 diabetic patients with DN. Therefore, understanding how peripheral nerves metabolically adapt to the unique type 2 diabetic environment is critical to develop disease-modifying treatments. In the current study, we utilized targeted liquid chromatography–tandem mass spectrometry (LC/MS/MS) to characterize the glycolytic and tricarboxylic acid (TCA) cycle metabolomes in sural nerve, sciatic nerve, and dorsal root ganglia (DRG) from male type 2 diabetic mice (BKS.Cg-m+/+Leprdb;db/db) and controls (db/+). We report depletion of glycolytic intermediates in diabetic sural nerve and sciatic nerve (glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-bisphosphate (sural nerve only), 3-phosphoglycerate, 2-phosphoglycerate, phosphoenolpyruvate, and lactate), with no significant changes in DRG. Citrate and isocitrate TCA cycle intermediates were decreased in sural nerve, sciatic nerve, and DRG from diabetic mice. Utilizing LC/electrospray ionization/MS/MS and HPLC methods, we also observed increased protein and lipid oxidation (nitrotyrosine; hydroxyoctadecadienoic acids) indb/dbtissue, with a proximal-to-distal increase in oxidative stress, with associated decreased aconitase enzyme activity. We propose a preliminary model, whereby the greater change in metabolomic profile, increase in oxidative stress, and decrease in TCA cycle enzyme activity may cause distal peripheral nerves to rely on truncated TCA cycle metabolism in the type 2 diabetes environment.

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L-Carnosine Stimulation of Coenzyme Q10 Biosynthesis Promotes Improved Mitochondrial Function and Decreases Hepatic Steatosis in Diabetic Conditions

Antioxidants ◽

10.3390/antiox10050793 ◽

2021 ◽

Vol 10 (5) ◽

pp. 793

Author(s):

Cheng Schwank-Xu ◽

Elisabete Forsberg ◽

Magnus Bentinger ◽

Allan Zhao ◽

Ishrath Ansurudeen ◽

...

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Mouse Model ◽

Mitochondrial Function ◽

Diabetes Complications ◽

Synergistic Effects ◽

Coenzyme Q ◽

Protective Effects ◽

Beneficial Effects

Mitochondrial dysfunction in type 2 diabetes leads to oxidative stress, which drives disease progression and diabetes complications. L-carnosine, an endogenous dipeptide, improves metabolic control, wound healing and kidney function in animal models of type 2 diabetes. Coenzyme Q (CoQ), a component of the mitochondrial electron transport chain, possesses similar protective effects on diabetes complications. We aimed to study the effect of carnosine on CoQ, and assess any synergistic effects of carnosine and CoQ on improved mitochondrial function in a mouse model of type 2 diabetes. Carnosine enhanced CoQ gene expression and increased hepatic CoQ biosynthesis in db/db mice, a type 2 diabetes model. Co-administration of Carnosine and CoQ improved mitochondrial function, lowered ROS formation and reduced signs of oxidative stress. Our work suggests that carnosine exerts beneficial effects on hepatic CoQ synthesis and when combined with CoQ, improves mitochondrial function and cellular redox balance in the liver of diabetic mice. (4) Conclusions: L-carnosine has beneficial effects on oxidative stress both alone and in combination with CoQ on hepatic mitochondrial function in an obese type 2 diabetes mouse model.

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Additive protection by LDR and FGF21 treatment against diabetic nephropathy in type 2 diabetes model

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00026.2015 ◽

2015 ◽

Vol 309 (1) ◽

pp. E45-E54 ◽

Cited By ~ 13

Author(s):

Minglong Shao ◽

Lechu Yu ◽

Fangfang Zhang ◽

Xuemian Lu ◽

Xiaokun Li ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Diabetic Nephropathy ◽

Combination Treatment ◽

Combined Treatment ◽

Protective Effects ◽

Diabetic Mice ◽

Renal Protection ◽

Glucose Levels

The onset of diabetic nephropathy (DN) is associated with both systemic and renal changes. Fibroblast growth factor (FGF)-21 prevents diabetic complications mainly by improving systemic metabolism. In addition, low-dose radiation (LDR) protects mice from DN directly by preventing renal oxidative stress and inflammation. In the present study, we tried to define whether the combination of FGF21 and LDR could further prevent DN by blocking its systemic and renal pathogeneses. To this end, type 2 diabetes was induced by feeding a high-fat diet for 12 wk followed by a single dose injection of streptozotocin. Diabetic mice were exposed to 50 mGy LDR every other day for 4 wk with and without 1.5 mg/kg FGF21 daily for 8 wk. The changes in systemic parameters, including blood glucose levels, lipid profiles, and insulin resistance, as well as renal pathology, were examined. Diabetic mice exhibited renal dysfunction and pathological abnormalities, all of which were prevented significantly by LDR and/or FGF21; the best effects were observed in the group that received the combination treatment. Our studies revealed that the additive renal protection conferred by the combined treatment against diabetes-induced renal fibrosis, inflammation, and oxidative damage was associated with the systemic improvement of hyperglycemia, hyperlipidemia, and insulin resistance. These results suggest that the combination treatment with LDR and FGF21 prevented DN more efficiently than did either treatment alone. The mechanism behind these protective effects could be attributed to the suppression of both systemic and renal pathways.

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Beneficial Effects of Poplar Buds on Hyperglycemia, Dyslipidemia, Oxidative Stress, and Inflammation in Streptozotocin-Induced Type-2 Diabetes

Journal of Immunology Research ◽

10.1155/2018/7245956 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Shiqin Peng ◽

Ping Wei ◽

Qun Lu ◽

Rui Liu ◽

Yue Ding ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Blood Glucose ◽

Crude Extract ◽

Liver Homogenate ◽

Control Group ◽

Diabetic Mice ◽

Model Control

The effects of propolis on blood glucose regulation and the alleviation of various complications caused by diabetes have been widely studied. The main source of propolis in the northern temperate zone is poplar buds. However, there is limited research on the antidiabetic activity of poplar buds. In order to evaluate the effect of poplar buds on type-2 diabetes, crude extract and 50% fraction of poplar buds were used to feed streptozotocin-induced type-2 diabetic mice. The results showed that 50% fraction could increase insulin sensitivity and reduce insulin resistance, as well as decrease the levels of fasting blood glucose, glycated hemoglobin, and glycosylated serum proteins in diabetic mice. Compared with the model control group, the 50% fraction-treated group showed significant decreases of malondialdehyde (MDA) and increases of superoxide dismutase (SOD) in serum and liver homogenate. Moreover, 50% fraction could significantly decrease total cholesterol (TC), alleviate abnormal lipid metabolism, and enhance antioxidant capacity in the serum. For inflammatory factors, feeding of 50% fraction could also reduce the levels of interleukin 6 (IL-6), tumor necrosis factorα(TNF-α), monocyte chemotactic protein 1 (MCP-1), and cyclooxygenase-2 (COX-2) in liver homogenate. Taken together, our results suggest that crude extract and 50% fraction of poplar buds, particularly the latter, can decrease blood glucose levels and insulin resistance, and 50% fraction can significantly relieve dyslipidemia, oxidative stress, and inflammation caused by type-2 diabetes.

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Administration of Lactobacillus paracasei ameliorates type 2 diabetes in mice

Food & Function ◽

10.1039/c8fo00081f ◽

2018 ◽

Vol 9 (7) ◽

pp. 3630-3639 ◽

Cited By ~ 22

Author(s):

Fangfang Dang ◽

Yujun Jiang ◽

Ruili Pan ◽

Yanhong Zhou ◽

Shuang Wu ◽

...

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Lipid Metabolism ◽

Glucose Metabolism ◽

Lactobacillus Paracasei ◽

Akt Pathway ◽

Diabetic Mice ◽

Diabetes In Mice ◽

Dose Dependent

Lactobacillus paracasei TD062 with high inhibitory activity ameliorated lipid metabolism, oxidative stress, glucose metabolism and the PI3K/Akt pathway in diabetic mice, and the effects were dose-dependent to some extent.

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Abstract 038: Hyperglycemia Mediated Cardiac Damage in High-Fat Fed E487K Aldehyde Dehydrogenase 2 (ALDH 2*2) Mutant Diabetic Mice: Role for ALDH2 Activation

Hypertension ◽

10.1161/hyp.68.suppl_1.038 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Guodong Pan ◽

Suresh Palaniyandi

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Cardiac Function ◽

Aldehyde Dehydrogenase ◽

Diabetic Mice ◽

High Fat ◽

Aldehyde Dehydrogenase 2 ◽

Cardiac Damage

Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme in the heart, detoxifies reactive aldehydes and protects heart from oxidative stress. East Asians (~700 million) are carriers of E487K point mutation of ALDH2 (ALDH2*2) with intrinsically low ALDH2 activity. ALDH2*2 is associated with increased maternal inheritance of diabetes mellitus (DM), and DM-induced neuropathy and vasculopathy. However the pathophysiology of diabetic cardiac damage.is not studied in ALDH2*2 carriers. DM is a polygenic disease and DM-induced cardiac damage may be multifactorial. However we hypothesis that hyperglycemia-induced oxidative stress mediated 4-hydroxy-2-nonel (4HNE) toxicity contributes to the cardiac damage in ALDH2*2 mutant mice (low intrinsic ALDH2 activity) with type-2 diabetes. We induced type-2 diabetes by feeding high-fat diet and found they developed hyperglycemia (blood glucose (BG) levels increased to 357 ± 100 mg/dl vs 137 ± 7 mg/dl) and insulin resistance as measured by glucose tolerance test (GTT) (BG levels 408 ± 50 mg/dl vs 165 ± 18 mg/dl at 2 hours after GTT). To delineate the role of hyperglycemia, we treated the diabetic mice with a sodium-glucose co-transporter 2 (SGLT2) inhibitor, Empaglifuzin (EMP) (3mg/kg/day) or Vehicle for 8 weeks. EMP reduced BG levels from 502 ± 75 mg/dl to 193 ± 50 mg/dl by enhancing urinary glucose excretion. Surprisingly EMP reversed insulin resistance as maintained similar BG levels before and after 2 hours of GTT; 190 ± 23 mg/dl vs 188 ± 16 mg/dl. EMP also increased ALDH2 activity to 22 ± 8 % from 7 ± 3 % and 4HNE protein adduct levels. Finally EMP improved cardiac function i.e. % fractional shortening (FS) is increased to 70 ± 4 compared to 53 ± 10. Our data suggested hyperglycemia partially contribute to the diabetic cardiac damage via increasing 4HNE protein adducts. Alda-1 (10 mg/kg/day) treatment further augmented ALDH2 activity, reduced 4HNE adducts and improved cardiac function in EMP-treated ALDH2*2 mice. Thus hyperglycemia mediated secondary events in type-2 DM are significant pathomechanism of the cardiac damage. In conclusion, we propose ALDH2 activation may ameliorate diabetic patients from cardiac complications who receive glucose lowering treatments.

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Triphala improves glucose homeostasis by alleviating atherogenic lipids and oxidative stress in human Type 2 diabetes mellitus

International Journal of Ayurvedic Medicine ◽

10.47552/ijam.v6i3.503 ◽

2015 ◽

Vol 6 (3) ◽

Author(s):

Nita Singh ◽

Sunil Mahajan ◽

Senthil K Subramani ◽

Dhananjay Yadav ◽

Lokendra Singh ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Blood Glucose ◽

Protective Effect ◽

Tail Length ◽

Protective Effects ◽

Lipid Levels

Aims: â€˜Triphalaâ€™ constituting equal parts of three medicinal dried plant fruits Emblica Officinalis Gaertn., Terminalia chebula Retz. and Terminalia bellerica Gaertn. is an antioxidant rich Ayurvedic formulation. The present study assessed therapeutic as well as protective effects of Triphala on human subjects with Type 2 diabetes mellitus (T2DM) and Impaired glucose tolerance (IGT).Â Materials and methods: Triphala at a dose of 5 gms BD was administered to two cohorts viz., IGT, N= 20 and T2DM, N=30 consecutively for a period of 12 months. The therapeutic efficacy was assessed quarterly by monitoring blood glucose and lipid levels; the protective effect by monitoring antioxidants level quarterly and DNA damage annually. Toxicity if any, to liver and kidney due to long term administration was assessed quarterly in both cohorts.Results: Continuous â€˜Triphalaâ€™ therapy for 12 months significantly reduced blood glucose (pâ‰¤0.001) and lipid levels (pâ‰¤0.05) in both the cohorts. Triphala resisted oxidative stress generated during the course of hyperglycemia by significantly increasing the activity of super oxide dismutase and Catalase (pâ‰¤0.001) and the level of reduced glutathione (pâ‰¤0.001). Protective effect on DNA was accessed through significant reduction in the comet tail length (pâ‰¤0.001).Conclusions: â€˜Triphalaâ€™ ameliorated not only the oxidative stress but also normalized glucose and lipid homeostasis in subjects with impaired glucose and T2DM.Â

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