scholarly journals Estrogen and Glycemic Homeostasis: The Fundamental Role of Nuclear Estrogen Receptors ESR1/ESR2 in Glucose Transporter GLUT4 Regulation

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 99
Author(s):  
Karen Cristina Rego Gregorio ◽  
Caroline Pancera Laurindo ◽  
Ubiratan Fabres Machado
Keyword(s):  
Estrogen Receptors ◽  
Glucose Transporter ◽  
Estrogen Regulation ◽  
Great Opportunity ◽  
Mediated Effects ◽  
Glut4 Expression ◽  
Glucose Transporter Glut4 ◽  
Nuclear Estrogen Receptors ◽  
The Relationship

Impaired circulating estrogen levels have been related to impaired glycemic homeostasis and diabetes mellitus (DM), both in females and males. However, for the last twenty years, the relationship between estrogen, glycemic homeostasis and the mechanisms involved has remained unclear. The characterization of estrogen receptors 1 and 2 (ESR1 and ESR2) and of insulin-sensitive glucose transporter type 4 (GLUT4) finally offered a great opportunity to shed some light on estrogen regulation of glycemic homeostasis. In this manuscript, we review the relationship between estrogen and DM, focusing on glycemic homeostasis, estrogen, ESR1/ESR2 and GLUT4. We review glycemic homeostasis and GLUT4 expression (muscle and adipose tissues) in Esr1−/− and Esr2−/− transgenic mice. We specifically address estradiol-induced and ESR1/ESR2-mediated regulation of the solute carrier family 2 member 4 (Slc2a4) gene, examining ESR1/ESR2-mediated genomic mechanisms that regulate Slc2a4 transcription, especially those occurring in cooperation with other transcription factors. In addition, we address the estradiol-induced translocation of ESR1 and GLUT4 to the plasma membrane. Studies make it clear that ESR1-mediated effects are beneficial, whereas ESR2-mediated effects are detrimental to glycemic homeostasis. Thus, imbalance of the ESR1/ESR2 ratio may have important consequences in metabolism, highlighting that ESR2 hyperactivity assumes a diabetogenic role.

C2C12 myocytes lack an insulin-responsive vesicular compartment despite dexamethasone-induced GLUT4 expression

2002 ◽  
Vol 283 (3) ◽  
pp. E514-E524 ◽  
Author(s):  
Lori L. Tortorella ◽  
Paul F. Pilch
Keyword(s):  
Glucose Transporter ◽  
Fold Increase ◽  
Snare Proteins ◽  
Vesicular Traffic ◽  
Glut4 Expression ◽  
Protein Receptor ◽  
Syntaxin 4 ◽  
Insulin Dependent ◽  
Glucose Transporter Glut4 ◽  
Vesicular Compartment

Insulin regulates the uptake of glucose into skeletal muscle and adipocytes by redistributing the tissue-specific glucose transporter GLUT4 from intracellular vesicles to the cell surface. To date, GLUT4 is the only protein involved in insulin-regulated vesicular traffic that has this tissue distribution, thus raising the possibility that its expression alone may allow formation of an insulin-responsive vesicular compartment. We show here that treatment of differentiating C2C12myoblasts with dexamethasone, acting via the glucocorticoid receptor, causes a ≥10-fold increase in GLUT4 expression but results in no significant change in insulin-stimulated glucose transport. Signaling from the insulin receptor to its target, Akt2, and expression of the soluble N-ethylmaleimide-sensitive factor-attachment protein receptor, or SNARE, proteins syntaxin 4 and vesicle-associated membrane protein are normal in dexamethasone-treated C2C12 cells. However, these cells show no insulin-dependent trafficking of the insulin-responsive aminopeptidase or the transferrin receptor, respective markers for intracellular GLUT4-rich compartments and endosomes that are insulin responsive in mature muscle and adipose cells. Therefore, these data support the hypothesis that GLUT4 expression by itself is insufficient to establish an insulin-sensitive vesicular compartment.

Altered renal expression of the insulin-responsive glucose transporter GLUT4 in experimental diabetes mellitus

1994 ◽  
Vol 267 (5) ◽  
pp. F816-F824 ◽  
Author(s):  
R. G. Marcus ◽  
R. England ◽  
K. Nguyen ◽  
M. J. Charron ◽  
J. P. Briggs ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Experimental Diabetes ◽  
Diabetic Rats ◽  
Experimental Diabetes Mellitus ◽  
Early Diabetes ◽  
Glut4 Expression ◽  
Microvascular Cells ◽  
Glucose Transporter Glut4

Because the insulin-responsive glucose transporter, GLUT4, is expressed in renal vascular and glomerular cells, we determined the effects of experimental diabetes mellitus on GLUT4 expression and glucose uptake by these tissues. Quantitative reverse-transcription polymerase chain reaction studies of microdissected afferent microvessels and renal glomeruli showed that, after 1 wk of diabetes, GLUT4 mRNA was decreased to 26 and 34% of control values, respectively. GLUT4 immunoblots of renal glomerular and microvessel samples showed that GLUT4 polypeptide was decreased to 51% of control values. These results were confirmed by indirect immunofluorescence, which showed decreased GLUT4 expression in glomerular cells and in vascular smooth muscle cells of the afferent microvasculature of diabetic animals. Uptake of the glucose analogue, 2-deoxyglucose, was also depressed in microvessels of diabetic rats to 57% of control values, supporting the conclusion that fewer total glucose transporters were available for glucose uptake into diabetic renal glomerular and microvascular cells. Thus both GLUT4 expression and glucose uptake by glomerular and microvascular cells are decreased in diabetic animals. These results have led us to suggest a mechanism by which decreased renal GLUT4 expression could contribute to glomerular hyperfiltration and hypertension seen in early diabetes.

scholarly journals Potential role of Rab4 in the regulation of subcellular localization of Glut4 in adipocytes.

1996 ◽  
Vol 16 (12) ◽  
pp. 6879-6886 ◽  
Author(s):  
M Cormont ◽  
M N Bortoluzzi ◽  
N Gautier ◽  
M Mari ◽  
E van Obberghen ◽  
...  
Keyword(s):  
Cell Surface ◽  
Subcellular Distribution ◽  
Potential Role ◽  
Glucose Transporter ◽  
Small Gtpase ◽  
Wild Type ◽  
Transfected Cells ◽  
Isolated Adipocytes ◽  
Glucose Transporter Glut4

A role for Rab4 in the translocation of the glucose transporter Glut4 induced by insulin has been recently proposed. To study more directly the role of this small GTPase, freshly isolated adipocytes were transiently transfected with the cDNAs of both an epitope-tagged Glut4-myc and Rab4, a system which allows direct measurement of the concentration of Glut4 molecules at the cell surface. When cells were cotransfected with Glut4-myc and Rab4, the concentration of Glut4-myc at the cell surface decreased in parallel with the increased expression of Rab4, suggesting that Rab4 participates in the intracellular retention of Glut4. In parallel, the amount of Rab4 associated with the Glut4-containing vesicles increased. When Rab4 was moderately overexpressed, the number of Glut4-myc molecules recruited to the cell surface in response to insulin was similar to that observed in mock-transfected cells, and thus the insulin efficiency was increased. When Rab4 was expressed at a higher level, the amount of Glut4-myc present at the cell surface in response to insulin decreased. Since the overexpressed protein was predominantly cytosolic, this suggests that the cytosolic Rab4 might complex some factor(s) necessary for insulin action. This hypothesis was strengthened by the fact that Rab4 deltaCT, a Rab4 mutant lacking the geranylgeranylation sites, inhibited insulin-induced recruitement of Glut4-myc to the cell surface, even when moderately overexpressed. Rab3D was without effect on Glut4-myc subcellular distribution in basal or insulin-stimulated conditions. While two mutated proteins unable to bind GTP did not decrease the number of Glut4-myc molecules in basal or insulin-stimulated conditions at the plasma membrane, the behavior of a mutated Rab4 protein without GTPase activity was similar to that of the wild-type Rab4 protein, indicating that GTP binding but not its hydrolysis was required for the observed effects. Altogether, our results suggest that Rab4, but not Rab3D, participates in the molecular mechanism involved in the subcellular distribution of the Glut4 molecules both in basal and in insulin-stimulated conditions in adipocytes.

Glucose transporter expression and functional role of hexokinase in insulin biosynthesis in mouse beta TC3 cells

1995 ◽  
Vol 269 (2) ◽  
pp. C480-C486 ◽  
Author(s):  
S. Nagamatsu ◽  
Y. Nakamichi ◽  
H. Sawa
Keyword(s):  
Glucose Transporter ◽  
Immunoblot Analysis ◽  
Insulin Biosynthesis ◽  
Hexokinase Activity ◽  
Glut 1 ◽  
Close Relationship ◽  
The Relationship ◽  
Effect Of Glucose ◽  
Transporter Expression

It was previously reported that insulin biosynthesis in mouse beta TC3 cells was regulated by glucose (Nagamatsu, S., and D. F. Steiner. Endocrinology 130: 748-754, 1992). In the present study, we examined the effect of glucose on the glucose transporter expression and hexokinase activities and determined the relationship between them and glucose-stimulated insulin biosynthesis in beta TC3 cells. Reverse transcriptase-polymerase chain reaction and Northern blot analysis revealed that beta TC3 cells expressed GLUT-1 and GLUT-3 glucose transporter mRNAs, but not GLUT-2. The levels of GLUT-1 and GLUT-3 mRNAs were not affected by glucose (0 or 11 mM glucose) over a period of 48 h. Immunoprecipitation of metabolically labeled beta TC3 cells with specific antibodies against GLUT-1 or GLUT-3 proteins revealed no effect of glucose on the biosynthesis of glucose transporters. Hexokinase [low Michaelis constant (Km) hexokinase] activity from cells incubated in 11 mM glucose for 48 h increased nearly twofold compared with cells maintained in 0 mM glucose, although the amount of cellular hexokinase protein detected by immunoblot analysis was unchanged between 0 and 11 mM glucose conditions. Glucokinase (high Km hexokinase) activity, in contrast, was not affected by glucose. Preincubation of beta TC3 cells with 2-deoxyglucose to inhibit hexokinase, thereby inhibiting all glycolysis, resulted in the decrease of glucose-stimulated insulin biosynthesis. Thus, in mouse beta TC3 cells that do not express GLUT-2, there is a close relationship between hexokinase activity and glucose-stimulated insulin biosynthesis, but not between the glucose transporter and glucose-stimulated insulin biosynthesis.

scholarly journals Estrogen receptors in the diagnosis and treatment of hormone-dependent tumors

2009 ◽  
Vol 55 (4) ◽  
pp. 34-36
Author(s):  
V N Babichev ◽  
E I Marova ◽  
T A Fedotcheva ◽  
N L Shimanovskiy
Keyword(s):  
Estrogen Receptors ◽  
Pituitary Adenomas ◽  
Current Data ◽  
Selective Effect ◽  
Tumor Diseases ◽  
Estradiol Receptor ◽  
Different Types ◽  
Nuclear Estrogen Receptors ◽  
Receptor Agonists And Antagonists

The paper presents the current data available on the etiology of tumor diseases, among other things, shows the role of hormones, namely: estrogens and their receptors, in the mechanism responsible for the occurrence of these diseases. Each tumor was shown to have its receptor status and to be unresponsive to this or that therapy differently. The efficiency of treatment and its prognosis may be determined if the receptor composition of an involved organ is estimated correctly. The authors summarize the data available in the literature, as well as the results of their own investigations explaining the selective effect of estradiol receptor agonists and antagonists in various tissues. The mRNA varieties that potentially encoding for the synthesis of different subtypes of estrogen receptors (ER) - ER-α and ERβ, which are also coded by various genes located in different chromosomes. Pituitary adenomas as hormone-dependent masses are described in detail. The authors data on the concentration of nuclear estrogen receptors in different types of adenomas are given.

A dual role of the N-terminal FQQI motif in GLUT4 trafficking

2009 ◽  
Vol 390 (9) ◽  
Author(s):  
Ulrike Bernhardt ◽  
Françoise Carlotti ◽  
Rob C. Hoeben ◽  
Hans-Georg Joost ◽  
Hadi Al-Hasani
Keyword(s):  
Cell Surface ◽  
Glucose Transporter ◽  
Dual Role ◽  
Endosomal Trafficking ◽  
Endosomal Sorting ◽  
Storage Compartment ◽  
Storage Vesicles ◽  
Intracellular Storage ◽  
Glucose Transporter Glut4

AbstractIn adipocytes, the glucose transporter GLUT4 recycles between intracellular storage vesicles and the plasma membrane. GLUT4 is internalized by a clathrin- and dynamin-dependent mechanism, and sorted into an insulin-sensitive storage compartment. Insulin stimulation leads to GLUT4 accumulation on the cell surface. The N-terminal F5QQI motif in GLUT4 has been shown previously to be required for sorting of the protein in the basal state. Here, we show that the FQQI motif is a binding site for the medium chain adaptin μ1, a subunit of the AP-1 adaptor complex that plays a role in post-Golgi/endosomal trafficking events. In order to investigate the role of AP-1 and AP-2 in GLUT4 trafficking, we generated 3T3-L1 adipocytes expressing HA-GLUT4-GFP and knocked down the AP-1 and AP-2 complex by RNAi, respectively. In AP-1 and AP-2 knockdown adipocytes, GLUT4 accumulates at the cell surface in the basal state, consistent with a role of AP-1 in post-endosomal sorting of GLUT4 to the insulin-sensitive storage compartment, and of AP-2 in clathrin-mediated endocytosis. Our data demonstrate a dual role of the F5QQI motif and support the conclusion that the AP complexes direct GLUT4 trafficking and endocytosis.

scholarly journals CCL24 Protects Renal Function by Controlling Inflammation in Podocytes

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Youdi Wang ◽  
Xue Wu ◽  
Mengya Geng ◽  
Jiamin Ding ◽  
Kangjia Lv ◽  
...  
Keyword(s):  
High Glucose ◽  
Glucose Transporter ◽  
Cell Model ◽  
Serum Levels ◽  
Control Group ◽  
Knock Out ◽  
Lethal Complications ◽  
Glucose Transporter Glut4

Diabetic nephropathy (DN) is one of the most lethal complications of diabetes mellitus with chronic inflammation. We have examined the role of the inflammatory chemokine CCL24 in DN. We observed that serum levels of CCL24 were significantly elevated in patients with DN. Not only that, the expression of CCL24 was significantly increased in the kidneys of DN mice. The kidney of DN mice showed increased renal fibrosis and inflammation. We characterized an in vitro podocyte cell model with high glucose. Western blot analysis showed that expression of CCL24 was significantly increased under high-glucose conditions. Stimulation with high glucose (35 mmol/L) resulted in an increase in CCL24 expression in the first 48 hours but changed little after 72 hours. Moreover, with glucose stimulation, the level of podocyte fibrosis gradually increased, the expression of the proinflammatory cytokine IL-1β was upregulated, and the expression of the glucose transporter GLUT4, involved in the insulin signal regulation pathway, also increased. It is suggested that CCL24 is involved in the pathogenesis of DN. In order to study the specific role of CCL24 in this process, we used the CRISPR-Cas9 technique to knock out CCL24 expression in podocytes. Compared with the control group, the podocyte inflammatory response induced by high glucose after CCL24 knockout was significantly increased. These results suggest that CCL24 plays a role in the development of early DN by exerting an anti-inflammatory effect, at least, in podocytes.

Role of SGK1 kinase in regulating glucose transport via glucose transporter GLUT4

2007 ◽  
Vol 356 (3) ◽  
pp. 629-635 ◽  
Author(s):  
Sankarganesh Jeyaraj ◽  
Christoph Boehmer ◽  
Florian Lang ◽  
Monica Palmada
Keyword(s):  
Glucose Transport ◽  
Glucose Transporter ◽  
Glucose Transporter Glut4

scholarly journals The Role of Phosphoinositide 3-Kinase C2α in Insulin Signaling

2007 ◽  
Vol 282 (38) ◽  
pp. 28226-28236 ◽  
Author(s):  
Marco Falasca ◽  
William E. Hughes ◽  
Veronica Dominguez ◽  
Gianluca Sala ◽  
Florentia Fostira ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Insulin Signaling ◽  
Glucose Transporter ◽  
Class Ii ◽  
Metabolic Labeling ◽  
Insulin Dependent ◽  
Phosphoinositide 3 Kinase ◽  
Glucose Transporter Glut4

The members of the class II phosphoinositide 3-kinase (PI3K) family can be activated by several stimuli, indicating that these enzymes can regulate many intracellular processes. Nevertheless, to date, there has been no definitive identification of their in vivo product, their mechanism(s) of activation, or their precise intracellular roles. By metabolic labeling, we here identify phosphatidylinositol 3-phosphate as the sole in vivo product of the insulin-dependent activation of PI3K-C2α, confirming the emerging role of such a phosphoinositide in signaling. We demonstrate that activation of PI3K-C2α involves its recruitment to the plasma membrane and that activation is mediated by the GTPase TC10. This is the first report showing a membrane targeting-mediated mechanism of activation for PI3K-C2α and that a small GTP-binding protein can activate a class II PI3K isoform. We also demonstrate that PI3K-C2α contributes to maximal insulin-induced translocation of the glucose transporter GLUT4 to the plasma membrane and subsequent glucose uptake, definitely assessing the role of this enzyme in insulin signaling.

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