Empagliflozin and Liraglutide Differentially Modulate Cardiac Metabolism in Diabetic Cardiomyopathy in Rats

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are antihyperglycemic agents with cardioprotective properties against diabetic cardiomyopathy (DCM). However, the distinctive mechanisms underlying GLP-1RAs and SGLT2is in DCM are not fully elucidated. The purpose of this study was to investigate the impacts of GLP1RAs and/or SGLT2is on myocardial energy metabolism, cardiac function, and apoptosis signaling in DCM. Biochemistry and echocardiograms were studied before and after treatment with empagliflozin (10 mg/kg/day, oral gavage), and/or liraglutide (200 μg/kg every 12 h, subcutaneously) for 4 weeks in male Wistar rats with streptozotocin (65 mg/kg intraperitoneally)-induced diabetes. Cardiac fibrosis, apoptosis, and protein expression of metabolic and inflammatory signaling molecules were evaluated by histopathology and Western blotting in ventricular cardiomyocytes of different groups. Empagliflozin and liraglutide normalized myocardial dysfunction in diabetic rats. Upregulation of phosphorylated-acetyl coenzyme A carboxylase, carnitine palmitoyltransferase 1β, cluster of differentiation 36, and peroxisome proliferator-activated receptor-gamma coactivator, and downregulation of glucose transporter 4, the ratio of phosphorylated adenosine monophosphate-activated protein kinase α2 to adenosine monophosphate-activated protein kinase α2, and the ratio of phosphorylated protein kinase B to protein kinase B in diabetic cardiomyocytes were restored by treatment with empagliflozin or liraglutide. Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3, interleukin-1β, tumor necrosis factor-α, and cleaved caspase-1 were significantly downregulated in empagliflozin-treated and liraglutide-treated diabetic rats. Both empagliflozin-treated and liraglutide-treated diabetic rats exhibited attenuated myocardial fibrosis and apoptosis. Empagliflozin modulated fatty acid and glucose metabolism, while liraglutide regulated inflammation and apoptosis in DCM. The better effects of combined treatment with GLP-1RAs and SGLT2is may lead to a potential strategy targeting DCM.

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Inhibitory effect of hyperglycemia on insulin-induced Akt/protein kinase B activation in skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2001.280.5.e816 ◽

2001 ◽

Vol 280 (5) ◽

pp. E816-E824 ◽

Cited By ~ 45

Author(s):

Akira Oku ◽

Masao Nawano ◽

Kiichiro Ueta ◽

Takuya Fujita ◽

Itsuro Umebayashi ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Protein Kinase ◽

Insulin Receptor ◽

Soleus Muscle ◽

Insulin Signaling ◽

Skeletal Muscles ◽

Glucose Transporter ◽

Protein Kinase B ◽

Diabetic Rats

To determine the molecular mechanism underlying hyperglycemia-induced insulin resistance in skeletal muscles, postreceptor insulin-signaling events were assessed in skeletal muscles of neonatally streptozotocin-treated diabetic rats. In isolated soleus muscle of the diabetic rats, insulin-stimulated 2-deoxyglucose uptake, glucose oxidation, and lactate release were all significantly decreased compared with normal rats. Similarly, insulin-induced phosphorylation and activation of Akt/protein kinase B (PKB) and GLUT-4 translocation were severely impaired. However, the upstream signal, including phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS)-1 and -2 and activity of phosphatidylinositol (PI) 3-kinase associated with IRS-1/2, was enhanced. The amelioration of hyperglycemia by T-1095, a Na+-glucose transporter inhibitor, normalized the reduced insulin sensitivity in the soleus muscle and the impaired insulin-stimulated Akt/PKB phosphorylation and activity. In addition, the enhanced PI 3-kinase activation and phosphorylation of IR and IRS-1 and -2 were reduced to normal levels. These results suggest that sustained hyperglycemia impairs the insulin-signaling steps between PI 3-kinase and Akt/PKB, and that impaired Akt/PKB activity underlies hyperglycemia-induced insulin resistance in skeletal muscle.

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α-amyrin induce GLUT4 translocation mediated by AMPK and PPARδ/γ in C2C12 myoblasts

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2021-0027 ◽

2021 ◽

Author(s):

Abraham Giacoman-Martínez ◽

Francisco Javier Alarcón-Aguilar ◽

Alejandro Zamilpa-Alvarez ◽

Fengyang Huang ◽

Rodrigo Romero ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Glucose Transporter ◽

Metabolic Diseases ◽

Muscle Cells ◽

Skeletal Muscle Cells ◽

Peroxisome Proliferator ◽

Glut4 Translocation ◽

Pentacyclic Triterpene ◽

C2c12 Myoblasts

α-amyrin, a natural pentacyclic triterpene, have anti-hyperglycemic effect in mice and dual PPARδ/γ action in 3T3-L1 adipocytes, and potential in the control of type 2 diabetes (T2D). About 80% of glucose uptake occurs in skeletal muscle cells, playing a significant role in IR and T2D. Peroxisome-proliferator activated receptors (PPARs), in particular PPARδ and PPARγ, are involved in the regulation of lipids and carbohydrates and, along adenosine-monophosphate (AMP)-activated protein kinase (AMPK) and protein kinase B (Akt/PKB), are implicated in translocation of glucose transporter 4 (GLUT4). However, it is still unknown whether α-amyrin can affect these pathways in skeletal muscle cells. The work's objective was to determine the action of α-amyrin in PPARδ, PPARγ, AMPK, and Akt/PKB in C2C12 myoblasts. The expression of PPARδ, PPARγ, FATP, and GLUT4 was quantified using RT-qPCR and Western blot. α-amyrin increased these markers along with p-AMPK but not p-Akt/PKB. Molecular docking showed that α-amyrin acts as an AMPK-allosteric activator, and may be related to GLUT4 translocation, evidenced by confocal microscopy. These data support that α-amyrin could have an insulin-mimetic action in C2C12 myoblasts and should be considered as a bioactive molecule for new multitarget drugs with utility in T2D and other metabolic diseases.

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Lycopsamine Attenuates Diabetes Mellitus via The Nuclear Factor Kappa B-Induced 5′ Adenosine Monophosphate-Activated Protein Kinase Signal Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.20:169-176 ◽

2021 ◽

Vol 20 (1) ◽

pp. 169-176

Author(s):

Jingfang Hu ◽

Jie Jin ◽

Yan Chen ◽

Jinyi Wei ◽

Hanbei Chen

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Protein Kinase ◽

Nuclear Factor Kappa B ◽

Adenosine Monophosphate ◽

Interleukin 10 ◽

Diabetic Rats ◽

Nuclear Factor ◽

Nonesterified Fatty Acids ◽

Nuclear Factor Kappa

Diabetes mellitus is a metabolic disorder characterized by inflammation, abnormal glycolipid metabolism, insulin resistance, and mitochondrial dysfunction leading to hyperglycemia. The aim of the present investigation was to determine the efficacy of lycopsamine in a rat model of diabetes mellitus to understand its mechanism. Lycopsamine treatment markedly lowered the level of total cholesterol, triglyceride, nonesterified fatty acids, and low-density lipoprotein in diabetic rats. There was also a reduction in interleukin-6, interleukin-10, C-reactive protein, and tumor necrosis factor-α levels. Lycopsamine treatment normalized the metabolism of lipid and glucose, insulin resistance, and body weight of diabetic rats. Findings of immunohistochemical analyses exhibited rise in precipitation of immunocytes in renal cells. Results potentially demonstrated that lycopsamine treatment remarkably reduced the nuclear factor-kappa B level and enhanced the 5′ adenosine monophosphate-activated protein kinase expression. Altogether, administration of lycopsamine suppressed the expression of inflammatory cytokines and attenuated the metabolic symptoms in diabetes mellitus experimental rats.

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Piper retrofractumVahl. Extract, as a PPARδand AMPK Activator, Suppresses UVB-Induced Photoaging through Mitochondrial Biogenesis and MMPs Inhibition in Human Dermal Fibroblasts and Hairless Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/6172954 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Jungon Yun ◽

Changhee Kim ◽

Mi-Bo Kim ◽

Jae-Kwan Hwang

Keyword(s):

Protein Kinase ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Mouse Skin ◽

Adenosine Monophosphate ◽

Dermal Fibroblasts ◽

Mitogen Activated Protein Kinase ◽

Peroxisome Proliferator ◽

Human Dermal Fibroblasts ◽

Piper Retrofractum

Photoaging occurs by UVB-irradiation and involves production of reactive oxygen species (ROS) and overexpression of matrix metalloproteinases (MMPs), leading to extracellular matrix damage.Piper retrofractumVahl. is used as a traditional medicine for antiflatulence, expectorant, sedative, and anti-irritant; however, its antiphotoaging effect has not yet been studied. The current study investigated the antiphotoaging effect of standardizedPiper retrofractumextract (PRE) on UVB-damaged human dermal fibroblasts and hairless mouse skin. PRE treatment activated the peroxisome proliferator-activated receptor delta (PPARδ) and the adenosine monophosphate-activated protein kinase (AMPK), consequently upregulating mitochondrial synthesis and reducing ROS production. Additionally, PRE inhibited MMPs expression via suppressing mitogen-activated protein kinase (MAPK) and activator protein-1 (AP-1). PRE downregulated UVB-induced inflammatory reactions by inhibiting the nuclear factor-kappa B (NF-κB) activity. PRE also enhanced transforming growth factor-beta (TGF-β) and the Smad signaling pathway, thereby promoting procollagen gene transcription. Furthermore, oral administration of PRE (300 mg/kg/day) similarly regulated the signaling pathways and increased antioxidant enzyme expression, thus attenuating physiological deformations, such as wrinkle formation and erythema response. Collectively, these results suggest that PRE acts as a potent antiphotoaging agent via PPARδand AMPK activation.

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Protective effects of BiP inducer X (BIX) against diabetic cardiomyopathy in rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2020-0419 ◽

2020 ◽

Author(s):

Gholamreza Idari ◽

Pouran Karimi ◽

Samad Ghaffari ◽

Seyed Isaac Hashemy ◽

Baratali Mashkani

Keyword(s):

Er Stress ◽

Diabetic Cardiomyopathy ◽

Cell Apoptosis ◽

Cardiac Fibrosis ◽

Tissue Expression ◽

Myocardial Cell ◽

Diabetic Rats ◽

Mrna Levels ◽

Protective Effects ◽

Cardiac Cell

Diabetic cardiomyopathy (DC) is associated with impaired endoplasmic reticulum (ER) function, development of ER stress, and induction of cardiac cell apoptosis. Preventive effects of BiP inducer X (BIX) were investigated against DC characteristic changes in a type 2 diabetes rat model. To establish diabetes, a high-fat diet and a single dose of streptozotocin were administered. Then, animals were assigned into following groups: control, BIX, diabetic animals monitored for one, two, and three weeks. Diabetic rats treated with BIX for one, two, and three weeks. Expressions of various ER stress and apoptotic markers were assessed by immunoblotting method. CHOP gene expression was assessed by Real-time PCR. Tissue expression of BiP was evaluated by immunohistochemistry method. Hematoxylin and eosin and Masson's trichrome staining were performed to assess histological changes in the left ventricle. Cardiac cell apoptosis was examined using TUNEL assay. BIX administration suppressed the activation of the ER stress markers and cleavage of pro-caspase 3 in the diabetic rats. Likewise, tissue expression of BiP protein was increased, while CHOP mRNA levels were decreased. These results were accompanied by reducing cardiac fibrosis and myocardial cell apoptosis suggesting protective effects of BIX against the development of DC by decreasing cardiomyocyte apoptosis and fibrosis.

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Vitamin D3 Activates Phosphatidylinositol-3-Kinase/Protein Kinase B via Insulin-Like Growth Factor-1 to Improve Testicular Function in Diabetic Rats

Journal of Diabetes Research ◽

10.1155/2019/7894950 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8

Author(s):

Yanyan He ◽

Yang Liu ◽

Qing-Zhu Wang ◽

Feng Guo ◽

Fengjuan Huang ◽

...

Keyword(s):

Vitamin D ◽

Growth Factor ◽

Protein Kinase ◽

Protein Kinase B ◽

Diabetic Rats ◽

Testicular Function ◽

Insulin Like Growth Factor ◽

Wild Type ◽

Phosphatidylinositol 3 Kinase ◽

Phosphatidylinositol 3

Objective. In diabetes mellitus, vitamin D3 deficiency affects sex hormone levels and male fertility; however, the mechanism leading to the disorder is unclear. This research was designed to investigate the mechanism of vitamin D3 deficiency and hypogonadism in diabetic rats. Our aim was to assess serum vitamin D3 levels and the relationship among vitamin D3, insulin-like growth factor-1 (IGF-1), and testicular function. Materials and Methods. Rats with streptozotocin-induced diabetes were randomly divided into four groups and treated with different doses of vitamin D3: no vitamin D3, low (0.025 μg/kg/day), high (0.1 μg/kg/day), and high (0.1 μg/kg/day) with JB-1 (the insulin-like growth factor-1 receptor inhibitor group, 100 μg/kg/day). The groups were compared with wild-type rats, which function as the control group. Various parameters such as vitamin D3 and IGF-1 were compared between the experimental and wild-type groups, and their correlations were determined. Results. Twelve weeks of vitamin D3 supplementation improved the testosterone levels, as shown by the increase in the level of serum IGF-1 in diabetic rats. Phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT), which was a downstream of the signaling pathway of IGF-1, was significantly increased after vitamin D3 treatment. Conclusions. The study shows that vitamin D3 may promote the expression of testosterone and improve testicular function in diabetic rats by activating PI3K/AKT via IGF-1.

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Early growth retardation induced by excessive exposure to glucocorticoids in utero selectively increases cardiac GLUT1 protein expression and Akt/protein kinase B activity in adulthood

Journal of Endocrinology ◽

10.1677/joe.0.1690011 ◽

2001 ◽

Vol 169 (1) ◽

pp. 11-22 ◽

Cited By ~ 34

Author(s):

ML Langdown ◽

MJ Holness ◽

MC Sugden

Keyword(s):

Protein Kinase ◽

Protein Expression ◽

Adult Male ◽

Growth Retardation ◽

Glucose Transporter ◽

Protein Kinase B ◽

Early Growth ◽

Male Offspring ◽

Dexamethasone Treatment ◽

Glut1 Protein

In the rat, dexamethasone treatment during late pregnancy leads to intrauterine growth retardation and is used as a model of early programming of adult onset disease. The present study investigated whether pre-natal dexamethasone treatment modifies cardiac glucose transporter (GLUT) protein expression in adulthood and identified signalling pathways involved in the response. Dexamethasone (100 microg/kg body wt per day) administered via an osmotic pump to pregnant rats (day 15 to day 21; term=22 to 23 days) reduced fetal weight at day 21 and caused hypertension, hyperinsulinaemia and elevated corticosterone levels in the adult (24-week-old) male offspring. Cardiac GLUT1 protein expression was selectively up-regulated (2.5-fold; P<0.001), in the absence of altered cardiac GLUT4 protein expression, in adult male offspring of dexamethasone-treated dams. Maternal dexamethasone treatment did not influence cardiac GLUT1 protein expression during fetal or early post-natal life. We examined potential regulatory signalling proteins that might mediate up-regulation of cardiac GLUT1 protein expression in adulthood. We observed marked (2.2-fold; P<0.01) activation of Akt/protein kinase B (PKB), together with modest activation of the anti-apoptotic protein kinase C (PKC) isoforms PKC alpha (88%, P<0.05) and PKC epsilon (56%, P<0.05) in hearts of the early-growth-retarded male offspring. These effects were, however, observed in conjunction with up-regulation of cardiac protein expression of PKC beta(1) (191%, P<0.01), PKC beta(2) (49%, P<0.05) and PKC delta (35%; P<0.01), effects that may have adverse consequences. Maternal dexamethasone treatment was without effect on cardiac extracellular signal-related kinase (ERK) 1 or ERK2 activity in adulthood. In conclusion, our data demonstrate an effect of maternal dexamethasone treatment to up-regulate cardiac GLUT1 protein expression in early-growth-retarded, hypertensive, hyperinsulinaemic adult male offspring, an effect observed in conjunction with activation of Akt/PKB.

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