GLUT4 Expression In Skeletal Muscle Research Articles

Hypoglycemic and Hypolipogenic Action of Acetic Acid and Monascus-Fermented Grain Vinegar: A Comparative Study.

Acetic acid has been proposed to improve lifestyle-related diseases, including hyperlipidemia and hyperglycemia. This study compared the hypoglycemic and hypolipogenic effects of acetic acid vinegar (AV, contains only 4% acetic acid) and Monascus-fermented grain vinegar (MV) containing various bioactive compounds in 3T3L1 cells and C57BL/KsJ-db/db mice (DB). The DB were divided randomly into three treatment groups containing nine mice each; DB-, AV-, and MV-groups were orally administered 1 mL/kg/day of distilled water, acetic acid vinegar, and Monascus vinegar, respectively, for 8 weeks. Exposure to AV and MV inhibited the adipogenic differentiation of 3T3L1 preadipocytes and lipid accumulation during differentiation. Oral administration of AV or MV to the mice resulted in a marked reduction in the body weight, liver weight, and hepatic triglyceride content compared to the control DB-group. Moreover, treatment with AV and MV clearly increased the expression of cyclic adenosine monophosphate (cAMP) and AMP-activated protein kinase (AMPK) and suppressed the expression of fatty acid synthetase in liver tissues of DB. Significantly, lower levels of fasting blood glucose, insulin, leptin, and the glycosylated hemoglobin (HbA1c) as well as higher levels of the skeletal muscle GLUT4 expression were obtained in the AV- or MV-groups than levels determined in the control DB-group (P < .05). Although MV has the potential to be a natural alternative treatment for obesity-associated type 2 diabetes, this study suggests that acetic acid is the central ingredient in MV responsible for the hypoglycemic and hypolipogenic effects in the DB mice.

Chronic Antidiabetic Actions of Leptin: Evidence From Parabiosis Studies for a CNS-Derived Circulating Antidiabetic Factor.

We used parabiosis to determine whether the central nervous system (CNS)-mediated antidiabetic effects of leptin are mediated by release of brain-derived circulating factors. Parabiosis was surgically induced at 4 weeks of age, and an intracerebroventricular (ICV) cannula was placed in the lateral cerebral ventricle at 12 weeks of age for ICV infusion of leptin or saline vehicle. Ten days after surgery, food intake, body weight, and blood glucose were measured for 5 consecutive days, and insulin-deficiency diabetes was induced in all rats by a single streptozotocin (STZ) injection (40 mg/kg). Five days after STZ injection, leptin or vehicle was infused ICV for 7 days, followed by 5-day recovery period. STZ increased blood glucose and food intake. Chronic ICV leptin infusion restored normoglycemia in leptin-infused rats while reducing blood glucose by ∼27% in conjoined vehicle-infused rats. This glucose reduction was caused mainly by decreased hepatic gluconeogenesis. Chronic ICV leptin infusion also reduced net cumulative food intake and increased GLUT4 expression in skeletal muscle in leptin/vehicle compared with vehicle/vehicle conjoined rats. These results indicate that leptin's CNS-mediated antidiabetic effects are mediated, in part, by release into the systemic circulation of leptin-stimulated factors that enhance glucose utilization and reduce liver gluconeogenesis.

Development of metabolic dysfunction in mice lacking chemerin

Chemerin, an adipocyte-secreted adipokine, is hypothesized to participate in energy homeostasis and glucoregulation. However, the physiologic effect of endogenous chemerin on glucose metabolism is unclear. The present studies tested the hypotheses that chemerin deficiency alters whole-body glucose homeostasis following switches to high-fat diet. Adult, male chemerin knockout and C57BL/6J control wild type mice were studied. During the following 4 weeks, chow- or high-fat diet maintained chemerin knockout mice showed elevated fasting glucose levels and glucose intolerance as well as insulin intolerance. Chemerin deficiency impaired adaptation to glucose and insulin challenge, leading to increased glucose levels. Moreover, the mRNA and protein levels of GLUT4 and PGC-1α expression in both skeletal muscle and adipose tissue were significantly decreased in chemerin knockout mice relative to the wild type, respectively. Taken together, the results support the hypotheses that chemerin helps adapt glucose metabolism to changes in dietary fat and modulates glucose consumption in mice by activation of PGC-1α/GLUT4 axis. Chemerin may play a significant role in elevation of glucose uptake and insulin sensitivity to promote glucose clearance.

14-Deoxy-11,12-Didehydroandrographolide Ameliorates Glucose Intolerance Enhancing the LKB1/AMPK[Formula: see text]/TBC1D1/GLUT4 Signaling Pathway and Inducing GLUT4 Expression in Myotubes and Skeletal Muscle of Obese Mice.

14-Deoxy-11,12-didehydroandrographolide (deAND), a bioactive component of Andrographis paniculata, has antidiabetic activity. AMP-activated protein kinase (AMPK) regulates glucose transport and ameliorates insulin resistance. The aim of the present study was to investigate whether activation of AMPK is involved in the mechanism by which deAND ameliorates insulin resistance in muscles. deAND amounts up to 40 [Formula: see text]M dose-dependently activated phosphorylation of AMPK[Formula: see text] and TBC1D1 in C2C12 myotubes. In addition, deAND significantly activated phosphorylation of LKB1 at 6 h after treatment, and this activation was maintained up to 48 h. deAND increased glucose uptake at 18 h after treatment, and this increase was time dependent up to 72 h. Compound C, an inhibitor of AMPK, suppressed deAND-induced phosphorylation of AMPK[Formula: see text] and TBC1D1 and reversed the effect on glucose uptake. In addition, the expression of GLUT4 mRNA and protein in C2C12 myotubes was up-regulated by deAND in a time-dependent manner. Promotion of GLUT4 gene transcription was verified by a pGL3-GLUT4 (837 bp) reporter assay. deAND also increased the nuclear translocation of MEF-2A and PPAR[Formula: see text]. After 16 weeks of feeding, the high-fat diet (HFD) inhibited phosphorylation of AMPK[Formula: see text] and TBC1D1 in skeletal muscle of obese C57BL/6JNarl mice, and deactivation of AMPK[Formula: see text] and TBC1D1 by the HFD was abolished by deAND supplementation. Supplementation with deAND significantly promoted membrane translocation of GLUT4 compared with the HFD group. Supplementation also significantly increased GLUT4 mRNA and protein expression in skeletal muscle compared with the HFD group. The hypoglycemic effects of deAND are likely associated with activation of the LKB1/AMPK[Formula: see text]/TBC1D1/GLUT4 signaling pathway and stimulation of MEF-2A- and PPAR[Formula: see text]-dependent GLUT4 gene expression, which account for the glucose uptake into skeletal muscle and lower blood glucose levels.

Benzyl Isothiocyanate Ameliorates High-Fat Diet-Induced Hyperglycemia by Enhancing Nrf2-Dependent Antioxidant Defense-Mediated IRS-1/AKT/TBC1D1 Signaling and GLUT4 Expression in Skeletal Muscle.

Obesity caused lipotoxicity, which results in insulin resistance. We studied whether benzyl isothiocyanate (BITC) improved insulin resistance in muscle. BITC was studied in vivo in mice fed a high-fat diet (HFD) and in vitro in C2C12 myotubes treated with palmitic acid (PA). In C2C12 cells, BITC mitigated PA inhibition of glucose uptake and phosphorylation of IRS-1, AKT, and TBC1D1 in response to insulin. BITC upregulated the expression of HO-1, GSTP, and GCLM mRNA and protein as well as GSH contents, which suppressed oxidative damage. Knockdown of Nrf2 abrogated BITC enhancement of antioxidant defense and subsequently reversed BITC protection against PA-induced insulin resistance. Moreover, BITC upregulated the expression of GLUT4, PPARγ, and C/EBPα. In HFD-fed mice, plasma total cholesterol, nonesterified fatty acid, and glucose levels and HOMA-IR were dose-dependently decreased with 0.05 or 0.1% BITC administration. In gastrocnemius muscle, compared with the HFD group, BITC increased the phosphorylation of AKT and TBC1D1, GSH contents, and the expression of antioxidant enzymes as well as GLUT4. These results indicate that BITC ameliorates obesity-induced hyperglycemia by enhancing insulin sensitivity in muscle. This is partly attributed to its inhibition of lipotoxicity-induced oxidative insult and upregulation of GLUT4 expression.

Antidiabetic effect of a flavonoid-rich extract from Sophora alopecuroides L. in HFD- and STZ- induced diabetic mice through PKC/GLUT4 pathway and regulating PPARα and PPARγ expression

Headings ethnopharmacological relevanceSophora alopecuroides L. is a traditional ethnopharmacological plant, which is widely used in traditional Chinese medicine and Mongolian and Uighur medicine to ameliorate “thirst disease”. Aim of the studyThis study aimed to investigate the antidiabetic activities and mechanisms of a flavonoid-rich extract from Sophora alopecuroides L. (SA-FRE) both in vivo and vitro. Materials and methodsThe main six chemical constituents of SA-FRE were elucidated based on an off-line semi-preparative liquid chromatography nuclear magnetic resonance (LC-NMR) protocol. Myc-GLUT4-mOrange-L6 cell models and mouse model with diabetes induced by high-fat diet combined with STZ injection were respectively adopted to investigate the antidiabetic effects of SA-FRE both in vitro and vivo. ResultsIn vivo, 4-week treatment of SA-FRE ameliorated hyperglycemia, dyslipidemia, and insulin resistance in diabetic mice. Mechanically, SA-FRE regulated PPARα and PPARγ expression in white adipose tissue (WAT) and liver, thereby ameliorating dyslipidemia. Moreover, SA-FRE increased the phosphorylation of PKC and further stimulated the GLUT4 expression in WAT and skeletal muscle, thus increasing the glucose utilization in vivo. In vitro, 50 μg/mL SA-FRE increased GLUT4 translocation to about 1.91-fold and glucose uptake to 1.82-fold in L6-myotubes. SA-FRE treatment increased the GLUT4 expression at both gene and protein levels. Furthermore, only Gö6983, a PKC inhibitor, reversed the SA-FRE-induced GLUT4 translocation and expression at the gene and protein levels. ConclusionsGenerally, SA-FRE ameliorated hyperglycemia, dyslipidemia, and insulin resistance partly through activating PKC/GLUT4 pathway and regulating PPARα and PPARγ expression.

Anti-diabetic effects of a phenolic-rich extract from Hypericum attenuatum Choisy in KK-Ay mice mediated through AMPK /PI3K/Akt/GSK3β signaling and GLUT4, PPARγ, and PPARα expression

Abstract In this study, we investigated anti-diabetic activities of a phenolic-rich extract from Hypericum attenuatum Choisy (HA-PRE). In vivo, 4-week treatment of HA-PRE improved hyperglycemia, obesity, glucose tolerance, and hyperinsulinism. Western blot analysis revealed that HA-PRE increased AMPKα and Akt phosphorylation in skeletal muscle, liver and white adipose tissue (WAT); increased GSK3β phosphorylation in skeletal muscle and liver; and enhanced GLUT4 expression in WAT and skeletal muscle. HA-PRE reduced PPARγ expression, increased PPARα expression, and enhanced ACC phosphorylation in liver and WAT. In vitro, HA-PRE enhanced glucose uptake. Mechanisms analysis revealed that HA-PRE increased GLUT4, p-AMPKα, p-Akt, and p-GSK3β expression in L6 myotubes. Moreover, Compound C, an AMPK inhibitor, partly inhibited these effects. Wortmannin, a PI3K inhibitor, inhibited HA-PRE-stimulated Akt phosphorylation and GSK3β phosphorylation, but had no effects on AMPKα phosphorylation. Taken together, these findings indicate that HA-PRE alleviate diabetes through AMPK/PI3K/Akt/GSK3β and regulating GLUT4, PPARα, and PPARγ expression.

Efek kandungan serat beras analog terhadap ekspresi GLUT4 otot rangka tikus diabetes

Effect of analog rice’s fiber on skeletal muscles GLUT4 expression in diabetic rats Background: Disruption of glucose transportation in skeletal muscle through GLUT4 becomes a problem in diabetes. Analog rice that had been modified by adding dietary fiber could improve the expression of GLUT4.Objective: This study aims to know the effect of dietary fiber toward GLUT4 expression and to know the dietary fiber percentage in analog rice.Method: The research type is true experimental with post-test only group design. The samples consist of 24 male Wistar rats that are group into 4 groups (n=6 each group). Three groups were induced by giving a high-fat diet for 40 days and streptozotocin (STZ) 35 mg/kg BW was given at 33th day and one group was not induced. After the blood glucose level exceeded 135 mg/dl, the treatment was given. After 3 weeks, the rats were terminated and quadriceps femoris muscle tissue was taken for immunohistochemistry examination using rat GLUT4 polyclonal antibody. GLUT4 expression was quantified using an immunoreactive score (IRS-GLUT4). The data were analyzed using the Kruskal-Wallis test and Spearman test.Results: Statistical analyses showed that there were significant differences between groups with a moderate positive correlation (correlation coefficient=0,651; p=0,003).Conclusion: Dietary fiber in analog rice could improve skeletal muscle GLUT4 expression in Wistar rat diabetic model.

Diabetes induces tri-methylation at lysine 9 of histone 3 at Slc2a4 gene in skeletal muscle: A new target to improve glycemic control

Expression of the glucose transporter GLUT4, encoded by Slc2a4 gene, is reduced in both type 1 and type 2 diabetes (T1D and T2D), contributing to glycemic impairment. The present study investigated epigenetic regulations at the Slc2a4 promoter in skeletal muscle of T1D- and T2D-like experimental models. Slc2a4/GLUT4 repression was observed in T1D and T2D and that was reversed by insulin and resveratrol treatments, respectively. In both T1D-like and T2D-like animals, tri-methylation at lysine 9 of histone 3 (H3K9me3) increased in the Slc2a4 enhancer segment, whereas MEF2A/D binding into this segment was reduced; all effects were reversed by respective treatments. This study reveals that increased H3K9me3 in the Slc2a4 promoter enhancer segment contributes to reduce GLUT4 expression in skeletal muscle and to worse glycemic control in diabetes, pointing to the H3K9me3 of Slc2a4 promoter as a potential target for development of new approaches for treating diabetes.

Exercise and GLUT4 in human subcutaneous adipose tissue.

To examine the effect of acute and chronic exercise on adipose tissue GLUT4 expression, a total of 20 healthy, male subjects performed one of two studies. Ten subjects performed cycle ergometer exercise for 60 min at 73 ± 2% VO 2 peak and abdominal adipose tissue samples were obtained immediately before and after exercise and after 3 h of recovery. Another 10 subjects completed 10 days of exercise training, comprising a combination of six sessions of 60 min at 75% VO 2 peak and four sessions of 6 × 5 min at 90% VO 2 peak, separated by 3 min at 40% VO 2 peak. Abdominal adipose tissue and vastus lateralis muscle samples were obtained before training and 24 h after the last training session. A single bout of exercise did not change adipose tissue GLUT4 mRNA; however, there was a small, but significant, reduction in adipose tissue GLUT4 protein expression 3 h after exercise. There were no changes in adipose tissue GLUT4 or COX‐IV expression following exercise training. In contrast, skeletal muscle GLUT4 and COX‐IV were increased by 47% and 44%, respectively following exercise training. The exercise training‐induced increase in GLUT4 expression was similar in both type I and type IIa single muscle fibers. Our results indicate that neither a single exercise bout, nor 10 days of exercise training, increased adipose tissue GLUT4, in contrast with the increases observed in skeletal muscle GLUT4 expression.

Myostatin inhibits glucose uptake via suppression of insulin-dependent and -independent signaling pathways in myoblasts.

The glucose transporter 4 (Glut4) mediates insulin‐dependent glucose uptake. Glut4 expression levels are correlated with whole‐body glucose homeostasis. Insulin signaling is known to recruit Glut4 to the cell surface. Expression of Glut4 is subject to tissue‐specific hormonal and metabolic regulation. The molecular mechanisms regulating skeletal muscle Glut4 expression remain to be elucidated. Myostatin (Mstn) is reported to be involved in the regulation of energy metabolism. While elevated Mstn levels in muscle are associated with obesity and type‐2 diabetes in both human and mouse models, Mstn null mice exhibit immunity to dietary‐induced obesity and insulin resistance. The molecular mechanisms by which Mstn initiates the development of insulin resistance and disorders of glucose disposal are not well delineated. Here we investigated effects of Mstn on insulin action in C2C12 cells. Mstn significantly reduced basal and insulin‐induced IRS‐1 tyrosine (Tyr495) phosphorylation, and expression and activation of PI3K, associated with diminished AKT phosphorylation and elevated GSK3β phosphorylation at Ser9. In addition, Mstn inhibited Glut4 mRNA and protein expression, and reduced insulin‐induced Glut4 membrane translocation and glucose uptake. Conversely, SB431542, a Smad2/3 inhibitor, significantly increased cellular response to insulin. Mstn decreased AMP‐activated protein kinase (AMPK) activity accompanied by reduced Glut4 gene expression and glucose uptake, which were partially reversed by AICAR, an AMPK activator. These data suggest that Mstn inhibits Glut4 expression and insulin‐induced Glut4 integration into cytoplasmic membranes and glucose uptake and that these changes are mediated by direct insulin‐desensitizing effect and indirect suppression of AMPK activation.

NaoXinTong Capsules inhibit the development of diabetic nephropathy in db/db mice

NaoXinTong Capsule (NXT), a Chinese medicine, is currently used to treat patients with cardiovascular and cerebrovascular diseases. Clinical observations indicate its anti-diabetic functions with unclear mechanisms. Herein, we report the effect of NXT on diabetic nephropathy (DN). Type 2 diabetic db/db mice were treated with NXT for 14 weeks. In the course of treatment, NXT reduced diabetes-increased glucose levels and improved renal functions. At the end of treatment, we found that NXT ameliorated serum lipid profiles and other biochemical parameters. In the kidney, NXT inhibited mesangial matrix expansion, expression of vascular endothelial growth factor A, fibronectin, advanced glycation end product and its receptor. Meanwhile, it reduced the diabetes-induced podocyte injury by increasing WT1 and nephrin expression. In addition, NXT inhibited accumulation of extracellular matrix proteins by increasing MMP2/9 expression through inactivation of TGFβ/Smad pathway and CTGF expression. Mechanically, NXT activated insulin signaling pathway by increasing expression of INSR, IRS and FGF21, phosphorylation of Akt and AMPKα in the liver, INSR phosphorylation in the kidney, and FGF21 and GLUT4 expression in adipose tissue and skeletal muscle. Taken together, our study demonstrates that NXT inhibits DN by ameliorating glucose/lipid metabolism, maintaining tissue structure integrity, and correcting diabetes-induced renal dysfunctions.

Advanced glycation end products-induced insulin resistance involves repression of skeletal muscle GLUT4 expression

Little is known about advanced glycation end products (AGEs) participation in glucose homeostasis, a process in which skeletal muscle glucose transporter GLUT4 (Scl2a4 gene) plays a key role. This study investigated (1) the in vivo and in vitro effects of AGEs on Slc2a4/GLUT4 expression in skeletal muscle of healthy rats, and (2) the potential involvement of endoplasmic reticulum and inflammatory stress in the observed regulations. For in vivo analysis, rats were treated with advanced glycated rat albumin (AGE-albumin) for 12 weeks; for in vitro analysis, soleus muscles from normal rats were incubated with bovine AGE-albumin for 2.5 to 7.5 hours. In vivo, AGE-albumin induced whole-body insulin resistance; decreased (~30%) Slc2a4 mRNA and GLUT4 protein content; and increased (~30%) the nuclear content of nuclear factor NF-kappa-B p50 subunit (NFKB1), and cellular content of 78 kDa glucose-regulated protein (GRP78). In vitro, incubation with AGE-albumin decreased (~50%) the Slc2a4/GLUT4 content; and increased cellular content of GRP78/94, phosphorylated-IKK-alpha/beta, nuclear content of NFKB1 and RELA, and the nuclear protein binding into Slc2a4 promoter NFKB-binding site. The data reveal that AGEs impair glucose homeostasis in non-diabetic states of increased AGEs concentration; an effect that involves activation of endoplasmic reticulum- and inflammatory-stress and repression of Slc2a4/GLUT4 expression.

지구성 운동에 의한 PPARβ의 발현이 고지방 식이에 의한 골격근 미토콘드리아 H2O2의 배출과 GLUT4 발현에 미치는 영향

지구성 운동에 의한 PPARβ의 발현이 고지방 식이에 의한 골격근 미토콘드리아 H2O2의 배출과 GLUT4 발현에 미치는 영향

Exercise training, Glut-4 protein abundance and glutamine in skeletal muscle of mature and very old horses

Two groups of unfit Standardbred mares (adult: 9-14 years, 540 kg, n=7) and old (20-25 years, 530 kg, n=5) were used to test two hypotheses, first, that aging and training would alter plasma and muscle glutamine [Gln] and glutamate [Glu] and second, that aging and training would alter Glut-4 expression in skeletal muscle. All animals were housed on pasture with free access to grass and all received hay and supplementation with a commercially prepared supplement (15% crude protein and 3.00 Mcal/kg dry matter) in individual stalls. Mares were fed to meet or exceed NRC (2007) nutrient recommendations for moderate to heavy exercise. The mares were exercise trained in a free-stall motorised circular exercise machine for 30 min/d, 5 d/week, for 8 weeks. Work intensity during training was set at a relative intensity of ~60% of the maximum heart rate, previously determined during an incremental exercise test (GXT). Blood samples and muscle biopsies (gluteus) obtained before and after 8 weeks of training were used for measurement of [Gln], [Glu] and Glut-4 abundance. Samples were collected before the initiation of training and at 24 h after cessation of last bout of exercise in the training period. All samples were immediately frozen in liquid nitrogen and stored at -80 °C until enzymatic analysis for [Gln], [Glu] and Western Blot analysis for Glut-4 protein abundance. Data were analysed by one-way or two-way ANOVA for repeated measures and the Pearson correlation method. Post-hoc differences were identified with the Tukey test. Significance was set at P&lt;0.05. There were no differences (P&gt;0.05) in muscle [Glu] due to aging. Training decreased (P&lt;0.05) muscle [Glu] from 7,561±701 nmol/g of tissue (mean ± standard error) in pre-training samples to 4,491±701 nmol/g of tissue post-training. Plasma [Gln] decreased (P&lt;0.05) with training (368±14 nmol/ml vs 317±14 nmol/ml). There was a trend (P=0.063) towards an effect of aging. There were significant interactions between age and training for plasma [Gln]. Old mares had lower (P&lt;0.05) post-exercise plasma [Gln] (224±21 nmol/ml) when compared with pre-exercise plasma [Gln] (372±21 nmol/ml). Post-training, plasma [Gln] was lower (P&lt;0.05) in the old mares compared to adult mares [Gln] (224±21 nmol/ml vs 410±18 nmol/ml). There was an effect (P&lt;0.05) of age on muscle [Gln] (old = 6,126 ±870 nmol/g of tissue; adult = 3,176±735 nmol/g of tissue); however, there were no changes (P&gt;0.05) due to training. Glut-4 abundance analysis did not differ (P&gt;0.05) between the young adult and old horses; however, there was a trend (P=0.063) towards an effect of training when samples from both groups were pooled. It was concluded that training and aging produce changes in plasma and muscle [Gln], which may affect immune function in athletic horses, but not in Glut-4.

Non-alcoholic fatty liver disease, vascular inflammation and insulin resistance are exacerbated by TRAIL deletion in mice

Non-alcoholic fatty liver disease (NAFLD) incorporates steatosis, non-alcoholic steato-hepatitis (NASH) and liver cirrhosis, associating with diabetes and cardiovascular disease (CVD). TNF-related apoptosis-inducing ligand (TRAIL) is protective of CVD. We aimed to determine whether TRAIL protects against insulin resistance, NAFLD and vascular injury. Twelve-week high fat diet (HFD)-fed Trail−/− mice had increased plasma cholesterol, insulin and glucose compared to wildtype. Insulin tolerance was impaired with TRAIL-deletion, with reduced p-Akt, GLUT4 expression and glucose uptake in skeletal muscle. Hepatic triglyceride content, inflammation and fibrosis were increased with TRAIL-deletion, with elevated expression of genes regulating lipogenesis and gluconeogenesis. Moreover, Trail−/− mice exhibited reduced aortic vasorelaxation, impaired insulin signaling, and >20-fold increased mRNA expression for IL-1β, IL-6, and TNF-α. In vitro, palmitate treatment of hepatocytes increased lipid accumulation, inflammation and fibrosis, with TRAIL mRNA significantly reduced. TRAIL administration inhibited palmitate-induced hepatocyte lipid uptake. Finally, patients with NASH had significantly reduced plasma TRAIL compared to control, simple steatosis or obese individuals. These findings suggest that TRAIL protects against insulin resistance, NAFLD and vascular inflammation. Increasing TRAIL levels may be an attractive therapeutic strategy, to reduce features of diabetes, as well as liver and vascular injury, so commonly observed in individuals with NAFLD.

Changes in photoperiod alter Glut4 expression in skeletal muscle of C57BL/6J mice

Seasonal changes in photoperiod influence body weight and metabolism in mice. Here, we examined the effect of changes in photoperiod on the expression of glucose transporter genes in the skeletal muscle and adipose tissue of C57BL/6J mice. Glut4 expression was lower in the gastrocnemius muscle of mice exposed to a short-duration day (SD) than those to a long-duration day (LD), with accompanying changes in GLUT4 protein levels. Although Glut4 expression in the mouse soleus muscle was higher under SD than under LD, GLUT4 protein levels remained unchanged. To confirm the functional significance of photoperiod-induced changes in Glut4 expression, we checked for variations in insulin sensitivity. Blood glucose levels after insulin injection remained high under SD, suggesting that the mice exposed to SD showed lower sensitivity to insulin than those exposed to LD. We also attempted to clarify the relationship between Glut4 expression and physical activity in the mice following changes in photoperiod. Locomotor activity, as detected via infrared beam sensor, was lower under SD than under LD. However, when we facilitated voluntary activity by using running wheels, the rotation of wheels was similar for both groups of mice. Although physical activity levels were enhanced due to running wheels, Glut4 expression in the gastrocnemius muscle remained unchanged. Thus, variations in photoperiod altered Glut4 expression in the mouse skeletal muscle, with subsequent changes in GLUT4 protein levels and insulin sensitivity; these effects might be independent of physical activity.

Anti-diabetic activity of stigmasterol from soybean oil by targeting the GLUT4 glucose transporter

ABSTRACTThe present study investigated the anti-diabetic activity and potential mechanism of stigmasterol (SMR), which is a kind of phytosterols derived from the edible soybean oil in vitro and in vivo. SMR displayed a mild GLUT4 translocation activity by 1.44-fold in L6 cells. L6 cells were treated with different concentration of SMR, showing significant effects on the enhancing glucose uptake. SMR administrated orally to the KK-Ay mice significantly alleviated their insulin resistance and oral glucose tolerance with reducing fasting blood-glucose levels and blood lipid indexes such as triglyceride and cholesterol. Moreover, the GLUT4 expression in L6 cells, skeletal muscle and white adipose tissue had been also enhanced. In this paper we conclude that, stigmasterol seems to have potential beneficial effects on the treatment of type 2 diabetes mellitus with the probable mechanism of targeting GLUT4 glucose transporter included increasing GLUT4 translocation and expression.

Increased Skeletal Muscle GLUT4 Expression in Obese Mice After Voluntary Wheel Running Exercise Is Posttranscriptional.

Exercise promotes glucose clearance by increasing skeletal muscle GLUT4-mediated glucose uptake. Importantly, exercise upregulates muscle GLUT4 expression in an insulin-independent manner under conditions of insulin resistance, such as with type 2 diabetes. However, the insulin-independent mechanism responsible for rescued muscle GLUT4 expression is poorly understood. We used voluntary wheel running (VWR) in mice to test the prevailing hypothesis that insulin-independent upregulation of skeletal muscle GLUT4 protein expression with exercise is through increased Glut4 transcription. We demonstrate that 4 weeks of VWR exercise in obese mice rescued high-fat diet-induced decreased muscle GLUT4 protein and improved both fasting plasma insulin and hepatic triacylglyceride levels, but did not rescue muscle Glut4 mRNA. Persistent reduction in Glut4 mRNA suggests that a posttranscriptional mechanism regulated insulin-independent muscle GLUT4 protein expression in response to exercise in lean and obese mice. Reduction of GLUT4 protein in sedentary animals upon treatment with rapamycin revealed mTORC1-dependent GLUT4 regulation. However, no difference in GLUT4 protein expression was observed in VWR-exercised mice treated with either rapamycin or Torin 1, indicating that exercise-dependent regulation on GLUT4 was mTOR independent. The findings provide new insight into the mechanisms responsible for exercise-dependent regulation of GLUT4 in muscle.

Abstract 614: TRAIL Deletion in Mice Promotes Vascular Insulin Resistance

TNF-related apoptosis-inducing ligand (TRAIL) is protective in cardiovascular disease and diabetes; whether it regulates insulin resistance and inflammation in the vessel wall is unknown. Wildtype and Trail -/- mice were placed on a high fat diet (HFD) for 12 w. Plasma chemistries were assessed; glucose and insulin tolerance tests performed. Histological GLUT4 expression in skeletal muscle was assessed. Aortic inflammatory marker expression and downstream insulin signaling was also measured; myography was performed. In response to a HFD for 12 w, wildtype mice had increased aortic IL-1beta, MCP-1, IL-6, TNF-alpha and TRAIL mRNA, with reduced circulating TRAIL levels. Compared to 12 w HFD-fed wildtype mice, Trail -/- mice had significantly increased plasma glucose, insulin, and cholesterol levels. Insulin intolerance was worse with TRAIL deletion, with reduced GLUT4 expression and glucose uptake in skeletal muscle. In response to insulin, Trail -/- aortas displayed impaired vasorelaxation and reduced aortic p-Akt expression. Importantly, aortic insulin resistance was associated with &gt; 20-fold increased aortic mRNA expression for IL-1beta, IL-6, and TNF-alpha. We show that TRAIL protects against insulin resistance and type-2 diabetes, in part by regulating downstream insulin signals and inflammation in the vessel wall. These findings suggest that TRAIL may offer a novel therapeutic solution to combat inflammation and insulin resistance in diabetic vascular diseases.