Muscle GLUT4 Research Articles

Skeletal Muscle Glycogen Concentrations And Glut4 Concentrations 72 H Following Eccentric Exercise

Muscle glycogen concentrations are significantly reduced 24-72 h after eccentric exercise that produces indices of skeletal muscle damage. It is suggested that the muscle damage produced by eccentric exercise contributes to the decrease in skeletal muscle glycogen concentrations after eccentric exercise. Decreased skeletal muscle glycogen concentrations are associated with lower GLUT4 protein concentrations 48 h after eccentric exercise. PURPOSE: To determine muscle glycogen concentrations and GLUT4 concentrations 72 h after eccentric exercise. METHODS: A total of 12 individuals performed concentric knee extensions (CON) with one leg, while the contralateral leg performed eccentric knee extensions (ECC). Subjects then cycled for 1 h at 65% of VO2peak. Muscle biopsies were obtained from the vastus lateralis of CON and ECC legs 72 h after exercise. Muscle biopsies were analyzed for muscle glycogen concentrations. Muscle damage was assessed by electron microscopy. Muscle soreness ratings were determined using a 10 point scale. Muscle biopsies were pooled and analyzed for total GLUT4 protein concentrations. RESULTS: Compared to the CON leg, muscle glycogen concentrations in the ECC leg were 25% lower 72 h after exercise (120.7 ± 8.28 vs. 157.3 ± 7.7 μmol.g wet wt-1, p < 0.05). Muscle damage such as myofibrillar disruptions and necrotic fibers were apparent in the ECC leg 72 h after exercise. Indices of muscle damage were not apparent in the CON leg. Ratings of muscle soreness in the ECC leg were higher than for the CON leg (4.43 ± 0.57 vs. 1.36 ± 0.50, p < 0.05). Total pooled GLUT4 protein concentrations were similar 72 h after exercise. CONCLUSIONS: Muscle glycogen concentrations were reduced and muscle damage was produced in the ECC leg 72 h after exercise. Pooled muscle GLUT4 protein concentrations were not altered 72 h after exercise.

Diabetes is accompanied by changes in the levels of proteins involved in endosomal GLUT4 trafficking in obese human skeletal muscle.

IntroductionThe regulated delivery of the glucose transporter GLUT4 from intracellular stores to the plasma membrane underpins insulin‐stimulated glucose transport. Insulin‐stimulated glucose transport is impaired in skeletal muscle of patients with type‐2 diabetes, and this may arise because of impaired intracellular trafficking of GLUT4. However, molecular details of any such impairment have not been described. We hypothesized that GLUT4 and/or levels of proteins involved in intracellular GLUT4 trafficking may be impaired in skeletal muscle in type‐2 diabetes and tested this in obese individuals without and without type‐2 diabetes.MethodsWe recruited 12 participants with type‐2 diabetes and 12 control participants. All were overweight or obese with BMI of 25–45 kg/m2. Insulin sensitivity was measured using an insulin suppression test (IST), and vastus lateralis biopsies were taken in the fasted state. Cell extracts were immunoblotted to quantify levels of a range of proteins known to be involved in intracellular GLUT4 trafficking.ResultsObese participants with type‐2 diabetes exhibited elevated fasting blood glucose and increased steady state glucose infusion rates in the IST compared with controls. Consistent with this, skeletal muscle from those with type‐2 diabetes expressed lower levels of GLUT4 (30%, p = .014). Levels of Syntaxin4, a key protein involved in GLUT4 vesicle fusion with the plasma membrane, were similar between groups. By contrast, we observed reductions in levels of Syntaxin16 (33.7%, p = 0.05), Sortilin (44%, p = .006) and Sorting Nexin‐1 (21.5%, p = .039) and −27 (60%, p = .001), key proteins involved in the intracellular sorting of GLUT4, in participants with type‐2 diabetes.ConclusionsWe report significant reductions of proteins involved in the endosomal trafficking of GLUT4 in skeletal muscle in obese people with type 2 diabetes compared with age‐ and weight‐matched controls. These abnormalities of intracellular GLUT4 trafficking may contribute to reduced whole body insulin sensitivity.

Human umbilical cord-derived mesenchymal stromal cells ameliorate aging-associated skeletal muscle atrophy and dysfunction by modulating apoptosis and mitochondrial damage in SAMP10 mice

BackgroundSkeletal muscle mass and function losses in aging individuals are associated with quality of life deterioration and disability. Mesenchymal stromal cells exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in aging-related degenerative disease.Methods and resultsWe investigated the efficacy of umbilical cord-derived mesenchymal stromal cells (UC-MSCs) on sarcopenia-related skeletal muscle atrophy and dysfunction in senescence-accelerated mouse prone 10 (SAMP10) mice. We randomly assigned 24-week-old male SAMP10 mice to a UC-MSC treatment group and control group. At 12 weeks post-injection, the UC-MSC treatment had ameliorated sarcopenia-related muscle changes in performance, morphological structures, and mitochondria biogenesis, and it enhanced the amounts of proteins or mRNAs for myosin heavy chain, phospho-AMP-activated protein kinase, phospho-mammalian target of rapamycin, phospho-extracellular signal-regulated kinase1/2, peroxisome proliferator-activated receptor-γ coactivator, GLUT-4, COX-IV, and hepatocyte growth factor in both gastrocnemius and soleus muscles, and it reduced the levels of proteins or mRNAs for cathepsin K, cleaved caspase-3/-8, tumor necrosis factor-α, monocyte chemoattractant protein-1, and gp91phox mRNAs. The UC-MSC treatment retarded mitochondria damage, cell apoptosis, and macrophage infiltrations, and it enhanced desmin/laminin expression and proliferating and CD34+/Integrin α7+ cells in both types of skeletal muscle of the SAMP10 mice. In vitro, we observed increased levels of HGF, PAX-7, and MoyD mRNAs at the 4th passage of UC-MSCs.ConclusionsOur results suggest that UC-MSCs can improve sarcopenia-related skeletal muscle atrophy and dysfunction via anti-apoptosis, anti-inflammatory, and mitochondrial biogenesis mechanisms that might be mediated by an AMPK-PGC1-α axis, indicating that UC-MSCs may provide a promising treatment for sarcopenia/muscle diseases.

Effects of Moderate-Intensity Physical Training on Skeletal Muscle Substrate Transporters and Metabolic Parameters of Ovariectomized Rats.

A deficit of estrogen is associated with energy substrate imbalance, raising the risk of metabolic diseases. Physical training (PT) is a potent metabolic regulator through oxidation and storage of substrates transported by GLUT4 and FAT CD36 in skeletal muscle. However, little is known about the effects of PT on these carriers in an estrogen-deficit scenario. Thus, the aim of this study was to determine the influence of 12 weeks of PT on metabolic variables and GLUT4 and FAT CD36 expression in the skeletal muscle of animals energetically impaired by ovariectomy (OVX). The trained animals swam 30 min/day, 5 days/week, at 80% of the critical load intensity. Spontaneous physical activity was measured biweekly. After training, FAT CD36 and GLUT4 expressions were quantified by immunofluorescence in the soleus, as well as muscular glycogen and triglyceride of the soleus, gluteus maximus and gastrocnemius. OVX significantly reduced FAT CD36, GLUT4 and spontaneous physical activity (p < 0.01), while PT significantly increased FAT CD36, GLUT4 and spontaneous physical activity (p < 0.01). PT increased soleus glycogen, and OVX decreased muscular triglyceride of gluteus maximus. Therefore, OVX can cause energy disarray through reduction in GLUT4 and FAT CD36 and their muscle substrates and PT prevented these metabolic consequences, masking ovarian estrogen’s absence.

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.

Effect of 4 Weeks of Moderate-Intensity Endurance Exercise and Lithium Administration on Blood Glucose Level in STZ-Induced Type 1 Diabetes Mellitus Mice

PURPOSE: The purpose of this study was to investigate the effects of short-term endurance exercise and lithium treatment on fasting blood glucose in rats with type 1 diabetes (T1DM).METHODS: Ten-week-old male C57BL/6J mice were induced with T1DM using streptozotocin (STZ) injection. They were then randomly assigned to five groups and treated for a total of 4 weeks. For lithium treatment, 10 mg/kg LiCl was orally administered once a day, 5 days a week, and endurance exercise was performed at 21 m/minutes for 60 minutes, 5 days a week. After four weeks of treatment, blood and the plantaris muscle were extracted under anesthesia, and blood glucose and biomolecular factors were analyzed.RESULTS: 4 weeks of moderate-intensity endurance exercise significantly reduced fasting blood glucose in T1DM mice, increased the expression of GLUT4 in skeletal muscle, and significantly decreased the expression of dynamin, a GLUT4 endocytosis-related factor. Endurance exercise significantly increased mitochondrial biosynthesis in the skeletal muscles and significantly reduced the expression of the MAPK family. However, no biochemical or physiological changes were associated with lithium alone or in combination.CONCLUSIONS: 4 weeks of moderate-intensity endurance exercise improves fasting blood sugar levels through positive changes in glycemic control factors in the skeletal muscle. However, lithium treatment has no resultant effect. These results are thought to have been influenced by the decrease in the expression of the MAPK family and the increase in mitochondrial biosynthesis by endurance exercise for 4 weeks. However, further research is required to establish a clear causal relationship.

Ameliorative Effects of Malonyl Ginsenoside from Panax ginseng on Glucose-Lipid Metabolism and Insulin Resistance via IRS1/PI3K/Akt and AMPK Signaling Pathways in Type 2 Diabetic Mice.

Our previous study has revealed that malonyl-ginsenosides from Panax ginseng (PG-MGR) play a crucial role in the treatment of T2DM. However, its potential mechanism was still unclear. In this study, we investigated the anti-diabetic mechanisms of action of PG-MGR in high fat diet-fed (HFD) and streptozotocin-induced diabetic mice and determined the main constituents of PG-MGR responsible for its anti-diabetic effects. Our results showed that 16 malonyl ginsenosides were identified in PG-MGR by HPLC-ESI-MS/MS. PG-MGR treatment significantly reduced fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels and improved insulin resistance and glucose tolerance. Simultaneously, PG-MGR treatment improved liver injury by decreasing aspartate aminotransferase (AST) and alanine aminotransferase (ALT) expression. Furthermore, Western blot analysis demonstrated that the protein expression levels of p-PI3K/PI3K, p-AKT/AKT, p-AMPK/AMPK, p-ACC/ACC and GLUT4 in liver and skeletal muscle were significantly up-regulated after PG-MGR treatment, and the protein expression levels of p-IRS-1/IRS-1, Fas and SREBP-1c were significantly reduced. These findings revealed that PG-MGR has the potential to improve glucose and lipid metabolism and insulin resistance by activating the IRS-1/PI3K/AKT and AMPK signal pathways.

Baicalin protects against insulin resistance and metabolic dysfunction through activation of GALR2/GLUT4 signaling

BackgroundType 2 diabetes mellitus is a complex metabolic disorder associated with obesity, glucose intolerance and insulin resistance. Activation of GALR2 has been proposed as a therapeutic target for the treatment of insulin resistance. The previous studies showed that baicalin could mitigate insulin resistance, but the detailed mechanism of baicalin on insulin resistance has not been fully explored yet. PurposeIn the present study, we evaluated whether baicalin mitigated insulin resistance via activation of GALR2 signaling pathway. Study design/methodsBaicalin (25 mg/kg/d and 50 mg/kg/d) and/or GALR2 antagonist M871 (10 mg/kg/d) were injected individually or in combinations into obese mice once a day for three weeks, and normal and GALR2 knockdown myotubes were treated with baicalin (100 μM and 400 μM) or metformin (4 mM) in the absence or presence of M871 (800 nM) for 12 h, respectively. The molecular mechanism was explored in skeletal muscle and L6 myotubes. ResultsThe present findings showed that baicalin mitigated hyperglycemia and insulin resistance and elevated the levels of PGC-1α, GLUT4, p-p38MAPK, p-AKT and p-AS160 in skeletal muscle of obese mice. Strikingly, the baicalin-induced beneficial effects were abolished by GALR2 antagonist M871 in obese mice. In vitro, baicalin dramatically augmented glucose consumption and the activity of PGC1α-GLUT4 axis in myotubes through activation of p38MAPK and AKT pathways. Moreover, baicalin-induced elevations in glucose consumption related genes were abolished by GALR2 antagonist M871 or silencing of GALR2 in myotubes. ConclusionsThe present study for the first time demonstrated that baicalin protected against insulin resistance and metabolic dysfunction mainly through activation of GALR2-GLUT4 signal pathway. Our findings identified that activation of GALR2-GLUT4 signal pathway by baicalin could be a new therapeutic approach to treat insulin resistance and T2DM in clinic.

Bridelia ferruginea Benth. (Euphorbiaceae) mitigates oxidative imbalance and lipotoxicity, with concomitant modulation of insulin signaling pathways via GLUT4 upregulation in hepatic tissues of diabetic rats

Ethnopharmacological relevanceBridelia ferruginea Benth. (Euphorbiaceae) is among the medicinal plants commonly used for the management of type 2 diabetes (T2D) and its complications. Aim of the studyThe hepato-therapeutic effect of the butanol fraction of Bridelia ferruginea leaves was investigated in diabetic rats. MethodsThe butanol fraction of B. ferruginea was given to type 2 diabetic rats at both low and high doses (150 and 300 mg/kg bodyweight, respectively), while metformin and glibenclamide served as the standard anti-diabetic drugs. A normal toxicological group was administered a high dose of the fraction. At the end of the experimental period, the rats were sacrificed, and their livers and psoas muscle collected. The liver was assayed for oxidative stress markers, liver glycogen content, lipid metabolite profile (using GC-MS) and their metabolic pathways were analyzed using the MetaboAnalyst 5.0 online server. The expression of GLUT4 was also assayed in the liver and muscle as well as the identification of signaling pathways associated with GLUT4 expression using the Enrichr online server. In silico molecular docking was used to investigate the molecular interactions of some postulated compound found in B. ferruginea with GLUT4. The ability of the fraction to stimulate muscle glucose uptake was determined in isolated rat psoas muscle ex vivo. ResultsTreatment with the high dose of fraction caused an inhibition of lipid peroxidation as well as the elevation of catalase, SOD, glutathione reductase and glutathione peroxidase activities in the rat liver. There was an increased expression of GLUT4 in livers and muscles of diabetic rats following treatment with B. ferruginea. Treatment with the fraction also caused inactivation of diabetes-activated pathways and changes in the distribution of the hepatic lipid metabolites. Molecular docking analysis revealed strong molecular interactions of pyrogallol and sitosterol with GLUT4. ConclusionsThese data illustrate the hepato-protective effect of B. ferruginea in diabetic rats which compare favorably with the tested anti-diabetic drugs (metformin and glibenclamide).

Exercise-Induced Improvement in Insulin-Stimulated Glucose Uptake by Rat Skeletal Muscle Is Absent in Male AS160-Knockout Rats, Partially Restored by Muscle Expression of Phosphomutated AS160, and Fully Restored by Muscle Expression of Wild-Type AS160.

One exercise session can elevate insulin-stimulated glucose uptake (ISGU) in skeletal muscle, but the mechanisms remain elusive. Circumstantial evidence suggests a role for Akt substrate of 160 kDa (AS160 or TBC1D4). We used genetic approaches to rigorously test this idea. The initial experiment evaluated the role of AS160 in postexercise increase in ISGU using muscles from male wild-type (WT) and AS160-knockout (KO) rats. The next experiment used AS160-KO rats with an adeno-associated virus (AAV) approach to determine if rescuing muscle AS160 deficiency could restore the ability of exercise to improve ISGU. The third experiment tested if eliminating the muscle GLUT4 deficit in AS160-KO rats via AAV-delivered GLUT4 would enable postexercise enhancement of ISGU. The final experiment used AS160-KO rats and AAV delivery of AS160 mutated to prevent phosphorylation of Ser588, Thr642, and Ser704 to evaluate their role in postexercise ISGU. We discovered the following: 1) AS160 expression was essential for postexercise increase in ISGU; 2) rescuing muscle AS160 expression of AS160-KO rats restored postexercise enhancement of ISGU; 3) restoring GLUT4 expression in AS160-KO muscle did not rescue the postexercise increase in ISGU; and 4) although AS160 phosphorylation on three key sites was not required for postexercise elevation in ISGU, it was essential for the full exercise effect.

Evaluation of Gamma Amino Butyric Acid (GABA) and Glibenclamide Combination Therapy in Streptozotocin Induced Diabetes.

Type 1-diabetes (T1D) is characterized by autoimmune destruction of β-cells and loss of endogenous insulin. A lifelong dependency on exogenous supply of insulin presents a great challenge in the pharmacotherapy of T1D that elicits a quest for alternative therapies, which can protect β-cells and revive their insulinogenic functions. GABA (γ-aminobutyric acid) has immunoprotective and β-cell regenerative capabilities. Co-administration of an insulin secretagogue, such as glibenclamide (Glib), along with GABA may enhance the pancreatic insulin output in T1D. The present study evaluated the possible mechanism of GABA in the improvement of glucose tolerance and its effects in streptozotocin (STZ) induced T1D along with Glib. Wistar rats (180-220 g) were administered a single dose of STZ (55 mg/kg, i.p.). GABA (100 mg/kg, i.p.) and Glib (5 or 10 mg/kg, i.p.) alone or in combination were administered for 28 days. Body weight (b.w.), water consumption, fasting blood glucose (FBG), oral glucose tolerance, plasma lipids, insulin, and muscle GLUT-4 (glucose transporters) protein level were assessed. T1D significantly decreased b.w. and increased water-intake in rats. An increase in FBG and a decrease in plasma insulin and muscle GLUT-4 indicated STZ-triggered destruction of β-cells in diabetic rats accompanied with dyslipidemia. GABA or Glib (10 mg/kg) significantly improved b.w., plasma insulin and GLUT-4 levels, and ameliorated FBG and blood lipid profile in diabetic rats. GABA and Glib (5 mg/kg) combination therapy achieved far better control over hyperglycemia and related pathogenic conditions (b.w., water-intake, insulin, GLUT-4, lipids). The anti-diabetic effect of combination therapy was significantly more pronounced in comparison to individual drug treatments. Histopathological analysis revealed an increase in the number of functional pancreatic-islets by combination therapy. GABA revitalized β-cells against STZ-toxicity. GABA and Glib synergistically augmented insulin secretion that can be used to manage T1D and its complications. GABA has the potential to remarkably enhance the therapeutic outcome in diabetic patients and reduce the dose of existing anti-diabetic drugs such as Glib.

Acute melatonin administration improves exercise tolerance and the metabolic recovery after exhaustive effort

The present study investigated the effects of acute melatonin administration on the biomarkers of energy substrates, GLUT4, and FAT/CD36 of skeletal muscle and its performance in rats subjected to exhaustive swimming exercise at an intensity corresponding to the maximal aerobic capacity (tlim). The incremental test was performed to individually determine the exercise intensity prescription and 48 h after, the animals received melatonin (10 mg·kg−1) or vehicles 30 min prior to tlim. Afterwards, the animals were euthanized 1 or 3 h after the exhaustion for blood and muscles storage. The experiment 1 found that melatonin increased the content of glycogen and GLUT4 in skeletal muscles of the animals that were euthanized 1 (p < 0.05; 22.33% and 41.87%) and 3 h (p < 0.05; 37.62% and 57.87%) after the last procedures. In experiment 2, melatonin enhanced the tlim (p = 0.01; 49.42%), the glycogen content (p < 0.05; 40.03%), GLUT4 and FAT/CD36 in exercised skeletal muscles (F = 26.83 and F = 25.28, p < 0.01). In summary, melatonin increased energy substrate availability prior to exercise, improved the exercise tolerance, and accelerated the recovery of muscle energy substrates after the tlim, possibly through GLUT4 and FAT/CD36.

Contraction-Mediated Glucose Transport in Skeletal Muscle Is Regulated by a Framework of AMPK, TBC1D1/4, and Rac1.

The two closely related RabGTPase-activating proteins (RabGAPs) TBC1D1 and TBC1D4, both substrates for AMPK, play important roles in exercise metabolism and contraction-dependent translocation of GLUT4 in skeletal muscle. However, the specific contribution of each RabGAP in contraction signaling is mostly unknown. In this study, we investigated the cooperative AMPK-RabGAP signaling axis in the metabolic response to exercise/contraction using a novel mouse model deficient in active skeletal muscle AMPK combined with knockout of either Tbc1d1, Tbc1d4, or both RabGAPs. AMPK deficiency in muscle reduced treadmill exercise performance. Additional deletion of Tbc1d1 but not Tbc1d4 resulted in a further decrease in exercise capacity. In oxidative soleus muscle, AMPK deficiency reduced contraction-mediated glucose uptake, and deletion of each or both RabGAPs had no further effect. In contrast, in glycolytic extensor digitorum longus muscle, AMPK deficiency reduced contraction-stimulated glucose uptake, and deletion of Tbc1d1, but not Tbc1d4, led to a further decrease. Importantly, skeletal muscle deficient in AMPK and both RabGAPs still exhibited residual contraction-mediated glucose uptake, which was completely abolished by inhibition of the GTPase Rac1. Our results demonstrate a novel mechanistic link between glucose transport and the GTPase signaling framework in skeletal muscle in response to contraction.

Raloxifene Ameliorates Glucosamine-Induced Insulin Resistance in Ovariectomized Rats.

Osteoarthritis (OA) and osteoporosis (OP) are common among older women, especially postmenopausal women. Glucosamine (GlcN) is a common medication for OA, but it may induce insulin resistance and β-cell dysfunction, especially if ovarian hormones are lacking. Raloxifene (RLX) is a selective estrogen receptor modulator and also an OP drug. Previously, we found that estrogen could improve GlcN-induced insulin resistance in ovariectomized (OVX) rats. Here, we further hypothesized that RLX, similarly to estrogen, can ameliorate GlcN-induced insulin resistance in OVX rats. We used GlcN to induce insulin resistance in OVX rats as a model for evaluating the protective effects of RLX in vivo. We used a pancreatic β-cell line, MIN-6, to study the mechanisms underlying the effect of RLX in GlcN-induced β-cell dysfunction in vitro. Increases in fasting plasma glucose, insulin, and homeostasis model assessments of insulin resistance in OVX Sprague Dawley rats treated with GlcN were reversed by RLX treatment (n = 8 in each group). Skeletal muscle GLUT-4 increased, liver PEPCK decreased, pancreatic islet hypertrophy, and β-cell apoptosis in OVX rats treated with GlcN was ameliorated by RLX. The negative effects of GlcN on insulin secretion and cell viability in MIN-6 cells were related to the upregulation of reticulum (ER) stress-associated proteins (C/EBP homologous protein, phospho-extracellular signal-regulated kinase, phospho-c-JunN-terminal kinase), the expression of which was reduced by RLX. Pretreatment with estrogen receptor antagonists reversed the protective effects of RLX. GlcN can induce insulin resistance, β-cell dysfunction, and apoptosis in OVX rats and increase ER stress-related proteins in β-cells, whereas RLX can reverse these adverse effects. The effects of RLX act mainly through estrogen receptor α; therefore, RLX may be a candidate drug for postmenopausal women with OA and OP.

High-intensity infrasound effects on glucose metabolism in rats

Recent focus has been given on the effects of high-intensity infrasound (HII) exposure, and whether it induces changes in pancreatic morphology and glucose metabolism is still unknown. As such, we have studied the impact of HII exposure on glucose tolerance, insulin sensitivity, pancreatic islet morphology, muscle GLUT4 and plasma insulin and corticosterone levels. Normal and glucose intolerant wild-type Wistar rats were randomly divided in two groups: one group not exposed to HII and the other continuously exposed to HII. Animals were sacrificed at three timepoints of exposure (1, 6 or 12 weeks). An intraperitoneal glucose tolerance test was performed, blood samples were collected and the pancreas and the quadriceps femoris muscle were excised. Circulating insulin and corticosterone levels were determined and pancreatic and muscular tissue were routinely processed for histochemistry and immunohistochemistry with an anti-GLUT4 antibody. Animals exposed to HII had higher corticosterone levels than animals not exposed. No differences were found on insulin concerning HII exposure or glucose intolerance. Glucose intolerant animals had pancreatic islet fibrosis and no differences were found in GLUT4 ratio concerning HII exposure. In conclusion, we found that continuous exposure to HII increases stress hormone levels without inducing glucose intolerance in rats.

Bitter gourd extract improves glucose homeostasis and lipid profile via enhancing insulin signaling in the liver and skeletal muscles of diabetic rats

Objective: To investigate the modulatory effects of bitter gourd extract on the insulin signaling pathway in the liver and skeletal muscle tissues of diabetic rats. Methods: The ethanolic extract of bitter gourd was prepared and its contents of total polyphenols and flavonoids were assayed. A neonatal streptozotocin-induced diabetic rat model was established and the diabetic rats were assigned into different groups and were treated with different doses of bitter gourd extract (100, 200, 400, or 600 mg/kg) or with glibenclamide (0.1 mg/kg) for 30 d. Fasting blood glucose, insulin, and lipid profile were evaluated and the insulin signaling pathway in the liver and skeletal muscle of rats was investigated. The correlations between homeostasis model assessment (HOMA) and the components of insulin signaling pathway were also evaluated. Results: Different doses of bitter gourd extract significantly ameliorated fasting blood glucose level and HOMA index for insulin resistance. Moreover, bitter gourd extract increased serum insulin and improved disrupted serum lipid profile. The levels of insulin receptor substrate-1 (IRS-1), p-insulin receptor β (p-IR-β), protein kinase C (PKC), GLUT2, and GLUT4 were improved by treatment with bitter gourd extract. The best results were obtained with 400 mg/kg dose of the extract, the effect of which was equivalent to that of glibenclamide. HOMA in the bitter gourd treated rats was negatively correlated with p-IR-β, IRS-1 and PKC in hepatic and skeletal muscle. HOMA was also negatively correlated with skeletal muscle GLUT4. Conclusions: Bitter gourd extract improves glucose homeostasis and lipid profile in diabetic rats via enhancement of insulin secretion and sensitivity. Therefore, bitter gourd can be used as a potential pharmacological agent for the treatment of type 2 diabetes mellitus.

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.

Gliquidone ameliorates hepatic insulin resistance in streptozotocin-induced diabetic Sur1−/− rats

Gliquidone was suggested to exert hypoglycemic effect through enhancing hepatic insulin sensitivity. However, inadequate in vivo evidences make this statement controversial. The aim of the present study was to clarify the insulin-sensitizer role of gliquidone in liver and muscle, so as to confirm its extra-pancreatic effects in vivo. TALEN technique was used to create Sur1 knockout (Sur1−/−) rats. Diabetic Sur1−/− rat models were established by high-fat diet combined with streptozotocin, and which were randomly divided into three groups: gliquidone, metformin and saline, treated for 8 weeks. Fasting blood glucose (FBG) and body mass were tested each week. IPGTT, IPITT and hyperinsulinemic-euglycemic clamp tests were used to evaluate glucose tolerance and insulin sensitivity, respectively. Key mediators of glucose metabolism in liver and skeletal muscle and the activity of AKT and AMPK in these tissues were further analyzed. We found that gliquidone decreased FBG and increased insulin sensitivity without increasing insulin secretion in diabetic Sur1−/− rats. Further exploration implied that gliquidone mainly increased hepatic glycogen storage and decreased gluconeogenesis, which were accompanied with activation of AKT, but not enhanced muscle GLUT4 expression. However, both these effects were still weaker than that of metformin. These results suggested that gliquidone could exerts an extra-pancreatic hypoglycemic effect by improving insulin sensitivity, which might be largely attributes to its additional insulin sensitizer role in hepatic glucose metabolism.

Mechanism of Electroacupuncture Regulating IRS-1 Phosphorylation in Skeletal Muscle to Improve Insulin Sensitivity.

Objective To explore the possible mechanism of electroacupuncture to improve insulin sensitivity in type 2 diabetes rats. Methods Fourteen Zucker Diabetic Fatty (ZDF) rats were randomly divided into two groups: a model group and an electroacupuncture group, with 7 rats in each group. Seven Zucker Lean (ZL) rats served as a control group. All rats were fed with Purina #5008 for 4 weeks, and the electroacupuncture group received 4-week electroacupuncture intervention, while the control group and model group received no intervention. We measured fasting blood glucose (FBG) on the fourth weekend. After 4 weeks of intervention, the expression levels of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, IRS-1 serine/threonine phosphorylation, and GLUT4 in quadriceps femoris muscles were detected by western Blot. Results Compared with the model group, the electroacupuncture group had a lower level of fasting blood glucose, serum insulin level, and insulin resistance index (P < 0.05). The electroacupuncture group had lower IRS-1 serine/threonine phosphorylation than the model group, with the difference showing statistical significance (P < 0.05). Furthermore, the mean score (MS) of the control group showed the lowest phosphorylation expression, followed by the electroacupuncture group, while the model group had the highest level of phosphorylated protein expression. The level of IRS-1 tyrosine phosphorylation at Tyr895 sites was compared, and the result showed that there was no significant difference between the electroacupuncture group and the control group (P > 0.05), and the electroacupuncture group had higher phosphorylation expression than the model group (P < 0.05). Compared with the control group and the model group, the expression level of GLUT4 protein in the electroacupuncture group was significantly increased (P < 0.05). Conclusion Electroacupuncture has the effect to improve the insulin sensitivity of type 2 diabetic ZDF rats by reducing fasting blood glucose, insulin level, and insulin resistance index, effectively up regulating the expression of GLUT4 protein in quadriceps femoris muscle. The mechanism is related to the regulation of skeletal muscle IRS-1 serine/threonine and tyrosine phosphorylation levels.

Potentilla fulgens upregulate GLUT4, AMPK, AKT and insulin in alloxan-induced diabetic mice: an in vivo and in silico study

Objective This study was designed to investigate whether the glucose lowering effects of Potentilla fulgens acts by modulating GLUT4, AKT2 and AMPK expression in the skeletal muscle and liver tissues. Methodology Alloxan-induced diabetic mice treated with Potentilla fulgens was assessed for their blood glucose and insulin level, mRNA and protein expression using distinguished methods. Additionally, GLUT4, AKT2 and AMPK were docked with catechin, epicatechin, kaempferol, metformin, quercetin and ursolic acid reportedly present in Potentilla fulgens. Results Potentilla fulgens ameliorates hyperglycaemia and insulin sensitivity via activation of AKT2 and AMPK, increases the expression of GLUT4, AKT2, AMPKα1 and AMPKα2 whose levels are reduced under diabetic condition. Molecular docking revealed interacting residues and their binding affinities (−4.56 to −8.95 Kcal/mol). Conclusions These findings provide more clarity vis-avis the mechanism of action of the phytoceuticals present in Potentilla fulgens extract which function through their action on GLUT4, PKB and AMPK.