scholarly journals Role of LXR alpha in regulating expression of glucose transporter 4 in adipocytes — Investigation on improvement of health of diabetic patients

2020 ◽  
Vol 13 (2) ◽  
pp. 244-252 ◽  
Author(s):  
Balamuralikrishnan Balasubramanian ◽  
Hak-J. Kim ◽  
Ramzi A. Mothana ◽  
Young O. Kim ◽  
Nasir A. Siddiqui
Keyword(s):  
Glucose Transporter ◽  
Diabetic Patients ◽  
Glucose Transporter 4

Abstract 112: A Pathological Role of Endothelial p53 in the Regulation of Endothelial Function and Glucose Metabolism

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Masataka YOKOYAMA ◽  
Yoshio KOBAYASHI ◽  
Tohru MINAMINO
Keyword(s):  
Skeletal Muscle ◽  
Endothelial Cell ◽  
Glucose Metabolism ◽  
Endothelial Function ◽  
Mitochondrial Biogenesis ◽  
Glucose Transporter ◽  
Diabetic Patients ◽  
Glucose Transporter 1 ◽  
P53 Activation

Cellular senescence is a state of irreversible growth arrest induced by various stresses such as oncogenic stimuli. This response is controlled by negative regulators of the cell cycle like the p53 tumor suppressor protein. Accumulating evidence has suggested a role of p53 activation in various age-associated conditions including atherosclerosis, heart failure and diabetes. Here we show that endothelial p53 activation plays a pathological role in the regulation of endothelial function and glucose metabolism under diabetic conditions. Endothelial expression of p53 was markedly up-regulated in a streptozotocin-induced diabetes model. Endothelial function such as acetylcholine-dependent vasodilatation was markedly impaired in this model. Although hyperglycemia was not altered, impairment of endothelial function was significantly improved in mice with endothelial cell-specific p53 deficiency. In same way, p53 was markedly activated in ischemic vessels, and endothelial p53 deficiency enhanced ischemia-induced angiogenesis. Mechanistically, endothelial p53 up-regulated the expression of PTEN that negatively regulated the Akt-eNOS pathway, and therefore disruption of p53 improved endothelial dysfunction. We also found that endothelial p53 was markedly activated, and the Akt-eNOS pathway was attenuated in a diet-induced obesity model. Disruption of endothelial p53 activation improved dietary inactivation of eNOS that up-regulated the expression of PGC-1α in skeletal muscle, thereby increasing mitochondrial biogenesis and oxygen consumption. Inhibition of endothelial p53 also improved dietary impairment of glucose transport into skeletal muscle by up-regulating endothelial expression of glucose transporter 1. Consequently, mice with endothelial cell-specific p53 deficiency fed a high-calorie diet showed improvement of insulin sensitivity and less fat accumulation compared with control littermates. These results indicate that endothelial p53 negatively regulates endothelium-dependent vasodilatation, ischemia-induced angiogenesis, and mitochondrial biogenesis by inhibiting the Akt-eNOS pathway and suggest that inhibition of endothelial p53 could be a novel therapeutic target in diabetic patients.

scholarly journals Insulin Signaling Attenuates GLUT4 Endocytosis in Muscle Cells via GSK3α-Dyn2-Bin1 Interplay

2021 ◽  
Author(s):  
Jessica Laiman ◽  
Julie Loh ◽  
Wei-Chun Tang ◽  
Mei-Chun Chuang ◽  
Bi-Chang Chen ◽  
...  
Keyword(s):  
Insulin Signaling ◽  
Glucose Transporter ◽  
Muscle Cells ◽  
Postprandial Glucose ◽  
Muscle Physiology ◽  
Centronuclear Myopathy ◽  
Glucose Transporter 4 ◽  
Membrane Fission ◽  
Dynamin 2

AbstractInsulin-induced translocation of glucose transporter 4 (GLUT4) to the plasma membrane of skeletal muscle is critical for postprandial glucose uptake; however, whether the internalization of GLUT4 into cells is also regulated by insulin signaling remains unclear. Here, we discover that the activity of dynamin-2 (Dyn2), pivotal GTPase catalyzing GLUT4 internalization, is regulated by insulin signaling in muscle cells. The membrane fission activity of Dyn2 is inhibited in muscle cells through binding with the SH3 domain-containing protein Bin1. Phosphorylation of Serine848 on Dyn2 by GSK3α or the mutations of Bin1-SH3 in patients with centronuclear myopathy, elevate the activity of Dyn2 due to reduced binding affinity toward Bin1. The augmented Dyn2 fission activity in muscle cells leads to GLUT4 internalization and Bin1-tubule vesiculation. Together, our findings reveal a new role of insulin signaling in glucose metabolism and muscle physiology via attenuating Dyn2 activity thus regulating GLUT4 endocytosis in muscle cell.

scholarly journals Adipocytes Exhibit Abnormal Subcellular Distribution and Translocation of Vesicles Containing Glucose Transporter 4 and Insulin-Regulated Aminopeptidase in Type 2 Diabetes Mellitus: Implications Regarding Defects in Vesicle Trafficking

2001 ◽  
Vol 86 (11) ◽  
pp. 5450-5456 ◽  
Author(s):  
Lidia Maianu ◽  
Susanna R. Keller ◽  
W. Timothy Garvey
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Body Mass Index ◽  
Body Mass ◽  
Glucose Transporter ◽  
Diabetic Patients ◽  
Low Density ◽  
Glucose Transporter 4 ◽  
Glut 4

Insulin resistance in type 2 diabetes is due to impaired stimulation of the glucose transport system in muscle and fat. Different defects are operative in these two target tissues because glucose transporter 4 (GLUT 4) expression is normal in muscle but markedly reduced in fat. In muscle, GLUT 4 is redistributed to a dense membrane compartment, and insulin-mediated translocation to plasma membrane (PM) is impaired. Whether similar trafficking defects are operative in human fat is unknown. Therefore, we studied subcellular localization of GLUT4 and insulin-regulated aminopeptidase (IRAP; also referred to as vp165 or gp160), which is a constituent of GLUT4 vesicles and also translocates to PM in response to insulin. Subcutaneous fat was obtained from eight normoglycemic control subjects (body mass index, 29 ± 2 kg/m2) and eight type 2 diabetic patients (body mass index, 30 ± 1 kg/m2; fasting glucose, 14 ± 1 mm). In adipocytes isolated from diabetics, the basal 3-O-methylglucose transport rate was decreased by 50% compared with controls (7.1 ± 2.9 vs. 14.1 ± 3.7 mmol/mm2 surface area/min), and there was no increase in response to maximal insulin (7.9 ± 2.7 vs. 44.5 ± 9.2 in controls). In membrane subfractions from controls, insulin led to a marked increase of IRAP in the PM from 0.103 ± 0.04 to 1.00± 0.33 relative units/mg protein, concomitant with an 18% decrease in low-density microsomes and no change in high-density microsomes (HDM). In type 2 diabetes, IRAP overall expression in adipocytes was similar to that in controls; however, two abnormalities were observed. First, in basal cells, IRAP was redistributed away from low-density microsomes, and more IRAP was recovered in HDM (1.2-fold) and PM (4.4-fold) from diabetics compared with controls. Second, IRAP recruitment to PM by maximal insulin was markedly impaired. GLUT4 was depleted in all membrane subfractions (43–67%) in diabetes, and there was no increase in PM GLUT4 in response to insulin. Type 2 diabetes did not affect the fractionation of marker enzymes. We conclude that in human adipocytes: 1) IRAP is expressed and translocates to PM in response to insulin; 2) GLUT4 depletion involves all membrane subfractions in type 2 diabetes, although cellular levels of IRAP are normal; and 3) in type 2 diabetes, IRAP accumulates in membrane vesicles cofractionating with HDM and PM under basal conditions, and insulin-mediated recruitment to PM is impaired. Therefore, in type 2 diabetes, adipocytes express defects in trafficking of GLUT4/IRAP-containing vesicles similar to those causing insulin resistance in skeletal muscle.

scholarly journals Golgi-Localized, γ-Ear-Containing, Arf-Binding Protein Adaptors Mediate Insulin-Responsive Trafficking of Glucose Transporter 4 in 3T3-L1 Adipocytes

2005 ◽  
Vol 19 (8) ◽  
pp. 2145-2153 ◽  
Author(s):  
Lin V. Li ◽  
Konstantin V. Kandror
Keyword(s):  
Glucose Transporter ◽  
Adaptor Proteins ◽  
Dominant Negative ◽  
Glucose Transporter 4 ◽  
Glutathione S Transferase ◽  
Insulin Responsiveness ◽  
Vhs Domain

Abstract Small glucose transporter 4 (Glut4)-containing vesicles represent the major insulin-responsive compartment in fat and skeletal muscle cells. The molecular mechanism of their biogenesis is not yet elucidated. Here, we studied the role of the newly discovered family of monomeric adaptor proteins, GGA (Golgi-localized, γ-ear-containing, Arf-binding proteins), in the formation of small Glut4 vesicles and acquisition of insulin responsiveness in 3T3-L1 adipocytes. In these cells, all three GGA isoforms are expressed throughout the differentiation process. In particular, GGA2 is primarily present in trans-Golgi network and endosomes where it demonstrates a significant colocalization with the recycling pool of Glut4. Using the techniques of immunoadsorption as well as glutathione-S-transferase pull-down assay we found that Glut4 vesicles (but not Glut4 per se) interact with GGA via the Vps-27, Hrs, and STAM (VHS) domain. Moreover, a dominant negative GGA mutant inhibits formation of Glut4 vesicles in vitro. To study a possible role of GGA in Glut4 traffic in the living cell, we stably expressed a dominant negative GGA mutant in 3T3-L1 adipocytes. Formation of small insulin-responsive Glut4-containing vesicles and insulin-stimulated glucose uptake in these cells were markedly impaired. Thus, GGA adaptors participate in the formation of the insulin-responsive vesicular compartment from the intracellular donor membranes both in vivo and in vitro.

Salacia oblonga extract increases glucose transporter 4-mediated glucose uptake in L6 rat myotubes: Role of mangiferin

2009 ◽  
Vol 28 (5) ◽  
pp. 565-574 ◽  
Author(s):  
María Dolores Girón ◽  
Natalia Sevillano ◽  
Rafael Salto ◽  
Ali Haidour ◽  
Manuel Manzano ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glucose Transporter ◽  
Glucose Transporter 4 ◽  
Salacia Oblonga

scholarly journals Crucial role of the small GTPase Rac1 in insulin‐stimulated translocation of glucose transporter 4 to the mouse skeletal muscle sarcolemma

2010 ◽  
Vol 24 (7) ◽  
pp. 2254-2261 ◽  
Author(s):  
Shuji Ueda ◽  
Sohei Kitazawa ◽  
Kota Ishida ◽  
Yuki Nishikawa ◽  
Megumi Matsui ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Crucial Role ◽  
Glucose Transporter ◽  
Small Gtpase ◽  
Glucose Transporter 4 ◽  
Mouse Skeletal Muscle

scholarly journals Simultaneous Effects of Metformin and Sitagliptin on the Contents of Insulin Resistance Proteins Glucose Transporter 4 and Protein Kinase B in Diabetic Patients' Adipose Tissue

2021 ◽  
Author(s):  
Didehdar Didehdar ◽  
Yousof Naghiaee ◽  
Javad Mohiti-Ardekani ◽  
Naeimeh Heiranizadeh ◽  
Masaoud Rahmanian
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Transporter ◽  
Protein Kinase B ◽  
P Value ◽  
Diabetic Patients ◽  
Glucose Transporter 4 ◽  
Resistance Proteins ◽  
Type 2 Diabetic

Objective: Obesity is a factor in the development of insulin resistance and type 2 diabetes. Obesity contributes a wide variety of metabolic changes such as insulin resistance. The insulin signal mechanism to intra-cells occurs in insulin resistance, primarily in adipose tissue cells, which can be appropriate targets for therapeutic approaches by recognizing the proteins in this pathway. The study aimed to evaluate the simultaneous impact of metformin and sitagliptin on the expression of protein levels involved in insulin resistance Protein Kinase B (Akt) and Glucose Transporter 4 (GLUT4) in diabetic adipose tissue. Materials and Methods: In order to evaluate the content of proteins involved in insulin resistance Akt and GLUT4 in adipose tissue of diabetic patients with the use of SDS-PAGE and western blot analyses, we studied 6 persons of type 2 diabetic patients who obtained 3 months of care with simultaneous metformin and sitagliptin, 4 persons returned from them after treatment and 8 persons as a stable case (control group). Results: There was an increase in glucose intake and a decrease in serum glucose levels (P-value= 0.025) and no decrease in insulin resistance (P-value= 0.6) following simultaneous metformin and sitagliptin therapy, but no improvement in serum insulin levels (Pvalue=1.01). Increases in the content of Akt protein (P-value= 0.682) and GLUT4 protein (P-value= 0.851) involved in insulin resistance in diabetic patients' adipose tissue, were not observed. Conclusion: Simultaneous treatment with metformin and sitagliptin had no effect on insulin resistance proteins Akt and GLUT4 in type 2 diabetic adipose tissue.

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