Verification of the antidiabetic effects of cinnamon (Cinnamomum zeylanicum) using insulin-uncontrolled type 1 diabetic rats and cultured adipocytes

It has long been believed that an intake of cinnamon (Cinnamomum zeylanicum) alleviates diabetic pathological conditions. However, it is still controversial whether the beneficial effect is insulin-dependent or insulin-mimetic. This study was aimed at determining the insulin-independent effect of cinnamon. Streptozotocin-induced diabetic rats were divided into four groups and orally administered with an aqueous cinnamon extract (CE) for 22 d. The diabetic rats that had taken CE at a dose of more than 30 mg/kg/d were rescued from their hyperglycemia and nephropathy, and these rats were found to have upregulation of uncoupling protein-1 (UCP-1) and glucose transporter 4 (GLUT4) in their brown adipose tissues as well as in their muscles. This was verified by using 3T3-L1 adipocytes in which CE upregulates GLUT4 translocation and increases the glucose uptake. CE exhibited its anti-diabetic effect independently from insulin by at least two mechanisms: i) upregulation of mitochondrial UCP-1, and ii) enhanced translocation of GLUT4 in the muscle and adipose tissues.     

诺沙坦改善非胰岛素依赖型糖尿病大鼠胰岛素敏感性的作用机制

本文研究血管紧张素Ⅱ受体拮抗剂诺沙坦对非胰岛素依赖型糖尿病(non-insulin-dependent diabetes mellitus,NIDDM)大鼠胰岛素敏感性的改善作用,并探讨其作用机制。从饮水中给予正常或高脂喂养加小剂量链脲佐菌素(STZ)诱发的NIDDM大鼠诺沙坦(4 mg/kg),连续6周。分离骨骼肌,用免疫印迹法检测诺沙坦对胰岛素受体底物1(insulin receptor substrate 1,IRS-1)、蛋白激酶B(protein kinase B,PKB)和葡萄糖转运因子4(glucose transporter 4,GLUT4)的表达,以及IRS-1的磷酸化、IRS-1与磷脂酰肌醇3激酶(phosphatidylinositol(PI)3-kinase)的结合。口服葡萄糖耐量试验表明,口服诺沙坦可改善糖尿病大鼠胰岛素敏感性。在骨骼肌组织,NIDDM和正常大鼠的IRS-1、PKB和GLUT4蛋白表达无差异,且不受诺沙坦处理的影响。NIDDM大鼠胰岛素刺激后的骨骼肌IRS-1酪氨酸磷酸化水平、PI 3-kinase结合IRS-1的活性和PKB活性较对照组显著降低(P<0.01),且不能被诺沙坦改善。诺沙坦显著增加NIDDM大鼠肌细胞质膜(plasma membrane,PM)和T管(T-tubules,TT)胰岛素诱导的GLUT4的 含量(P<0.05)。与该结果一致的是,诺沙坦处理的NIDDM大鼠血糖水平较未处理NIDDM大鼠下降(P<0.05)。结果表明,诺沙坦可改善胰岛素抵抗状态,主要是通过非PI 3-kinase依赖的     

Calorie restriction improves whole-body glucose disposal and insulin resistance in association with the increased adipocyte-specific GLUT4 expression in Otsuka Long-Evans Tokushima fatty rats

Calorie restriction (CR) has been shown to improve peripheral insulin resistance and type 2 diabetes in animal models. However, the exact mechanism of CR on GLUT4 expression and translocation in insulin-sensitive tissues has not been well elucidated. In the present study, we examine the effect of CR on the expression of glucose transporter 4 (GLUT4), GLUT4 translocation, and glucose transport activity in adipose tissue from Otsuka Long-Evans Tokushima Fatty (OLETF) rat and control (LETO) rats. CR (70% of satiated group) ameliorated hyperglycemia and improved impaired glucose tolerance (IGT) in OLETF rats. In skeletal muscle, the expression levels of GLUT4 and GLUT1 were not significantly different between LETO and OLETF rats, and were not affected by CR. By contrast, the expression level of GLUT4 was markedly decreased in the adipose tissue of OLETF rats, but was dramatically increased by CR. The GLUT4 recruitment stimulated by insulin was also improved in OLETF rat adipocytes by CR. The insulin-stimulated 2-deoxyglucose (2DG) uptake was significantly increased in adipocytes from the CR OLETF rats, as compared with the satiated OLETF rats. Taken together, these results suggest that CR improves whole body glucose disposal and insulin resistance in OLETF rats, and that these effects may associate with the increased adipocyte-specific GLUT4 expression.     

Cooperative effects of galanin and leptin on alleviation of insulin resistance in adipose tissue of diabetic rats

It was reported that either orexigenic neuropeptide galanin or anorexigenic hormone leptin caught benefit insulin sensitivity through increasing the translocation of glucose transporter 4 (GLUT4) in patients with diabetes. To date, it is unknown whether galanin can potentiate the effect of leptin on alleviation of insulin resistance. Therefore, in the current study we sought to assess the combined effect of central leptin and galanin on insulin resistance in the adipose tissues of type 2 diabetic rats. Galanin and leptin were injected into the intracerebroventricle of the diabetic rats, respectively, or cooperatively once a day for 2 weeks. Then, several indexes of insulin resistance were examined. The results showed that glucose infusion rates in the hyperinsulinaemic‐euglycaemic clamp test, plasma adiponectin content and GLUT4 translocation, as well as Akt phosphorylation in fat cells, were higher, not GLUT4 protein and GLUT4 mRNA expression, but HOMA index was lower in the galanin + leptin group than either one of them. Furthermore, treatment with MK‐2206, an Akt inhibitor, blocked the combined effects of galanin + leptin on alleviation of insulin resistance. These results suggest that galanin can improve the leptin‐induced mitigative effects on insulin resistance in the fat cells, and those provided new insights into the potential tactics for prevention and remedy of insulin resistance.     

Activation of the small GTPase Rac1 by a specific guanine-nucleotide-exchange factor suffices to induce glucose uptake into skeletal-muscle cells

Background information. Insulin‐stimulated glucose uptake into skeletal muscle is crucial for glucose homoeostasis, and depends on the recruitment of GLUT4 (glucose transporter 4) to the plasma membrane. Mechanisms underlying insulin‐dependent GLUT4 translocation, particularly the role of Rho family GTPases, remain controversial. Results. In the present study, we show that constitutively active Rac1, but not other Rho family GTPases tested, induced GLUT4 translocation in the absence of insulin, suggesting that Rac1 activation is sufficient for GLUT4 translocation in muscle cells. Rac1 activation occurred in dorsal membrane ruffles of insulin‐stimulated cells as revealed by a novel method to visualize activated Rac1 in situ. We further identified FLJ00068 as a GEF (guanine‐nucleotide‐exchange factor) responsible for this Rac1 activation. Indeed, constitutively active FLJ00068 caused Rac1 activation in dorsal membrane ruffles and GLUT4 translocation without insulin stimulation. Down‐regulation of Rac1 or FLJ00068 by RNA interference, on the other hand, abrogated insulin‐induced GLUT4 translocation. Basal, but not insulin‐stimulated, activity of the serine/threonine kinase Akt was required for the induction of GLUT4 translocation by constitutively active Rac1 or FLJ00068. Conclusion. Collectively, Rac1 activation specifically in membrane ruffles by the GEF FLJ00068 is sufficient for insulin induction of glucose uptake into skeletal‐muscle cells.     

D-Pinitol and myo-Inositol Stimulate Translocation of Glucose Transporter 4 in Skeletal Muscle of C57BL/6 Mice

Diabetes mellitus is a complex disease that is characterized by the defection of insulin sensitivity in such peripheral tissues as skeletal muscle, adipose tissue and liver. We have previously demonstrated that certain inositol derivatives stimulated glucose uptake accompanied by the translocation of glucose transporter 4 (GLUT4) to the plasma membrane in L6 myotubes. We investigated in this present study whether an oral intake of D-pinitol (PI) and myo-inositol (MI) would affect GLUT4 translocation in the skeletal muscle of mice. PI or MI at 1 g/kg BW administered orally to mice 30 min before a post-oral injection of glucose at 2 g/kg BW resulted in both PI and MI increasing GLUT4 translocation in the skeletal muscle and lowering the plasma glucose and insulin levels. PI and MI, therefore, have the potential to prevent diabetes mellitus by reducing the postprandial blood glucose level and stimulating GLUT4 translocation in the skeletal muscle.     

Current understanding of glucose transporter 4 expression and functional mechanisms

Glucose is used aerobically and anaerobically to generate energy for cells. Glucose transporters (GLUTs) are transmembrane proteins that transport glucose across the cell membrane. Insulin promotes glucose utilization in part through promoting glucose entry into the skeletal and adipose tissues. This has been thought to be achieved through insulin-induced GLUT4 translocation from intracellular compartments to the cell membrane, which increases the overall rate of glucose flux into a cell. The insulin-induced GLUT4 translocation has been investigated extensively. Recently, significant progress has been made in our understanding of GLUT4 expression and translocation. Here, we summarized the methods and reagents used to determine the expression levels of Slc2a4 mRNA and GLUT4 protein, and GLUT4 translocation in the skeletal muscle, adipose tissues, heart and brain. Overall, a variety of methods such real-time polymerase chain reaction, immunohistochemistry, fluorescence microscopy, fusion proteins, stable cell line and transgenic animals have been used to answer particular questions related to GLUT4 system and insulin action. It seems that insulin-induced GLUT4 translocation can be observed in the heart and brain in addition to the skeletal muscle and adipocytes. Hormones other than insulin can induce GLUT4 translocation. Clearly, more studies of GLUT4 are warranted in the future to advance of our understanding of glucose homeostasis.     

Prevention mechanisms of glucose intolerance and obesity by cacao liquor procyanidin extract in high-fat diet-fed C57BL/6 mice

In this study, we investigated whether cacao liquor procyanidin (CLPr) extract, which consists of 4.3% catechin, 6.1% epicatechin, 39.4% procyanidins and others, ameliorated hyperglycemia and obesity in C57BL/6 mice fed a control or high-fat diet for 13 weeks. CLPr suppressed high-fat diet-induced hyperglycemia, glucose intolerance and fat accumulation in white adipose tissue. CLPr also promoted translocation of glucose transporter 4 (GLUT4) and phosphorylation of AMP-activated protein kinase α (AMPKα) in the plasma membrane of skeletal muscle and brown adipose tissue. Phosphorylation of AMPKα was also enhanced in the liver and white adipose tissue. CLPr up-regulated the gene and protein expression levels of uncoupling protein (UCP)-1 in brown adipose tissue and UCP-3 in skeletal muscle. These results indicate that CLPr is a beneficial food material for the prevention of hyperglycemia and obesity. Activation of AMPKα, translocation of GLUT4 and up-regulation of UCP expression in skeletal muscle and adipose tissue are involved in the molecular mechanisms by which CLPr prevents hyperglycemia and obesity.     

Cinnamon extract and polyphenols affect the expression of tristetraprolin, insulin receptor, and glucose transporter 4 in mouse 3T3-L1 adipocytes

Cinnamon improves glucose and lipid profiles of people with type 2 diabetes. Water-soluble cinnamon extract (CE) and HPLC-purified cinnamon polyphenols (CP) with doubly linked procyanidin type-A polymers display insulin-like activity. The objective of this study was to investigate the effects of cinnamon on the protein and mRNA levels of insulin receptor (IR), glucose transporter 4 (GLUT4), and tristetraprolin (TTP/ZFP36) in mouse 3T3-L1 adipocytes. Immunoblotting showed that CP increased IRbeta levels and that both CE and CP increased GLUT4 and TTP levels in the adipocytes. Quantitative real-time PCR indicated that CE (100mug/ml) rapidly increased TTP mRNA levels by approximately 6-fold in the adipocytes. CE at higher concentrations decreased IRbeta protein and IR mRNA levels, and its effect on GLUT4 mRNA levels exhibited a biphasic pattern in the adipocytes. These results suggest that cinnamon exhibits the potential to increase the amount of proteins involved in insulin signaling, glucose transport, and anti-inflammatory/anti-angiogenesis response.     

Low doses of vanadate and Trigonella synergistically regulate Na+/K+-ATPase activity and GLUT4 translocation in alloxan-diabetic rats

Oral administration of vanadate to diabetic animals have been shown to stabilize the glucose homeostasis and restore altered metabolic pathways. However, vanadate exerts these effects at relatively high doses with several toxic effects. Low doses of vanadate are relatively safe but unable to elicit any antidiabetic effects. The present study explored the prospect of using low doses of vanadate with Trigonella foenum graecum, seed powder (TSP), another antidiabetic agent, and to evaluate their antidiabetic effect in diabetic rats. Alloxan diabetic rats were treated with insulin, vanadate, TSP and low doses of vanadate with TSP for three weeks. The effect of these antidiabetic compounds was examined on general physiological parameters, Na⁺/K⁺ ATPase activity, membrane lipid peroxidation and membrane fluidity in liver, kidney and heart tissues. Expression of glucose transporter (GLUT4) protein was also examined by immunoblotting method in experimental rat heart after three weeks of diabetes induction. Diabetic rats showed high blood glucose levels. Activity of Na⁺/K⁺ ATPase decreased in diabetic liver and heart. However, kidney showed a significant increase in Na⁺/K⁺ ATPase activity. Diabetic rats exhibited an increased level of lipid peroxidation and decreased membrane fluidity. GLUT4 distribution was also significantly lowered in heart of alloxan diabetic rats. Treatment of diabetic rats with insulin, TSP, vanadate and a combined therapy of lower dose of vanadate with TSP revived normoglycemia and restored the altered level of Na⁺/K⁺ ATPase, lipid peroxidation and membrane fluidity and also induced the redistribution of GLUT4 transporter. TSP treatment alone is partially effective in restoring the above diabetes-induced alterations. Combined therapy of vanadate and TSP was the most effective in normalization of altered membrane linked functions and GLUT4 distribution without any harmful side effect.     

In vivo effects of vanadium on GLUT4 translocation in cardiac tissue of STZ-diabetic rats

The effect of vanadium treatment on insulin-stimulated glucose transporter type 4 (GLUT4) translocation was studied in cardiac tissue of streptozotocin (STZ)-induced diabetic rats by determining the subcellular distribution of GLUT4. Four groups of rats were examined: control and diabetic, with or without bis(maltolato)oxovanadium(IV) (BMOV, an organic form of vanadium) treatment for 8 weeks. The effect of vanadium on insulin-induced GLUT4 translocation was studied at 5 min as the early insulin response and at 15 min after insulin injection as the maximal insulin response.At 5 min after insulin injection, plasma membrane GLUT4 level in the diabetic-treated group was not different from the control groups and was significantly higher than that of the insulin-stimulated diabetic group, indicating an enhancement of insulin response on GLUT4 translocation brought about by vanadium treatment. In contrast to that at 5 min after insulin injection, no significant difference in the plasma membrane GLUT4 level was observed between the diabetic and the diabetic-treated groups at 15 min after insulin injection. GLUT4 mobilization from the intracellular pool in response to insulin was also investigated at 15 min after insulin injection. Basal intracellular GLUT4 content was significantly higher in the diabetic-treated group when compared to the diabetic group under the same condition. However, the increased basal intracellular GLUT4 in the diabetic-treated group did not result in more insulin-mediated GLUT4 translocation at 15 min after insulin injection. In conclusion, the finding that plasma membrane GLUT4 in the diabetic-treated group is significantly higher than that of the diabetic group at 5 min but not at 15 min post-insulin injection indicates that vanadium treatment enhances insulin-mediated GLUT4 translocation in cardiac tissue by enhancing its early response.     

Rac-1 Superactivation Triggers Insulin-independent Glucose Transporter 4 (GLUT4) Translocation That Bypasses Signaling Defects Exerted by c-Jun N-terminal kinase (JNK)- and Ceramide-induced Insulin Resistance

Insulin activates a cascade of signaling molecules, including Rac-1, Akt, and AS160, to promote the net gain of glucose transporter 4 (GLUT4) at the plasma membrane of muscle cells. Interestingly, constitutively active Rac-1 expression results in a hormone-independent increase in surface GLUT4; however, the molecular mechanism and significance behind this effect remain unresolved. Using L6 myoblasts stably expressing myc-tagged GLUT4, we found that overexpression of constitutively active but not wild-type Rac-1 sufficed to drive GLUT4 translocation to the membrane of comparable magnitude with that elicited by insulin. Stimulation of endogenous Rac-1 by Tiam1 overexpression elicited a similar hormone-independent gain in surface GLUT4. This effect on GLUT4 traffic could also be reproduced by acutely activating a Rac-1 construct via rapamycin-mediated heterodimerization. Strategies triggering Rac-1 “superactivation” (i.e. to levels above those attained by insulin alone) produced a modest gain in plasma membrane phosphatidylinositol 3,4,5-trisphosphate, moderate Akt activation, and substantial AS160 phosphorylation, which translated into GLUT4 translocation and negated the requirement for IRS-1. This unique signaling capacity exerted by Rac-1 superactivation bypassed the defects imposed by JNK- and ceramide-induced insulin resistance and allowed full and partial restoration of the GLUT4 translocation response, respectively. We propose that potent elevation of Rac-1 activation alone suffices to drive insulin-independent GLUT4 translocation in muscle cells, and such a strategy might be exploited to bypass signaling defects during insulin resistance.     

PID1 regulates insulin-dependent glucose uptake by controlling intracellular sorting of GLUT4-storage vesicles

The phosphotyrosine interacting domain-containing protein 1 (PID1) serves as a cytosolic adaptor protein of the LDL receptor-related protein 1 (LRP1). By regulating its intracellular trafficking, PID1 controls the hepatic, LRP1-dependent clearance of pro-atherogenic lipoproteins. In adipose and muscle tissues, LRP1 is present in endosomal storage vesicles containing the insulin-responsive glucose transporter 4 (GLUT4). This prompted us to investigate whether PID1 modulates GLUT4 translocation and function via its interaction with the LRP1 cytosolic domain. We initially evaluated this in primary brown adipocytes as we observed an inverse correlation between brown adipose tissue glucose uptake and expression of LRP1 and PID1. Insulin stimulation in wild type brown adipocytes induced LRP1 and GLUT4 translocation from endosomal storage vesicles to the cell surface. Loss of PID1 expression in brown adipocytes prompted LRP1 and GLUT4 sorting to the plasma membrane independent of insulin signaling. When placed on a diabetogenic high fat diet, systemic and adipocyte-specific PID1-deficient mice presented with improved hyperglycemia and glucose tolerance as well as reduced basal plasma insulin levels compared to wild type control mice. Moreover, the improvements in glucose parameters associated with increased glucose uptake in adipose and muscle tissues from PID1-deficient mice. The data provide evidence that PID1 serves as an insulin-regulated retention adaptor protein controlling translocation of LRP1 in conjunction with GLUT4 to the plasma membrane of adipocytes. Notably, loss of PID1 corrects for insulin resistance-associated hyperglycemia emphasizing its pivotal role and therapeutic potential in the regulation of glucose homeostasis.     

Isoproterenol inhibits cyclic AMP-mediated but not insulin-mediated translocation of the GLUT4 glucose transporter isoform

Isoproterenol is a beta adrenergic agonist whose effects have been attributed to the generation of cAMP. Previous studies have shown that it inhibits glucose transport in adipocytes without changing the number of insulin-responsive glucose transporters (GLUT4) on the cell surface. However, we have shown previously that cAMP stimulates translocation of GLUT4 to the cell surface in adipocytes (Keladaet al. J Biol Chem 267, 7021–7025, 1992). We therefore further investigated the mechanisms involved in isoproterenol regulation of glucose transport. Consistent with the effects of dibutyryl cAMP, we found that a low concentration of isoproterenol (10 nM) stimulated glucose transport and the translocation of GLUT4 from the low density microsomal fraction to the plasma membrane. By contrast, a higher concentration of isoproterenol (1 M) did not stimulate transport or GLUT4 translocation and furthermore inhibited dibutyryl cAMP-stimulated GLUT4 translocation. This inhibitory effect was specific for cAMP since isoproterenol had no effect on insulin-stimulated GLUT4 translocation. We conclude that isoproterenol has a biphasic effect on glucose transport, mediated by acute translocation of GLUT4 at low concentrations and by inhibition of intrinsic activity at high concentration, both of which may be explained by effects of cAMP. It has a further cAMP-independent effect at high concentration to inhibit cAMP-mediated translocation of GLUT4.This work forms portions of the PhD thesis requirements.     

Identification of P-Rex1 as a novel Rac1-guanine nucleotide exchange factor (GEF) that promotes actin remodeling and GLUT4 protein trafficking in adipocytes

Phosphoinositide 3-kinase (PI3K) signaling promotes the translocation of the glucose transporter, GLUT4, to the plasma membrane in insulin-sensitive tissues to facilitate glucose uptake. In adipocytes, insulin-stimulated reorganization of the actin cytoskeleton has been proposed to play a role in promoting GLUT4 translocation and glucose uptake, in a PI3K-dependent manner. However, the PI3K effectors that promote GLUT4 translocation via regulation of the actin cytoskeleton in adipocytes remain to be fully elucidated. Here we demonstrate that the PI3K-dependent Rac exchange factor, P-Rex1, enhances membrane ruffling in 3T3-L1 adipocytes and promotes GLUT4 trafficking to the plasma membrane at submaximal insulin concentrations. P-Rex1-facilitated GLUT4 trafficking requires a functional actin network and membrane ruffle formation and occurs in a PI3K- and Rac1-dependent manner. In contrast, expression of other Rho GTPases, such as Cdc42 or Rho, did not affect insulin-stimulated P-Rex1-mediated GLUT4 trafficking. P-Rex1 siRNA knockdown or expression of a P-Rex1 dominant negative mutant reduced but did not completely inhibit glucose uptake in response to insulin. Collectively, these studies identify a novel RacGEF in adipocytes as P-Rex1 that, at physiological insulin concentrations, functions as an insulin-dependent regulator of the actin cytoskeleton that contributes to GLUT4 trafficking to the plasma membrane.     

Coordinated Regulation of Vasopressin Inactivation and Glucose Uptake by Action of TUG Protein in Muscle

In adipose and muscle cells, insulin stimulates the exocytic translocation of vesicles containing GLUT4, a glucose transporter, and insulin-regulated aminopeptidase (IRAP), a transmembrane aminopeptidase. A substrate of IRAP is vasopressin, which controls water homeostasis. The physiological importance of IRAP translocation to inactivate vasopressin remains uncertain. We previously showed that in skeletal muscle, insulin stimulates proteolytic processing of the GLUT4 retention protein, TUG, to promote GLUT4 translocation and glucose uptake. Here we show that TUG proteolysis also controls IRAP targeting and regulates vasopressin action in vivo. Transgenic mice with constitutive TUG proteolysis in muscle consumed much more water than wild-type control mice. The transgenic mice lost more body weight during water restriction, and the abundance of renal AQP2 water channels was reduced, implying that vasopressin activity is decreased. To compensate for accelerated vasopressin degradation, vasopressin secretion was increased, as assessed by the cosecreted protein copeptin. IRAP abundance was increased in T-tubule fractions of fasting transgenic mice, when compared with controls. Recombinant IRAP bound to TUG, and this interaction was mapped to a short peptide in IRAP that was previously shown to be critical for GLUT4 intracellular retention. In cultured 3T3-L1 adipocytes, IRAP was present in TUG-bound membranes and was released by insulin stimulation. Together with previous results, these data support a model in which TUG controls vesicle translocation by interacting with IRAP as well as GLUT4. Furthermore, the effect of IRAP to reduce vasopressin activity is a physiologically important consequence of vesicle translocation, which is coordinated with the stimulation of glucose uptake.     

Ginsenoside Rb1 exerts antidiabetic action on C2C12 muscle cells by leptin receptor signaling pathway

Context: Ginsenoside Rb1 improves insulin sensitivity and glucose uptake in muscle cells via different signaling pathways; however, it is not clear that it has any effect on leptin signaling in skeletal muscle.

Objectives: The aim of this study was to investigate the effect of ginsenoside Rb1 on leptin receptors expression and main signaling pathways of leptin (STAT3, PI3 kinase and ERK kinase) in C2C12 skeletal muscle cells.

Materials and methods: C2C12 myotubes were incubated with various concentrations of Rb1 (0.1, 1 and 10?μM) for different incubation times (1–12?h). Leptin receptors expression and GLUT-4 translocation were analyzed using realtime PCR and western blot analyses, respectively. PI3 and ERK kinases were blocked using their specific inhibitors (wortmannin and PD98059) in the presence and absence of RB1 to determine the main signaling pathway related to leptin receptor activation in C2C12 cells.

Results: Rb1 could maximally stimulate both leptin receptors (OBRa and OBRb) mRNA and protein expression and phosphorylation of STAT3, PI3K and ERK2 in C2C12 myotubes at 10?μM for 3?h. Rb1 induced GLUT4 translocation was inhibited by the silencing of OBRb mRNA, demonstrated that glucose uptake was mediated via leptin receptor activation. GLUT4 recruitment to the cell surface induced by Rb1 was inhibited by wortmannin, an inhibitor of PI3K in combination with OBRb siRNA, but not by PD98059 an ERK2 kinase-1 inhibitor, indicating that GLUT4 translocation induced by Rb1 was associated with the leptin receptor upregulation and subsequent activation of PI3K.

Conclusions: Our results suggest that Rb1 promote translocation of GLUT4 by upregulation of leptin receptors and activation of PI3K.     

Role of clusters in insulin-regulated GLUT4 trafficking in adipose cells: A new paradigm?

Insulin stimulates glucose transport in muscle and adipose cells by stimulating translocation of glucose transporter 4 (GLUT4) to the plasma membrane. In a recent Cell Metabolism paper, Stenkula et al. found that insulin controls the spatial distribution of GLUT4 on the surface of isolated adipose cells through regulation of their post-fusion dispersal. The presence of GLUT4 in plasma membrane-associated clusters is suggestive of a new paradigm in membrane protein recycling.