scholarly journals Rab5 Activity Regulates GLUT4 Sorting Into Insulin-Responsive and Non-Insulin-Responsive Endosomal Compartments: A Potential Mechanism for Development of Insulin Resistance

Endocrinology ◽  
2014 ◽  
Vol 155 (9) ◽  
pp. 3315-3328 ◽  
Author(s):  
Kandice L. Tessneer ◽  
Robert M. Jackson ◽  
Beth A. Griesel ◽  
Ann Louise Olson
Keyword(s):  
Insulin Resistance ◽  
Cell Surface ◽  
Glucose Transporter ◽  
Cell Model ◽  
Intracellular Localization ◽  
Early Event ◽  
Insulin Resistant ◽  
Peripheral Insulin Resistance ◽  
Intracellular Storage ◽  
Activity Dependent

Abstract Glucose transporter isoform 4 (GLUT4) is the insulin-responsive glucose transporter mediating glucose uptake in adipose and skeletal muscle. Reduced GLUT4 translocation from intracellular storage compartments to the plasma membrane is a cause of peripheral insulin resistance. Using a chronic hyperinsulinemia (CHI)-induced cell model of insulin resistance and Rab5 mutant overexpression, we determined these manipulations altered endosomal sorting of GLUT4, thus contributing to the development of insulin resistance. We found that CHI induced insulin resistance in 3T3-L1 adipocytes by retaining GLUT4 in a Rab5-activity-dependent compartment that is unable to equilibrate with the cell surface in response to insulin. Furthermore, CHI-mediated retention of GLUT4 in this non-insulin-responsive compartment impaired filling of the transferrin receptor (TfR)-positive and TfR-negative insulin-responsive storage compartments. Our data suggest that hyperinsulinemia may inhibit GLUT4 by chronically maintaining GLUT4 in the Rab5 activity-dependent endosomal pathway and impairing formation of the TfR-negative and TfR-positive insulin-responsive GLUT4 pools. This model suggests that an early event in the development of insulin-resistant glucose transport in adipose tissue is to alter the intracellular localization of GLUT4 to a compartment that does not efficiently equilibrate with the cell surface when insulin levels are elevated for prolonged periods of time.

Dexamethasone-induced insulin resistance is associated with increased connexin 36 mRNA and protein expression in pancreatic rat islets

2007 ◽  
Vol 85 (5) ◽  
pp. 536-545 ◽  
Author(s):  
A. Rafacho ◽  
L.P. Roma ◽  
S.R. Taboga ◽  
A.C. Boschero ◽  
J.R. Bosqueiro
Keyword(s):  
Insulin Resistance ◽  
Protein Expression ◽  
Pancreatic Islets ◽  
Connexin 43 ◽  
Glucose Transporter ◽  
Insulin Resistant ◽  
Protein Levels ◽  
Connexin 36 ◽  
Peripheral Insulin Resistance ◽  
Glucose Stimulated Insulin Secretion

Augmented glucose-stimulated insulin secretion (GSIS) is an adaptive mechanism exhibited by pancreatic islets from insulin-resistant animal models. Gap junction proteins have been proposed to contribute to islet function. As such, we investigated the expression of connexin 36 (Cx36), connexin 43 (Cx43), and the glucose transporter Glut2 at mRNA and protein levels in pancreatic islets of dexamethasone (DEX)-induced insulin-resistant rats. Study rats received daily injections of DEX (1 mg/kg body mass, i.p.) for 5 days, whereas control rats (CTL) received saline solution. DEX rats exhibited peripheral insulin resistance, as indicated by the significant postabsorptive insulin levels and by the constant rate for glucose disappearance (KITT). GSIS was significantly higher in DEX islets (1.8-fold in 16.7 mmol/L glucose vs. CTL, p < 0.05). A significant increase of 2.25-fold in islet area was observed in DEX vs. CTL islets (p < 0.05). Cx36 mRNA expression was significantly augmented, Cx43 diminished, and Glut2 mRNA was unaltered in islets of DEX vs. CTL (p < 0.05). Cx36 protein expression was 1.6-fold higher than that of CTL islets (p < 0.05). Glut2 protein expression was unaltered and Cx43 was not detected at the protein level. We conclude that DEX-induced insulin resistance is accompanied by increased GSIS and this may be associated with increase of Cx36 protein expression.

scholarly journals The Role of Overexpressed Apolipoprotein AV in Insulin-Resistant Hepatocytes

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Wang Zhao ◽  
Yaqiong Liu ◽  
Xiaobo Liao ◽  
Shuiping Zhao
Keyword(s):  
Insulin Resistance ◽  
G Protein ◽  
Microarray Data ◽  
Recombinant Adenovirus ◽  
Cell Model ◽  
Purinergic Receptor ◽  
Interaction Network ◽  
Angiotensin Ii Receptor ◽  
Insulin Resistant ◽  
Apolipoprotein Av

In this paper, we sought to explore the relationship between apolipoprotein AV (APOAV) overexpression and insulin resistance in hepatocytes. The insulin-resistant HepG2 cell model was constructed, and then, APOAV-overexpressed HepG2 cells (B-M) were induced by infecting with a recombinant adenovirus vector. Microarray data were developed from B-M samples compared with negative controls (A-con), and the microarray data were analyzed by bioinformatic methods. APOAV-overexpression induced 313 upregulated genes and 563 downregulated ones in B-M sample. The differentially expressed genes (DEGs) were significantly classified in fat digestion and absorption pathway. Protein-protein interaction network was constructed, and AGTR1 (angiotensin II receptor type 1) and P2RY2 (purinergic receptor P2Y, G-protein coupled 2) were found to be the significant nodes closely related with G-protein related signaling. Additionally, overexpression of APOAV could change the expression of Glut4 and release the insulin resistance of hepatic cells. Thus, APOAV overexpression may prevent the insulin resistance in liver cells by mediating the genes such as AGTR1 and P2RY2.

scholarly journals Mammalian Tribbles homolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance

2010 ◽  
Vol 298 (3) ◽  
pp. E565-E576 ◽  
Author(s):  
Jiarong Liu ◽  
Xuxia Wu ◽  
John L. Franklin ◽  
Joseph L. Messina ◽  
Helliner S. Hill ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Transporter ◽  
Vastus Lateralis ◽  
Glucose Deprivation ◽  
Muscle Cells ◽  
Diabetic Rats ◽  
Glucose Disposal ◽  
Insulin Resistant ◽  
Protein Levels

Tribbles homolog 3 (TRIB3) was found to inhibit insulin-stimulated Akt phosphorylation and modulate gluconeogenesis in rodent liver. Currently, we examined a role for TRIB3 in skeletal muscle insulin resistance. Ten insulin-sensitive, ten insulin-resistant, and ten untreated type 2 diabetic (T2DM) patients were metabolically characterized by hyperinsulinemic euglycemic glucose clamps, and biopsies of vastus lateralis were obtained. Skeletal muscle samples were also collected from rodent models including streptozotocin (STZ)-induced diabetic rats, db/db mice, and Zucker fatty rats. Finally, L6 muscle cells were used to examine regulation of TRIB3 by glucose, and stable cell lines hyperexpressing TRIB3 were generated to identify mechanisms underlying TRIB3-induced insulin resistance. We found that 1) skeletal muscle TRIB3 protein levels are significantly elevated in T2DM patients; 2) muscle TRIB3 protein content is inversely correlated with glucose disposal rates and positively correlated with fasting glucose; 3) skeletal muscle TRIB3 protein levels are increased in STZ-diabetic rats, db/db mice, and Zucker fatty rats; 4) stable TRIB3 hyperexpression in muscle cells blocks insulin-stimulated glucose transport and glucose transporter 4 (GLUT4) translocation and impairs phosphorylation of Akt, ERK, and insulin receptor substrate-1 in insulin signal transduction; and 5) TRIB3 mRNA and protein levels are increased by high glucose concentrations, as well as by glucose deprivation in muscle cells. These data identify TRIB3 induction as a novel molecular mechanism in human insulin resistance and diabetes. TRIB3 acts as a nutrient sensor and could mediate the component of insulin resistance attributable to hyperglycemia (i.e., glucose toxicity) in diabetes.

scholarly journals MON-LB116 FGF-21 Is A Reliable Marker Of Insulin Resistance Before The Occurrence Of Glucose Intolerance

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
ahmed sawah ◽  
Berhane Seyoum ◽  
Zaher Msallaty
Keyword(s):  
Insulin Resistance ◽  
Glucose Metabolism ◽  
Enzyme Linked Immunosorbent Assay ◽  
Insulin Resistant ◽  
Peripheral Insulin Resistance ◽  
Glucose And Lipid Metabolism ◽  
Institutional Review ◽  
Wide Range ◽  
Before And After ◽  
Clamp Study

Abstract Background and aims: Fibroblast growth factor (FGF)-21 is a polypeptide that results in metabolic rearrangement mostly related to glucose and lipid metabolism. Serum FGF-21 level is elevated in obesity and in type 2 diabetes. The goal of this study is to evaluate the relationship between FGF-21 and peripheral insulin resistance in a wide range of baseline BMI and glucose metabolism status. Materials and methods: seventy one participants reported to the clinical research center in a fasting state twice. BMI and fat mass were calculated. Glucose metabolism was determined by fasting glucose, hemoglobin A1c and OGTT. Serum lipids panel was measured. Peripheral insulin resistance was determined using the hyperinsulinemic euglycemic clamp study. FGF-21 level was measured using enzyme-linked immunosorbent assay before and after clamp study. Study was approved by university institutional review board. Results: Of 71 participants, 48 were obese and 23 were lean. Normal glucose metabolism was documented in 43 individuals. Serum FGF-21 was significantly elevated in insulin resistant compared to insulin sensitive subgroups (0.28 ng/ml ± 0.136 vs. 0.14 ng/ml ± 0.112. p &lt; 0.001). Despite the fact that FGF-21 is elevated in all obese population, the level was significantly higher in the insulin resistant obese subgroup compared to the insulin sensitive obese one (0.30 ng/ml ± 0.167 vs. 0.17 ng/ml ± 0.126. P =0.003). Furthermore, significantly higher FGF-21 level was also found in lean insulin resistant compared to lean insulin sensitive subgroups (0.18 ng/ml ± 0.106 vs. 0.09 ng/ml ± 0.061, p = 0.04]. Adjustment to preexisting impaired glucose tolerance did not affect the correlation between FGF-21 level and insulin resistance which remained statically significant in the seemingly healthy obese and lean subgroups. Conclusion: Serum FGF-21 level strongly correlates to peripheral insulin resistance in both obese and lean population. Nonetheless, FGF-21 level rises way before glucose metabolism abnormality can be detected. Our study suggests a cutoff level for each subgroup which may enable clinicians to risk-stratify patients and allow for early intervention.

scholarly journals Type 2 Diabetes Mouse Model: Insights into the Contribution of Metabolic Defects to Neurocognitive Decline

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Alexa Loncharich ◽  
Austin Reilly ◽  
Shijun Yan ◽  
Hongxia Ren
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Glucose Transporter ◽  
Metabolic Diseases ◽  
Neurocognitive Deficits ◽  
Treatment Needs ◽  
Resistant Mouse ◽  
Insulin Resistant ◽  
Metabolic Defects

Background and Hypothesis: Metabolic diseases, including type 2 diabetes (T2D), have become increasingly prevalent and their associated medical costs have skyrocketed. Furthermore, recent epidemiological evidence suggests links between metabolic defects and neurodegenerative diseases, such as Alzheimer’s Disease (AD). The increasing coincidence of AD and T2D, and unmet treatment needs, necessitates research investigating potential shared mechanisms. To study glucose and lipid metabolism defects and neurocognitive deficits, we have generated non-obese insulin resistant mouse models, named GLUT4-mediated Insulin Receptor KnockOut (GIRKO). Insulin-responsive glucose transporter, Glut4, is expressed in muscle, fat, and a subset of neurons in the brain. Our previous publications show that GIRKO mice are highly insulin resistant and insulin sensitive GLUT4 neurons are critical mediators for glucose metabolism. We hypothesize that central insulin resistance in GIRKO mice instigates neurocognitive defects.  Experimental Design: We will measure the neurocognitive function of 3- to 4-month old GIRKO mice using Morris water maze (MWM) test.   Results: GIRKO mice exhibited increased escape latency. Additionally, they spent less time in the target quadrant in the probe trial, in which the platform is removed. GIRKO performed equally compared to control mice in raised platform tests, which demonstrates that motor competencies do not confound our findings.  Conclusion and Potential Impact: GIRKO mice have learning and memory deficits, which illustrates a possible link between neurocognition and metabolism.  Our results support the notion that insulin resistance precedes cognitive decline and necessitates early intervention therapy to treat insulin resistance and protect cognitive function. 

scholarly journals Changes in FGF21 Serum Concentrations and Liver mRNA Expression in an Experimental Model of Complete Lipodystrophy and Insulin-Resistant Diabetes

2014 ◽  
pp. 483-490 ◽  
Author(s):  
A. ŠPOLCOVÁ ◽  
M. HOLUBOVÁ ◽  
B. MIKULÁŠKOVÁ ◽  
V. NAGELOVÁ ◽  
A. ŠTOFKOVÁ ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Mrna Expression ◽  
Plasma Levels ◽  
Glucose Transporter ◽  
Liver Fat ◽  
Fibroblast Growth Factor 21 ◽  
Glucose Transporter 1 ◽  
Insulin Resistant

Patients with obesity and type 2 diabetes often display high levels of the anti-diabetic factor fibroblast growth factor-21 (FGF21), suggesting that the overproduction of FGF21 may result from increased adiposity in an attempt by white adipose tissue (WAT) to counteract insulin resistance. However, the production of FGF21 diabetes in the absence of WAT has not been examined. In this study, we investigated the effects of lipodystrophy in A-ZIP F-1 mice on FGF21 production in relation to diabetes. A-ZIP F-1 mice displayed high FGF21 plasma levels resulting from enhanced FGF21 mRNA expression in the liver. Concomitant enhancement of FGF21 receptor (FGFR1) and glucose transporter 1 (GLUT-1) mRNA expression was observed in the muscles of A-ZIP F-1 mice. Furthermore, the activation of hypothalamic NPY and AgRP mRNA expression positively correlated with plasma levels of FGF21 but not active ghrelin. Our study demonstrates that an increased FGF21 plasma level in lipodystrophic A-ZIP F-1 mice results mainly from up-regulated liver production but does not suffice to overcome the lipodystrophy-induced severe type 2-diabetes and insulin resistance in the liver linked to the augmented liver fat deposition.

scholarly journals Plumbagin attenuates high glucose-induced trophoblast cell apoptosis and insulin resistance via activating AKT/mTOR pathway

2021 ◽  
Vol 13 (3) ◽  
pp. 102-108
Author(s):  
Yilin Zhang ◽  
Guantai Ni ◽  
Hongying Yang
Keyword(s):  
Insulin Resistance ◽  
Cell Viability ◽  
High Glucose ◽  
Cell Apoptosis ◽  
Glucose Transporter ◽  
Cell Model ◽  
Trophoblast Cell ◽  
Mtor Pathway ◽  
Potential Strategy ◽  
Glucose Transporter Type 4

Plumbagin, a bioactive phytoconstituent, is isolated from the root of Plumbago zeylanica L. Plumbagin pos-sesses antidiabetic effect to mediate glucose homeostasis, wound healing and diabetic nephropathy. However, the involvement of plumbagin in gestational diabetes mellitus (GDM) has not been reported yet. Trophoblast cell line (HTR8/SVneo) was incubated with high glucose to establish cell model of GDM. Cell viability and proliferation were detected by MTT and EdU staining. Flow cytometry was used to investigate cell apoptosis. Cell viability of HTR8/SVneo was reduced by high glucose or incubation of plumbagin. Plumbagin restored reduced cell viability and proliferation of HTR8/SVneo induced by high glucose. Plumbagin attenuated high glucose-induced cell apoptosis in HTR8/SVneo cells through upregulation of Bcl-2 and down-regulation of Bax, cleaved caspase-3 and cleaved caspase-9. Protein expression of glucose transporter type 4 (GLUT-4), insulin receptor (INSR)-B and INSR substrate (IRS1) was decreased in high glucose-induced HTR8/SVneo but increased by plumbagin. The suppressive effects of high glucose on phosphorylation of AKT and mTOR in HTR8/SVneo were reversed by plumbagin. Plumbagin improved high glucose-induced cell apoptosis and insulin resistance of HTR8/SVneo through activation of AKT/mTOR pathway, suggesting that plumbagin might be used as a potential strategy for the prevention of GDM.

scholarly journals Theaflavins Improve Insulin Sensitivity through Regulating Mitochondrial Biosynthesis in Palmitic Acid-Induced HepG2 Cells

2018 ◽  
Author(s):  
Tuantuan Tong ◽  
Ning Ren ◽  
Jiafan Wu ◽  
Na Guo ◽  
Xiaobo Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Palmitic Acid ◽  
Hepg2 Cells ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Hepatic Insulin Resistance ◽  
Insulin Resistant ◽  
Mitochondrial Dna Copy Number ◽  
Increase Glucose Uptake

Theaflavins, the characteristic and bioactive polyphenols in black tea, possess the potential improvement effects on insulin resistance-associated metabolic abnormalities including obesity and type 2 diebetes. However, the molecular mechanisms of theaflavins improving insulin sensitivity are still not clear. In this study, we investigated the protective effects and mechanisms of theaflavins on palmitic acid-induced insulin resistance in HepG2 cells. Theaflavins could significantly increase glucose uptake of insulin-resistant cells at noncytotoxic doses. This activity was mediated by upregulating the glucose transporter 4 protein expression, increasing the phosphorylation of IRS-1 at Ser307, and reduced the phosphor-Akt (Ser473) level. Moreover, theaflavins were found to enhance mitochondrial DNA copy number through down-regulate the PGC-1&beta; mRNA level and up-regulate PRC mRNA expression in insulin-resistant HepG2 cells. These results indicated that theaflavins could improve free fatty acid-induced hepatic insulin resistance by promoting mitochondrial biogenesis, and were promising functional food and medicines for insulin resistance-related disorders.

scholarly journals Serum from Jiao-Tai-Wan treated rats increases glucose consumption by 3T3-L1 adipocytes through AMPK pathway signaling

2019 ◽  
Vol 39 (4) ◽  
Author(s):  
Lin Yuan ◽  
Peng Tang ◽  
Hui-Jiao Li ◽  
Na Hu ◽  
Xiao-Yu Zhong ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Transporter ◽  
Glucose Consumption ◽  
Diabetic Mouse ◽  
Rat Serum ◽  
Insulin Resistant ◽  
Ampk Pathway ◽  
Compound C ◽  
Type 2 Diabetic

Abstract Type 2 diabetes (T2DM) is characterized by hyperglycemia resulting from insulin resistance. Jiao-Tai-Wan (JTW), a traditional Chinese medicine consisting of a 10:1 formulation of Rhizoma Coptidis (RC) and Cortex Cinnamomi (cinnamon) was shown to have hypoglycemic efficacy in a type 2 diabetic mouse model. Here we investigated whether glucose consumption by insulin-resistant adipocytes could be modulated by serum from JTW-treated rats, and if so, through what mechanism. JTW-medicated serum was prepared from rats following oral administration of JTW decoction twice a day for 4 days. Fully differentiated 3T3-L1 adipocytes – rendered insulin resistance by dexamethasone treatment – were cultured in medium containing JTW-medicated rat serum. JTW-medicated serum treatment increased glucose uptake, up-regulated levels of phosphorylated adenosine 5′-monophoshate-activated protein kinase (p-AMPK), and stimulated expression and translocation of glucose transporter 4 (GLUT4). JTW-medicated serum induced significantly greater up-regulation of p-AMPK and GLUT4 than either RC or cinnamon-medicated serum. JTW-medicated serum induced effects on 3T3-L1 adipocytes could be partially inhibited by treatment with the AMPK inhibitor compound C. In conclusion, JTW-medicated serum increased glucose consumption by IR adipocytes partially through the activation of the AMPK pathway, and JTW was more effective on glucose consumption than either RC or cinnamon alone.

scholarly journals Degradation of IRS1 leads to impaired glucose uptake in adipose tissue of the type 2 diabetes mouse model TALLYHO/Jng

2009 ◽  
Vol 203 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Yun Wang ◽  
Patsy M Nishina ◽  
Jürgen K Naggert
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Insulin Resistant

The TALLYHO/Jng (TH) mouse strain is a polygenic model for type 2 diabetes (T2D) characterized by moderate obesity, impaired glucose tolerance and uptake, insulin resistance, and hyperinsulinemia. The goal of this study was to elucidate the molecular mechanisms responsible for the reduced glucose uptake and insulin resistance in the adipose tissue of this model. The translocation and localization of glucose transporter 4 (GLUT4) to the adipocyte plasma membrane were impaired in TH mice compared to control C57BL6/J (B6) mice. These defects were associated with decreased GLUT4 protein, reduced phosphatidylinositol 3-kinase activity, and alterations in the phosphorylation status of insulin receptor substrate 1 (IRS1). Activation of c-Jun N-terminal kinase 1/2, which can phosphorylate IRS1 on Ser307, was significantly higher in TH mice compared with B6 controls. IRS1 protein but not mRNA levels was found to be lower in TH mice than controls. Immunoprecipitation with anti-ubiquitin and western blot analysis of IRS1 protein revealed increased total IRS1 ubiquitination in adipose tissue of TH mice. Suppressor of cytokine signaling 1, known to promote IRS1 ubiquitination and subsequent degradation, was found at significantly higher levels in TH mice compared with B6. Immunohistochemistry showed that IRS1 colocalized with the 20S proteasome in proteasomal structures in TH adipocytes, supporting the notion that IRS1 is actively degraded. Our findings suggest that increased IRS1 degradation and subsequent impaired GLUT4 mobilization play a role in the reduced glucose uptake in insulin resistant TH mice. Since low-IRS1 levels are often observed in human T2D, the TH mouse is an attractive model to investigate mechanisms of insulin resistance and explore new treatments.

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