Psidium guajava Linn. leaf extract affects hepatic glucose transporter-2 to attenuate early onset of insulin resistance consequent to high fructose intake: An experimental study

: Type 2 diabetes mellitus (T2DM) is characterized by a progressive beta cell dysfunction in the setting of peripheral insulin resistance. Insulin resistance in subjects with type 2 diabetes and metabolic syndrome is primarily caused by an ectopic fat accumulation in liver and skeletal muscle. Insulin sensitizers are particularly important in the management of T2DM. Though, thiazolidinediones (TZDs) are principally insulin sensitizers, they possess an ability to preserve pancreatic β-cell function and thereby exhibit durable glycemic control. Cardiovascular outcome trials (CVOTs) have shown that Glucagon-like-peptide 1 receptor agonists (GLP-1 RAs) and sodium glucose transporter-2 inhibitors (SGLT2i) have proven cardiovascular safety. In this era of CVOTs, drugs with proven cardiovascular (CV) safety are often preferred in patients with preexisting cardiovascular disease or at risk of cardiovascular disease. In this review, we will describe the three available drugs belonging to the TZD family, with special emphasis on their efficacy and CV safety.

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Alleviative Effect of Ruellia tuberosa L. on Insulin Resistance and Abnormal Lipid Accumulation in TNF-α-Treated FL83B Mouse Hepatocytes

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/9967910 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Hong-Jie Chen ◽

Chih-Yuan Ko ◽

Jian-Hua Xu ◽

Yu-Chu Huang ◽

James Swi-Bea Wu ◽

...

Keyword(s):

Insulin Resistance ◽

Ethyl Acetate ◽

Glucose Uptake ◽

Insulin Signaling ◽

Lipid Accumulation ◽

Glucose Transporter ◽

Peroxisome Proliferator ◽

Glucose Transporter 2 ◽

Tnf Α ◽

Mouse Hepatocytes

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, and most patients with T2DM develop nonalcoholic fatty liver disease (NAFLD). Both diseases are closely linked to insulin resistance (IR). Our previous studies demonstrated that Ruellia tuberosa L. (RTL) extract significantly enhanced glucose uptake in the skeletal muscles and ameliorated hyperglycemia and IR in T2DM rats. We proposed that RTL might be via enhancing hepatic antioxidant capacity. However, the potent RTL bioactivity remains unidentified. In this study, we investigated the effects of RTL on glucose uptake, IR, and lipid accumulation in vitro to mimic the T2DM accompanied by the NAFLD paradigm. FL83B mouse hepatocytes were treated with tumor necrosis factor-α (TNF-α) to induce IR, coincubated with oleic acid (OA) to induce lipid accumulation, and then, treated with RTL fractions, fractionated with n-hexane or ethyl acetate (EA), from column chromatography, and analyzed by thin-layer chromatography. Our results showed that the ethyl acetate fraction (EAf2) from RTL significantly increased glucose uptake and suppressed lipid accumulation in TNF-α plus OA-treated FL83B cells. Western blot analysis showed that EAf2 from RTL ameliorated IR by upregulating the expression of insulin-signaling-related proteins, including protein kinase B, glucose transporter-2, and peroxisome proliferator-activated receptor alpha in TNF-α plus OA-treated FL83B cells. The results of this study suggest that EAf2 from RTL may improve hepatic glucose uptake and alleviate lipid accumulation by ameliorating and suppressing the hepatic insulin signaling and lipogenesis pathways, respectively, in hepatocytes.

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Insulin Resistance Promotes Early Atherosclerosis via Increased Proinflammatory Proteins and Oxidative Stress in Fructose-Fed ApoE-KO Mice

Experimental Diabetes Research ◽

10.1155/2012/941304 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Beatriz Cannizzo ◽

Agustín Luján ◽

Natalia Estrella ◽

Carina Lembo ◽

Montserrat Cruzado ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Vascular Remodeling ◽

Oxidase Activity ◽

Fructose Intake ◽

High Fructose ◽

Study Results ◽

Apoe Ko Mice ◽

And Oxidative Stress ◽

Apoe Ko

High fructose intake induces an insulin resistance state associated with metabolic syndrome (MS). The effect of vascular inflammation in this model is not completely addressed. The aim of this study was to evaluate vascular remodeling, inflammatory and oxidative stress markers, and atheroma development in high-fructose diet-induced insulin resistance of ApoE-deficient mice (ApoE-KO). Mice were fed with either a normal chow or a 10% w/v fructose (HF) in drinking water over a period of 8 weeks. Thereafter, plasma metabolic parameters, vascular remodeling, atheroma lesion size, inflammatory markers, and NAD(P)H oxidase activity in the arteries were determined. HF diet induced a marked increase in plasma glucose, insulin, and triglycerides in ApoE-KO mice, provoked vascular remodeling, enhanced expression of vascular cell-adhesion molecule-1 (VCAM-1) and matrix metalloprotease 9 (MMP-9) and enlarged atherosclerotic lesion in aortic and carotid arteries. NAD(P)H oxidase activity was enhanced by fructose intake, and this effect was attenuated by tempol, a superoxide dismutase mimetic, and losartan, an Angiotensin II receptor antagonist. Our study results show that high-fructose-induced insulin resistance promotes a proinflammatory and prooxidant state which accelerates atherosclerotic plaque formation in ApoE-KO mice.

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Adipose-specific overexpression of GLUT4 reverses insulin resistance and diabetes in mice lacking GLUT4 selectively in muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00116.2005 ◽

2005 ◽

Vol 289 (4) ◽

pp. E551-E561 ◽

Cited By ~ 145

Author(s):

Eugenia Carvalho ◽

Ko Kotani ◽

Odile D. Peroni ◽

Barbara B. Kahn

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Glucose Transport ◽

Fat Mass ◽

Glucose Transporter ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Whole Body ◽

Hepatic Glucose ◽

Clamp Study

Adipose tissue plays an important role in glucose homeostasis and affects insulin sensitivity in other tissues. In obesity and type 2 diabetes, glucose transporter 4 (GLUT4) is downregulated in adipose tissue, and glucose transport is also impaired in muscle. To determine whether overexpression of GLUT4 selectively in adipose tissue could prevent insulin resistance when glucose transport is impaired in muscle, we bred muscle GLUT4 knockout (MG4KO) mice to mice overexpressing GLUT4 in adipose tissue (AG4Tg). Overexpression of GLUT4 in fat not only normalized the fasting hyperglycemia and glucose intolerance in MG4KO mice, but it reduced these parameters to below normal levels. Glucose infusion rate during a euglycemic clamp study was reduced 46% in MG4KO compared with controls and was restored to control levels in AG4Tg-MG4KO. Similarly, insulin action to suppress hepatic glucose production was impaired in MG4KO mice and was restored to control levels in AG4Tg-MG4KO. 2-Deoxyglucose uptake during the clamp was increased approximately twofold in white adipose tissue but remained reduced in skeletal muscle of AG4Tg-MG4KO mice. AG4Tg and AG4Tg-MG4KO mice have a slight increase in fat mass, a twofold elevation in serum free fatty acids, an ∼50% increase in serum leptin, and a 50% decrease in serum adiponectin. In MG4KO mice, serum resistin is increased 34% and GLUT4 overexpression in fat reverses this. Overexpression of GLUT4 in fat also reverses the enhanced clearance of an oral lipid load in MG4KO mice. Thus overexpression of GLUT4 in fat reverses whole body insulin resistance in MG4KO mice without restoring glucose transport in muscle. This effect occurs even though AG4Tg-MG4KO mice have increased fat mass and low adiponectin and is associated with normalization of elevated resistin levels.

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The Roles of Liver Inflammation and the Insulin Signaling Pathway in PM2.5 Instillation-Induced Insulin Resistance in Wistar Rats

Disease Markers ◽

10.1155/2021/2821673 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Zhihua Zhang ◽

Shujun Hu ◽

Ping Fan ◽

Ling Li ◽

Shanshan Feng ◽

...

Keyword(s):

Insulin Resistance ◽

Rat Liver ◽

Insulin Signaling ◽

Glucose Transporter ◽

Fasting Blood Glucose ◽

Model Assessment ◽

Glucose Transporter 2 ◽

Systemic Insulin Resistance ◽

Tnf Α ◽

Phosphorylated Akt

To elucidate the mechanism of how the liver participates in PM2.5-caused insulin resistance. A novel Wistar rat model was developed in this study by instilling a suspension of lyophilized PM2.5 sample (2.5 mg/kg, 5 mg/kg, or 10 mg/kg) collected from the atmosphere. Systemic insulin resistance indicators, including serum fasting blood glucose (FBG), fasting insulin (FINS), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and hemoglobin A1 (HbA1), were upregulated by the PM2.5 instillation. The area under the curve (AUCglu) calculated by intraperitoneal glucose tolerance testing (IPGTT) was also significantly greater in the PM2.5 instillation groups. Additionally, PM2.5 instillation was found to cause liver damage and inflammation. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were significantly elevated by PM2.5 instillation. PM2.5 also triggered IL-6 and TNF-α transcription but inhibited mRNA synthesis and suppressed signaling activation of the insulin-phosphoinositide 3-kinase- (PI3K-) Akt-glucose transporter 2 (GLUT2) pathway in the rat liver by reducing the ratio of phosphorylated Akt to phosphorylated insulin receptor substrate 1 (IRS-1). Thus, PM2.5-induced inflammation activation and insulin signaling inhibition in the rat liver contribute to the development of systemic insulin resistance.

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Mangiferin Improved Palmitate-Induced-Insulin Resistance by Promoting Free Fatty Acid Metabolism in HepG2 and C2C12 Cells via PPARα: Mangiferin Improved Insulin Resistance

Journal of Diabetes Research ◽

10.1155/2019/2052675 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

Qiao Zhang ◽

Xiangju Kong ◽

Hang Yuan ◽

Hongjun Guan ◽

Ying Li ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Free Fatty Acid ◽

Glucose Transporter ◽

C2c12 Cells ◽

Peroxisome Proliferator ◽

Glucose Content ◽

Peroxisome Proliferator Activated Receptor ◽

Glucose Transporter 2 ◽

Ffa Metabolism

Elevated free fatty acid (FFA) is a key risk factor for insulin resistance (IR). Our previous studies found that mangiferin could decrease serum FFA levels in obese rats induced by a high-fat diet. Our research was to determine the effects and mechanism of mangiferin on improving IR by regulating FFA metabolism in HepG2 and C2C12 cells. The model was used to quantify PA-induced lipid accumulation in the two cell lines treated with various concentrations of mangiferin simultaneously for 24 h. We found that mangiferin significantly increased insulin-stimulated glucose uptake, via phosphorylation of protein kinase B (P-AKT), glucose transporter 2 (GLUT2), and glucose transporter 4 (GLUT4) protein expressions, and markedly decreased glucose content, respectively, in HepG2 and C2C12 cells induced by PA. Mangiferin significantly increased FFA uptake and decreased intracellular FFA and triglyceride (TG) accumulations. The activity of the peroxisome proliferator-activated receptor α (PPARα) protein and its downstream proteins involved in fatty acid translocase (CD36) and carnitine palmitoyltransferase 1 (CPT1) and the fatty acid β-oxidation rate corresponding to FFA metabolism were also markedly increased by mangiferin in HepG2 and C2C12 cells. Furthermore, the effects were reversed by siRNA-mediated knockdown of PPARα. Mangiferin ameliorated IR by increasing the consumption of glucose and promoting the FFA oxidation via the PPARα pathway in HepG2 and C2C12 cells.

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Comparative effects of telmisartan, sitagliptin and metformin alone or in combination on obesity, insulin resistance, and liver and pancreas remodelling in C57BL/6 mice fed on a very high-fat diet

Clinical Science ◽

10.1042/cs20100061 ◽

2010 ◽

Vol 119 (6) ◽

pp. 239-250 ◽

Cited By ~ 88

Author(s):

Vanessa Souza-Mello ◽

Bianca M. Gregório ◽

Fernando S. Cardoso-de-Lemos ◽

Laís de Carvalho ◽

Márcia B. Aguila ◽

...

Keyword(s):

Insulin Resistance ◽

Hepatic Steatosis ◽

High Fat Diet ◽

Glucose Transporter ◽

Oral Glucose ◽

Free Access ◽

High Fat ◽

The Metabolic Syndrome ◽

Glucose Transporter 2 ◽

Drug Treatments

The aim of the present study was to evaluate the effects of monotherapies and combinations of drugs on insulin sensitivity, adipose tissue morphology, and pancreatic and hepatic remodelling in C57BL/6 mice fed on a very HF (high-fat) diet. Male C57BL/6 mice were fed on an HF (60% lipids) diet or SC (standard chow; 10% lipids) diet for 10 weeks, after which time the following drug treatments began: HF-T (HF diet treated with telmisartan; 5.2 mg·kg−1 of body weight·day−1), HF-S (HF diet treated with sitagliptin; 1.08 g·kg−1 of body weight·day−1), HF-M (HF diet treated with metformin; 310.0 mg·kg−1 of body weight·day−1), HF-TM (HF diet treated with telmisartan+metformin), HF-TS (HF diet treated with telmisartan+sitagliptin) and HF-SM (HF diet treated with sitagliptin+metformin). Treated groups also had free access to the HF diet, and treatments lasted for 6 weeks. Morphometry, stereological tools, immunostaining, ELISA, Western blot analysis and electron microscopy were used. The HF diet yielded an overweight phenotype, an increase in oral glucose intolerance, hyperinsulinaemia, hypertrophied islets and adipocytes, stage 2 steatosis (>33%), and reduced liver PPAR-α (peroxisome-proliferator-activated receptor-α) and GLUT-2 (glucose transporter-2) levels, concomitant with enhanced SREBP-1 (sterol-regulatory-element-binding protein-1) expression (P<0.0001). Conversely, all drug treatments resulted in significant weight loss, a reversal of insulin resistance, islet and adipocyte hypertrophy, and alleviated hepatic steatosis. Only the HF-T and HF-TS groups had body weights similar to the SC group at the end of the experiment, and the latter treatment reversed hepatic steatosis. Increased PPAR-α immunostaining in parallel with higher GLUT-2 and reduced SREBP-1 expression may explain the favourable hepatic outcomes. Restoration of adipocyte size was consistent with higher adiponectin levels and lower TNF-α (tumour necrosis factor-α) levels (P<0.0001) in the drug-treated groups. In conclusion, all of the drug treatments were effective in controlling the metabolic syndrome. The best results were achieved using telmisartan and sitagliptin as monotherapies or as a dual treatment, combining partial PPAR-γ agonism and PPAR-α activation in the liver with extended incretin action.

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Sasa quelpaertensis Leaf Extract Ameliorates Dyslipidemia, Insulin Resistance, and Hepatic Lipid Accumulation in High-Fructose-Diet-Fed Rats

Nutrients ◽

10.3390/nu12123762 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3762

Author(s):

Jeong Yong Park ◽

Mi Gyeong Jang ◽

Jung Min Oh ◽

Hee Chul Ko ◽

Sung-Pyo Hur ◽

...

Keyword(s):

Insulin Resistance ◽

Signaling Pathway ◽

Lipid Accumulation ◽

Leaf Extract ◽

Metabolic Disorders ◽

Metabolic Dysfunction ◽

Hepatic Lipid ◽

High Fructose Diet ◽

Hepatic Lipid Accumulation ◽

High Fructose

Background: Increased dietary fructose consumption is closely associated with lipid and glucose metabolic disorders. Sasa quelpaertensis Nakai possesses various health-promoting properties, but there has been no research on its protective effect against fructose-induced metabolic dysfunction. In this study, we investigated the effects of S. quelpaertensis leaf extract (SQE) on metabolic dysfunction in high-fructose-diet-fed rats. Methods: Animals were fed a 46% carbohydrate diet, a 60% high-fructose diet, or a 60% high-fructose diet with SQE (500 mg/kg of body weight (BW)/day) in drinking water for 16 weeks. Serum biochemical parameters were measured and the effects of SQE on hepatic histology, protein expression, and transcriptome profiles were investigated. Results: SQE improved dyslipidemia and insulin resistance induced in high-fructose-diet-fed rats. SQE ameliorated the lipid accumulation and inflammatory response in liver tissues by modulating the expressions of key proteins related to lipid metabolism and antioxidant response. SQE significantly enriched the genes related to the metabolic pathway, namely, the tumor necrosis factor (TNF) signaling pathway and the PI3K-Akt signaling pathway. Conclusions: SQE could effectively prevent dyslipidemia, insulin resistance, and hepatic lipid accumulation by regulation of metabolism-related gene expressions, suggesting its role as a functional ingredient to prevent lifestyle-related metabolic disorders.

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Aspalathin-Enriched Green Rooibos Extract Reduces Hepatic Insulin Resistance by Modulating PI3K/AKT and AMPK Pathways

International Journal of Molecular Sciences ◽

10.3390/ijms20030633 ◽

2019 ◽

Vol 20 (3) ◽

pp. 633 ◽

Cited By ~ 23

Author(s):

Sithandiwe Mazibuko-Mbeje ◽

Phiwayinkosi Dludla ◽

Candice Roux ◽

Rabia Johnson ◽

Samira Ghoor ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Insulin Sensitivity ◽

Protein Kinase ◽

Insulin Receptor ◽

Glucose Transporter ◽

Insulin Signalling ◽

Hepatic Insulin Resistance ◽

Insulin Resistant ◽

Glucose Transporter 2

We previously demonstrated that an aspalathin-enriched green rooibos extract (GRE) reversed palmitate-induced insulin resistance in C2C12 skeletal muscle and 3T3-L1 fat cells by modulating key effectors of insulin signalling such as phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and AMP-activated protein kinase (AMPK). However, the effect of GRE on hepatic insulin resistance is unknown. The effects of GRE on lipid-induced hepatic insulin resistance using palmitate-exposed C3A liver cells and obese insulin resistant (OBIR) rats were explored. GRE attenuated the palmitate-induced impairment of glucose and lipid metabolism in treated C3A cells and improved insulin sensitivity in OBIR rats. Mechanistically, GRE treatment significantly increased PI3K/AKT and AMPK phosphorylation while concurrently enhancing glucose transporter 2 expression. These findings were further supported by marked stimulation of genes involved in glucose metabolism, such as insulin receptor (Insr) and insulin receptor substrate 1 and 2 (Irs1 and Irs2), as well as those involved in lipid metabolism, including Forkhead box protein O1 (FOXO1) and carnitine palmitoyl transferase 1 (CPT1) following GRE treatment. GRE showed a strong potential to ameliorate hepatic insulin resistance by improving insulin sensitivity through the regulation of PI3K/AKT, FOXO1 and AMPK-mediated pathways.

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Fructose diet treatment in mice induces fundamental disturbance of cardiomyocyte Ca2+ handling and myofilament responsiveness

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00797.2011 ◽

2012 ◽

Vol 302 (4) ◽

pp. H964-H972 ◽

Cited By ~ 31

Author(s):

Kimberley M. Mellor ◽

Igor R. Wendt ◽

Rebecca H. Ritchie ◽

Lea M. D. Delbridge

Keyword(s):

Insulin Resistance ◽

Protein Expression ◽

Morphological Alterations ◽

Fructose Intake ◽

High Fructose ◽

Dietary Fructose ◽

Phase Loop ◽

Phosphatase 2A ◽

Myocardial Insulin Resistance ◽

And Control

High fructose intake has been linked to insulin resistance and cardiac pathology. Dietary fructose-induced myocardial signaling and morphological alterations have been described, but whether cardiomyocyte function is influenced by chronic high fructose intake is yet to be elucidated. The goal of this study was to evaluate the cardiomyocyte excitation-contraction coupling effects of high dietary fructose and determine the capacity for murine cardiomyocyte fructose transport. Male C57Bl/6J mice were fed a high fructose diet for 12 wk. Fructose- and control-fed mouse cardiomyocytes were isolated and loaded with the fura 2 Ca2+ fluorescent dye for analysis of twitch and Ca2+ transient characteristics (4 Hz stimulation, 37°C, 2 mM Ca2+). Myocardial Ca2+-handling protein expression was determined by Western blot. Gene expression of the fructose-specific transporter, GLUT5, in adult mouse cardiomyocytes was detected by real-time and conventional RT-PCR techniques. Diastolic Ca2+ and Ca2+ transient amplitude were decreased in isolated cardiomyocytes from fructose-fed mice relative to control (16 and 42%, respectively), coincident with an increase in the time constant of Ca2+ transient decay (24%). Dietary fructose increased the myofilament response to Ca2+ (as evidenced by a left shift in the shortening-Ca2+ phase loop). Protein expression of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), phosphorylated (P) phospholamban (Ser16), and P-phospholamban (Thr17) was reduced, and protein phosphatase 2A expression increased, in fructose-fed mouse hearts. Hypertension and cardiac hypertrophy were not evident. These findings demonstrate that fructose diet-associated myocardial insulin resistance induces profound disturbance of cardiomyocyte Ca2+ handling and responsiveness in the absence of altered systemic loading conditions.

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