Glucose Transport In Muscle Research Articles

Voluntary exercise opposes insulin resistance of skeletal muscle glucose transport during liquid fructose ingestion in rats.

We have recently reported that male rats given liquid fructose ingestion exhibit features of cardiometabolic abnormalities including non-obese insulin resistance with impaired insulin signaling transduction in skeletal muscle (Rattanavichit Y et al. Am J Physiol Regul Integr Comp Physiol 311: R1200-R1212, 2016). While exercise can attenuate obesity-related risks of cardiometabolic syndrome, the effectiveness and potential mechanism by which exercise modulates non-obese insulin resistance have not been fully studied. The present investigation evaluated whether regular exercise by voluntary wheel running (VWR) can reduce cardiometabolic risks induced by fructose ingestion. Moreover, the potential cellular adaptations following VWR on key signaling proteins known to influence insulin-induced glucose transport in skeletal muscle of fructose-ingested rats were investigated. Male Sprague-Dawley rats were given either water or liquid fructose (10% wt/vol) without or with access to running wheel for 6weeks. We demonstrated that VWR restored insulin-stimulated glucose transport in the soleus muscle by improving the functionality of several signaling proteins, including insulin-stimulated IRβ Tyr1158/Tyr1162/Tyr1163 (82%), IRS-1 Tyr989 (112%), Akt Ser473 (56%), AS160 Thr642 (76%), and AS160 Ser588 (82%). These effects were accompanied by lower insulin-stimulated phosphorylation of IRS-1 Ser307 (37%) and JNK Thr183/Tyr185 (49%), without significant changes in expression of proteins in the renin-angiotensin system. Intriguingly, multiple cardiometabolic abnormalities were not observed in fructose-ingested rats with access to VWR. Collectively, this study demonstrates that the development of cardiometabolic abnormalities as well as insulin resistance of skeletal muscle and defective signaling molecules in rats induced by fructose ingestion could be opposed by VWR.

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.

Exercise Increases Glucose Transporter-4 Levels on Peripheral Blood Mononuclear Cells.

Glucose transporter 4 (GLUT4) plays a key role in the pathophysiology of type 2 diabetes. Glucose transporter 4 is upregulated in response to exercise, enhancing cellular glucose transport in skeletal muscle tissue. This mechanism appears to remain intact in individuals with insulin resistance. Details of the mechanism are poorly understood and are challenging to study due to the invasive nature of muscle biopsy. Peripheral blood mononuclear cells (PBMC) have documented insulin-sensitive GLUT4 activity and may serve as a proxy tissue for studying skeletal muscle GLUT4. The purpose of this study was to investigate whether GLUT4 in PBMC is affected by conditioning. We recruited 16 student athletes from the cross-country running and skiing teams and fifteen sedentary students matched for age and sex from the University of Alaska Fairbanks. Peripheral blood mononuclear cells were collected with mononuclear cell separation tubes. The GLUT4 concentrations were measured using a commercially available enzyme linked immunosorbent assay. Additionally, correlations between PBMC GLUT4 and common indicators of insulin resistance were examined. Results indicate significantly higher PBMC GLUT4 levels in conditioned athletes than in their sedentary counterparts, similar to what has been documented in myocytes. Females were observed to have higher PBMC GLUT4 levels than males. Correlations were not detected between PBMC GLUT4 and hemoglobin A1c, glucose, insulin, homeostatic model assessment of insulin resistance, body mass index, or body fat. This study provides evidence to support exploration of PBMC as a proxy tissue for studying GLUT4 response to exercise or other noninsulin factors.

Exercise Protects Against Defective Insulin Signaling and Insulin Resistance of Glucose Transport in Skeletal Muscle of Angiotensin II-Infused Rat.

Objectives: The present study investigated the impact of voluntary exercise on insulin-stimulated glucose transport and the protein expression and phosphorylation status of the signaling molecules known to be involved in the glucose transport process in the soleus muscle as well as other cardiometabolic risks in a rat model with insulin resistance syndrome induced by chronic angiotensin II (ANGII) infusion.Materials and Methods: Male Sprague-Dawley rats were assigned to sedentary or voluntary wheel running (VWR) groups. Following a 6-week period, rats in each group were subdivided and subcutaneously administered either normal saline or ANGII at 100 ng/kg/min for 14 days. Blood pressure, glucose tolerance, insulin-stimulated glucose transport and signaling proteins, including insulin receptor (IR), insulin receptor substrate 1 (IRS-1), Akt, Akt substrate of 160 kDa (AS160), AMPKα, c-Jun NH2-terminal kinase (JNK), p38 MAPK, angiotensin converting enzyme (ACE), ANGII type 1 receptor (AT1R), ACE2, Mas receptor (MasR) and oxidative stress marker in the soleus muscle, were evaluated.Results: Exercise protected against the insulin resistance of glucose transport and defective insulin signaling molecules in the soleus muscle; this effect was associated with a significant increase in AMPK Thr172 (43%) and decreases in oxidative stress marker (31%) and insulin-induced p38 MAPK Thr180/Tyr182 (45%) and SAPK/JNK Thr183/Tyr185 (25%), without significant changes in expression of AT1R, AT2R, ACE, ACE2, and MasR when compared to the sedentary rats given ANGII infusion. At the systemic level, VWR significantly decreased body weight, fat weight, and systolic blood pressure as well as improved serum lipid profiles.Conclusion: Voluntary exercise can alleviate insulin resistance of glucose transport and impaired insulin signaling molecules in the soleus muscle and improve whole-body insulin sensitivity in rats chronically administered with ANGII.

High‐intensity Interval Exercise decreases IP6K1 Muscle Content & Improves Insulin Sensitivity (SI2*) in Pre‐diabetic Individuals

Insulin resistance in skeletal muscle contributes to whole body hyperglycaemia in pre‐diabetic and type 2 diabetic individuals. Insulin‐dependent glucose uptake in skeletal muscle requires the upregulation of the Akt‐AS160 signalling cascade (Bruss et al., 2005; Mackenzie & Elliott, 2014). Muscle contraction increases both insulin‐stimulated glucose uptake (Kramer et al., 2006) and Akt phosphorylation (Deshmukh et al., 2006) in the hours following exercise. Inositol hexakisphosphate kinase‐1 (IP6K1) produces IP7 (Chakraborty et al., 2010), which may inhibit insulin‐stimulated glucose transport in muscle by competing with PIP3 at the PH domain of Akt. Currently, there are no data on IP6K1 content in human skeletal muscle. Here we aimed to investigate the effects of two different types of exercise on insulin sensitivity and IP6K1 muscle content in pre‐diabetic individuals. This work also used an IP6K1 inhibitor (TNP) to investigate the potential role of IP6K1 in insulin signalling in the C2C12 skeletal muscle cell line.Nine pre‐diabetic [47 (3) yr; BMI, 32.0 (2.4); Body Fat, 39.0 (4.4)%; HbA1c 6.1 (0.2)%; fasting blood glucose 6.5 (0.4) mmol/l; HOMAIR 3.7 (0.7)] individuals were recruited to take part in a resting control, a continuous exercise (90% of lactate threshold) and a high‐intensity intermittent exercise trial (HIIE; 6 × 30 sec sprints). Muscle biopsies were taken pre‐ and post each 60‐minute trial. A labeled ([6,6‐2H2]glucose) intravenous glucose tolerance test (IVGTT) was performed immediately after the second muscle sample. The labelled IVGTT allows for the measurement of two‐compartment models of insulin sensitivity (SI2*) and hepatic glucose production (HGP). In an in vitro experiment, C2C12 cells were grown and differentiated under standard conditions before being treated with insulin (100 nM) +/− the IP6K1 inhibitor N2‐(m‐Trifluorobenzyl), N6‐(p‐nitrobenzyl)purine(TNP) (10μM) for 24 hours.Akt308 phosphorylation was significantly increased following HIIE (P = 0.003), with IP6K1 muscle protein content (P = 0.001) and mRNA expression (P = 0.02) reduced for the same exercise trial. Continuous exercise had no effect on either pAkt308 (P = 0.175) or IP6K1 protein content (P = 0.337). There was no effect on protein IP6K1 content following continuous exercise. HIIE also reduced HGP and improved SI2*. In addition, with HIIE, SI2* was significantly greater in the 4 hours after exercise than with continuous exercise. Chemical inhibition of IP6K1 with TNP in vitro increased p/t Akt308 and p/t AS160642 while decreasing IP6K1 in insulin treated myotubes.This work showed that high‐intensity interval exercise reduces muscle IP6K1 in prediabetic individuals, with the same exercise treatment increasing activity of the traditional insulin signaling cascade (Akt‐AS160). These data suggest that high‐intensity interval exercise is more effective than moderate‐intensity continuous exercise at improving glycaemic control acutely in individuals at risk of diabetes. Further, IP6K1 may be linked to reduced muscle responsiveness to insulin.Support or Funding InformationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Membrane Trafficking Protein CDP138 Regulates Fat Browning and Insulin Sensitivity through Controlling Catecholamine Release.

CDP138 is a calcium- and lipid-binding protein that is involved in membrane trafficking. Here, we report that mice without CDP138 develop obesity under normal chow diet (NCD) or high-fat diet (HFD) conditions. CDP138-/- mice have lower energy expenditure, oxygen consumption, and body temperature than wild-type (WT) mice. CDP138 is exclusively expressed in adrenal medulla and is colocalized with tyrosine hydroxylase (TH), a marker of sympathetic nervous terminals, in the inguinal fat. Compared with WT controls, CDP138-/- mice had altered catecholamine levels in circulation, adrenal gland, and inguinal fat. Adrenergic signaling on cyclic AMP (cAMP) formation and hormone-sensitive lipase (HSL) phosphorylation induced by cold challenge but not by an exogenous β3 adrenoceptor against CL316243 were decreased in adipose tissues of CDP138-/- mice. Cold-induced beige fat browning, fatty acid oxidation, thermogenesis, and related gene expression were reduced in CDP138-/- mice. CDP138-/- mice are also prone to HFD-induced insulin resistance, as assessed by Akt phosphorylation and glucose transport in skeletal muscles. Our data indicate that CDP138 is a regulator of stress response and plays a significant role in adipose tissue browning, energy balance, and insulin sensitivity through regulating catecholamine secretion from the sympathetic nervous terminals and adrenal gland.

β-Actin shows limited mobility and is required only for supraphysiological insulin-stimulated glucose transport in young adult soleus muscle.

Studies in skeletal muscle cell cultures suggest that the cortical actin cytoskeleton is a major requirement for insulin-stimulated glucose transport, implicating the β-actin isoform, which in many cell types is the main actin isoform. However, it is not clear that β-actin plays such a role in mature skeletal muscle. Neither dependency of glucose transport on β-actin nor actin reorganization upon glucose transport have been tested in mature muscle. To investigate the role of β-actin in fully differentiated muscle, we performed a detailed characterization of wild type and muscle-specific β-actin knockout (KO) mice. The effects of the β-actin KO were subtle; however, we confirmed the previously reported decline in running performance of β-actin KO mice compared with wild type during repeated maximal running tests. We also found insulin-stimulated glucose transport into incubated muscles reduced in soleus but not in extensor digitorum longus muscle of young adult mice. Contraction-stimulated glucose transport trended toward the same pattern, but the glucose transport phenotype disappeared in soleus muscles from mature adult mice. No genotype-related differences were found in body composition or glucose tolerance or by indirect calorimetry measurements. To evaluate β-actin mobility in mature muscle, we electroporated green fluorescent protein (GFP)-β-actin into flexor digitorum brevis muscle fibers and measured fluorescence recovery after photobleaching. GFP-β-actin showed limited unstimulated mobility and no changes after insulin stimulation. In conclusion, β-actin is not required for glucose transport regulation in mature mouse muscle under the majority of the tested conditions. Thus, our work reveals fundamental differences in the role of the cortical β-actin cytoskeleton in mature muscle compared with cell culture.

L-Carnitine supplementation increases expression of PPAR-γ and glucose transporters in skeletal muscle of chronically and acutely exercised rats.

In this study, the effects of L-Carnitine supplementation on the lipid peroxidation and expression of PPAR-γ and glucose transporters in the liver and muscles of chronically and acutely exercised rats were investigated. A total of 42 male Wistar Albino rats (8-week-old) were divided into six groups as follows: Control, L-Carnitine, Chronic Exercise (CE), Chronic Exercise + L-Carnitine, Acute Exercise (AE) and L-Carnitine + Acute Exercise. Chronic exercise consists of 30 m/min, 30 min/day, and 5 days/week for 6 weeks. Rats in the acute exercise groups were run on the treadmill at 30 m/min until exhaustion. L-Carnitine was given at the level of 300 mg per kilogram of diet for 6 weeks. There was no significant difference in the levels of serum ALT, AST, urea, creatinine and glucose levels between the exercise and L-Carnitine groups (P > 0.05). Cholesterol and triglyceride levels decreased by L- carnitine supplementation and chronic exercise in control groups but increased in the AE groups compared to the control group without reinforcement (P < 0.05). Serum, muscle, heart, and liver malondialdehyde (MDA) concentrations were lower in CE and higher in the AE groups (P < 0.001). However, L-Carnitine supplementation reduced MDA levels (P < 0.05). Liver and muscle PPAR-γ, liver GLUT-2 and muscle GLUT-4 mRNA expressions were lower in AE group than in all other groups (P < 0.001). Both chronic exercise and supplemental L-Carnitine increased liver and muscle PPAR-γ, GLUT-2 and GLUT-4 mRNA expression (P <0.05). As a result, although acute exercise increased oxidative stress, chronic exercise reduced oxidative stress by lowering lipid peroxidation level. L-Carnitine supplementation decreased oxidative stress and improved glucose and lipid metabolism by regulation of PPAR-γ, GLUT-2 and GLUT-4 mRNA expression in rats.

Triiodothyronine improves age-induced glucose intolerance and increases the expression of sirtuin-1 and glucose transporter-4 in skeletal muscle of aged rats.

To evaluate the potential beneficial impact and to clarify the underlying mechanisms of triiodothyronine (T3) on glucose intolerance in aged rats. Rats were divided into adult group, aged group, and T3-treated aged group (T3-aged). T3 was administered at a dose of 8 µg/kg body weight for 2 weeks. In comparison to adult group, aged rats presented significant higher levels of fasting insulin and homeostatic model assessment of insulin resistance (HOMA-IR). Glucose area under the curve (AUC), and peak glycemia, estimated from oral glucose tolerance curve, were significantly increased along with decreased mRNA expression of skeletal muscle sirtuin-1, glucose transporter-4 (GLUT-4) and uncoupling protein-3 (UCP-3) in aged versus adult group. T3 administration significantly decreased the serum levels of fasting insulin, HOMA-IR, glucose AUC, and peak glycemia in T3-aged versus aged rats. Skeletal muscle mRNA expression of sirtuin-1 and GLUT-4 were increased, whereas UCP-3 was not changed by T3 administration. T3 administration improved glucose intolerance, and decreased insulin resistance in aged rats. This was associated with upregulation of skeletal muscle sirtuin-1 and GLUT-4 which could mediate such beneficial effect.

GLUT4 Translocation in Single Muscle Cells in Culture: Epitope Detection by Immunofluorescence.

GLUT4 is the major glucose transporter in skeletal muscle. GLUT4 cycles to and from the plasma membrane and its exocytic rate is accelerated by insulin and muscle contraction to achieve a new steady state with more GLUT4 proteins at the muscle cell surface. To gain a better understanding of the molecular and cellular mechanisms that govern GLUT4 protein recycling, we developed an in vitro model in which myc-epitope-tagged GLUT4 or GLUT4-GFP is expressed in L6 skeletal muscle cells. The myc-epitope is inserted into an exofacial domain that is accessible to anti-myc antibodies from the outside of non-permeabilized cells, allowing one to count the number of transporters at the cell surface. This enables one to perform single-cell analysis using confocal fluorescence microscopy to quantify cell surface GLUT4myc or GLUT4myc-GFP in cells co-transfected with diverse cDNA constructs, treated with siRNAs, or co-stained with antibodies for other proteins of interest. Herein, we describe the methodology to perform these experimental approaches in insulin-stimulated L6 muscle cells.

Increased Insulin Resistance and Glucagon Levels in Mild/Inactive Systemic Lupus Erythematosus Patients Despite Normal Glucose Tolerance.

To assess insulin sensitivity in patients with systemic lupus erythematosus (SLE) in response to a meal tolerance test (MTT). In this cross-sectional study, 33 adult females with mild/inactive SLE (SLE group) and 16 age- and body mass index-matched female healthy controls (CTRL group) underwent an MTT and were assessed for insulin sensitivity and beta cell function. Skeletal muscle protein expressions of total and membrane insulin-dependent glucose transporter 4 (GLUT-4) were also evaluated (SLE group: n = 10, CTRL group: n = 5); muscle biopsies were performed after MTT. Further measurements included inflammatory cytokines, adipocytokines, physical activity level, body composition, and food intake. SLE and CTRL groups showed similar fasting glucose, glucose response, and skeletal muscle GLUT-4 translocation after MTT. However, the SLE group demonstrated higher fasting insulin levels (P = 0.01; effect size [ES] 1.2), homeostatic model assessment insulin resistance (IR) (P = 0.03; ES 1.1), insulin-to-glucose ratio response to MTT (P = 0.02; ES 1.2), fasting glucagon levels (P = 0.002; ES 2.7), glucagon response to MTT (P = 0.0001; ES 2.6), and a tendency toward lower Matsuda index of whole-body insulin sensitivity (P = 0.06; ES -0.5) when compared with the CTRL group. Fasting proinsulin-to-insulin ratio and proinsulin-to-insulin ratio response to MTT were similar between groups (P > 0.05), while the SLE group showed a higher insulinogenic index when compared with the CTRL group (P = 0.02; ES = 0.9). We have identified that SLE patients had a bi-hormone metabolic abnormality characterized by increased IR and hyperglucagonemia despite normal glucose tolerance and preserved beta cell function and skeletal muscle GLUT-4 translocation. Strategies capable of ameliorating insulin sensitivity to reduce the risk of type 2 diabetes mellitus and cardiovascular disease in SLE may require more than targeting IR alone.

Molecular responses of Nile tilapia (Oreochromis niloticus) to different levels of dietary carbohydrates

The objective of the study was to test for the first time the molecular adaptation of the glucose metabolism to this fish species know to be a good user of carbohydrates. In this way, Nile tilapia were fed with 3 different levels of carbohydrates 0% (CHO-L) 30% (CHO-M) and 50% (CHO-H) dextrin. After 45days and 90days of feeding we analyzed the plasma parameters, zootechnical performance and the mRNA levels for genes involved in glycolysis, gluconeogenesis, lipogenesis and glucose transport in liver and muscle. The best growth performance was found for fish fed M-CHO diet, the fish fed with the H-CHO diets showing the worst growth performance. Increased of hepatic and muscle glycogen, hepatic somatic index and plasma metabolites (glucose, triglycerides and cholesterol) was linked to the increased of dietary carbohydrates. However, no hyperglycemia, no change of body compositions was found showing that dietary carbohydrates are efficiently used as an energy source in tilapia. Moreover, in contrats to the dietary protein-linked decreased of amino acid catabolic mRNA levels, no clear molecular adaptation for glycolysis, gluconeogenesis, lipogenesis in liver and glycolysis in muscle was detected except higher mRNA levels for glucose transporter in muscle. Our data suggest that these metabolic pathways at a molecular level are not the main actors explaining the efficient use of glucose in tilapia. Statement of relevanceOur study aimed at characterizing for the first time the molecular effects of increased dietary carbohydrates (dextrin) from 0% up to 50% in Nile tilapia during 45 and 90days. Our study confirmed that Nile tilapia can use high level of carbohydrates without any deregulation of glucose homeostasis. However, no strong regulations of expression for genes involved in glucose metabolism in liver and muscle - which could explain the reasons for an efficient use of carbohydrate by this fish species - were detected.

Investigation of antidiabetic potential of Phyllanthus niruri L. using assays for α-glucosidase, muscle glucose transport, liver glucose production, and adipogenesis

Phyllanthus niruri is used in herbal medicine for treatment of diabetes. The objective of this study was to investigate the antidiabetic potential of P. niruri, using assays for α-glucosidase, muscle glucose transport, liver glucose production and adipogenesis. α-Glucosidase inhibitory activity was performed on aqueous and ethanolic extract of aerial parts of P. niruri. The aqueous and ethanolic extract of P. niruri showed α-glucosidase inhibitory activity with IC50 values of 3.7 ± 1.1 and 6.3 ± 4.8 μg/mL, respectively. HR-bioassay/HPLC-HRMS and NMR analysis was used for identification of compounds. Corilagin (1) and repandusinic acid A (2) were identified as α-glucosidase inhibitors in the water extract of P. niruri with IC50 values of 0.9 ± 0.1 and 1.9 ± 0.02 μM, respectively. In in vitro cell-based bioassays, cells were treated for 18 h with maximal non-toxic concentrations of the ethanolic extract of P. niruri, which were determined by the lactate dehydrogenase cytotoxicity assay. The ethanolic extract of P. niruri was not able to reduce glucose-6-phosphatase activity. However, the extract increased deoxyglucose uptake in C2C12 muscle cells and enhanced adipogenesis in 3T3-L1 fat cells which has been reported for the first time. The present study demonstrated that P. niruri may thus have potential application for treatment and/or management of type 2 diabetes.

Improvement of obesity-linked skeletal muscle insulin resistance by strength and endurance training

Obesity-linked insulin resistance is mainly due to fatty acid overload in non-adipose tissues, particularly skeletal muscle and liver, where it results in high production of reactive oxygen species and mitochondrial dysfunction. Accumulating evidence indicates that resistance and endurance training alone and in combination can counteract the harmful effects of obesity increasing insulin sensitivity, thus preventing diabetes. This review focuses the mechanisms underlying the exercise role in opposing skeletal muscle insulin resistance-linked metabolic dysfunction. It is apparent that exercise acts through two mechanisms: (1) it stimulates glucose transport by activating an insulin-independent pathway and (2) it protects against mitochondrial dysfunction-induced insulin resistance by increasing muscle antioxidant defenses and mitochondrial biogenesis. However, antioxidant supplementation combined with endurance training increases glucose transport in insulin-resistant skeletal muscle in an additive fashion only when antioxidants that are able to increase the expression of antioxidant enzymes and/or the activity of components of the insulin signaling pathway are used.

Salsalate Activates Skeletal Muscle Thermogenesis and Protects Mice from High-Fat Diet Induced Metabolic Dysfunction

Salsalate plays beneficial roles for ameliorating hyperglycemia and dyslipidemia in type 2 diabetes patients, but the underlying mechanisms are still poorly understood. In this study, by administering salsalate to mice fed with high fat diet and examining how salsalate rectifies metabolic dysfunction in these obese mice, we found that salsalate stimulated body temperature and attenuated body weight gain without affecting food intake. Our results showed that salsalate application decreased lipid accumulation in liver and epididymal white adipose tissue (eWAT), inhibited hepatic gluconeogenesis and improved insulin signaling transduction in eWAT. In addition, salsalate increased the expression of genes related to glucose and fatty acid transport and oxidation in skeletal muscle. Our results also showed that expression of genes in mitochondrial uncoupling and mitochondrial electron transport are strengthened by salsalate. Moreover, sarcolipin (Sln) and sarcoplasmic reticulum Ca2+ ATPase 2 (Serca2) in skeletal muscle were enhanced in salsalate-treated mice. Together, our data suggest that the beneficial metabolic effects of salsalate may depend, at least in part, on skeletal muscle thermogenesis via activation of mitochondrial uncoupling and the axis of Sln/Serca2a.

Acylated and unacylated ghrelin do not directly stimulate glucose transport in isolated rodent skeletal muscle.

Emerging evidence implicates ghrelin, a gut‐derived, orexigenic hormone, as a potential mediator of insulin‐responsive peripheral tissue metabolism. However, in vitro and in vivo studies assessing ghrelin's direct influence on metabolism have been controversial, particularly due to confounding factors such as the secondary rise in growth hormone (GH) after ghrelin injection. Skeletal muscle is important in the insulin‐stimulated clearance of glucose, and ghrelin's exponential rise prior to a meal could potentially facilitate this. This study was aimed at elucidating any direct stimulatory action that ghrelin may have on glucose transport and insulin signaling in isolated rat skeletal muscle, in the absence of confounding secondary factors. Oxidative soleus and glycolytic extensor digitorum longus skeletal muscles were isolated from male Sprague Dawley rats in the fed state and incubated with various concentrations of acylated and unacylated ghrelin in the presence or absence of insulin. Ghrelin did not stimulate glucose transport in either muscle type, with or without insulin. Moreover, GH had no acute, direct stimulatory effect on either basal or insulin‐stimulated muscle glucose transport. In agreement with the lack of observed effect on glucose transport, ghrelin and GH also had no stimulatory effect on Ser473 AKT or Thr172 AMPK phosphorylation, two key signaling proteins involved in glucose transport. Furthermore, to our knowledge, we are among the first to show that ghrelin can act independent of its receptor and cause an increase in calmodulin‐dependent protein kinase 2 (CaMKII) phosphorylation in glycolytic muscle, although this was not associated with an increase in glucose transport. We conclude that both acylated and unacylated ghrelin have no direct, acute influence on skeletal muscle glucose transport. Furthermore, the immediate rise in GH in response to ghrelin also does not appear to directly stimulate glucose transport in muscle.

Acute bout of exercise induced prolonged muscle glucose transporter-4 translocation and delayed counter-regulatory hormone response in type 1 diabetes.

Previous studies have demonstrated that an acute bout of aerobic exercise induces a subsequent delayed onset of hypoglycemia among patients with type 1 diabetes. However, the mechanisms of exercise-induced hypoglycemia in type 1 diabetes are still unclear. Streptozotocin (STZ) was injected to 6-week-old male Wistar rats, and three days after STZ injection, animals were randomly assigned into 2 groups: STZ with insulin only (STZ) and STZ with insulin and exercise (STZ+EX). Normal Wistar rats with exercise were used as control (CON+EX). Insulin was intraperitoneally injected (0.5 U/kg) to both STZ groups (−0.5 h), and a bout of aerobic exercise (15 m/min for 30 min) was conducted at euglycemic conditions (0 h). Blood was collected at 0, 1, 3, and 5 h after exercise from the carotid artery. While the blood glucose level was stable during the post-exercise period (0–5 h) in the STZ and CON+EX groups, it decreased significantly only in the STZ+EX group at 3 h. Plasma glucagon, adrenalin, and noradrenalin levels significantly increased at 1 h in the STZ group, whereas significant hormonal responses were observed at 5 h in the STZ+EX group. In skeletal muscle glucose metabolism-related pathway, the level of glucose transporter-4 (GLUT-4) translocation was significantly higher at 1 h in the CON and STZ groups. However, in the STZ+EX group, these activations were maintained by 5 h, indicating a sustained glucose metabolism in the STZ+EX group. A single bout of aerobic exercise induced a delayed onset of hypoglycemia in STZ-treated rats. A prolonged enhancement of GLUT-4 translocation and delayed counter-regulatory hormone responses may have contributed to the induction of hypoglycemia.

The Kv1.3 channel blocker Vm24 enhances muscle glucose transporter 4 mobilization but does not reduce body-weight gain in diet-induced obese male rats

AimsVoltage-gated potassium channels 1.3 (Kv1.3) can be targeted to reduce diet-induced obesity and insulin resistance in mice. Since species-specific differences in Kv1.3 expression and pharmacology have been observed, we tested the effect of Vm24, a high-affinity specific blocker of Kv1.3 channels from Vaejovis mexicanus smithi, on body weight (BW), glucose tolerance and insulin resistance in diet-induced obese rats. Materials and methodsYoung adult male Wistar rats were switched to a high-fat/high-fructose (HFF) diet. Eighteen days later animals were divided in two groups: vehicle and Vm24 group. Subcutaneous injections were applied every other day until sacrifice 2months later. An additional cohort was maintained on standard chow. Key findingsThe HFF diet promoted obesity. Treatment with Vm24 did not alter various metabolic parameters such as food intake, BW gain, visceral white adipose tissue mass, adipocyte diameter, serum glucose, leptin and thyroid hormone concentrations, brown adipose tissue mass or uncoupling protein-1 expression, and insulin tolerance. Vm24 did reduce basal and glucose-stimulated serum insulin concentrations, serum C-peptide concentration, increased QUICKI, and tended to lower HOMA-IR. Vm24 treatment did not change the activation of insulin receptor substrate-1, but enhanced protein-kinase B activation and membrane glucose-transporter 4 (GLUT4) protein levels in skeletal muscle. SignificanceIn conclusion, in male rats, long-term blockade of Kv1.3 channels with Vm24 does not reduce weight gain and visceral adiposity induced by HFF diet; instead, it reduces serum insulin concentration, and enhances GLUT4 mobilization in skeletal muscle.

Enhanced insulin secretion and insulin sensitivity in young lambs with placental insufficiency-induced intrauterine growth restriction.

Intrauterine growth restriction (IUGR) is associated with persistent metabolic complications, but information is limited for IUGR infants. We determined glucose-stimulated insulin secretion (GSIS) and insulin sensitivity in young lambs with placental insufficiency-induced IUGR. Lambs with hyperthermia-induced IUGR (n = 7) were compared with control lambs (n = 8). GSIS was measured at 8 ± 1 days of age, and at 15 ± 1 days, body weight-specific glucose utilization rates were measured with radiolabeled d-glucose during a hyperinsulinemic-euglycemic clamp (HEC). IUGR lambs weighed 23% less (P < 0.05) than controls at birth. Fasting plasma glucose and insulin concentrations were not different between IUGR and controls for either study. First-phase insulin secretion was enhanced 2.3-fold in IUGR lambs compared with controls. However, second-phase insulin concentrations, glucose-potentiated arginine-stimulated insulin secretion, and β-cell mass were not different, indicating that IUGR β-cells have an intrinsic enhancement in acute GSIS. Compared with controls, IUGR lambs had higher body weight-specific glucose utilization rates and greater insulin sensitivity at fasting (1.6-fold) and hyperinsulinemic periods (2.4-fold). Improved insulin sensitivity for glucose utilization was not due to differences in skeletal muscle insulin receptor and glucose transporters 1 and 4 concentrations. Plasma lactate concentrations during HEC were elevated in IUGR lambs compared with controls, but no differences were found for glycogen content or citrate synthase activity in liver and muscle. Greater insulin sensitivity for glucose utilization and enhanced acute GSIS in young lambs are predicted from fetal studies but may promote conditions that exaggerate glucose disposal and lead to episodes of hypoglycemia in IUGR infants.

Immunohistochemical and histochemical characterization of intraosseous arteriovenous malformations of the jaws: analysis of 16 cases with emphasis on GLUT-1 immunophenotype

Intraosseous vascular lesions of the craniofacial region are rare and may cause diagnostic and therapeutic challenges. The purpose of this study was to characterize 16 cases of intraosseous arteriovenous malformations (AVMs) affecting the jaws. Immunohistochemical evaluation was performed using antibodies against α-smooth muscle actin (α-SMA), desmin, CD31, D2-40, and glucose transporter 1 (GLUT-1). Staining with elastic Verhoeff-Van Gieson and Masson trichrome histochemical stains was also performed. No gender predilection (female:male ratio=1:1) was observed, with patients' mean age being 50.8years (SD of ±13.9; range 28-71years). Predilection for the mandible was observed (12 of 16 [75%]). Immunohistochemically, diffuse endothelial CD31 staining was noted, and α-SMA strongly highlighted smooth muscle cells and pericytes. Desmin-positive vessels were identified in 9 of 16 AVMs (56.3%). D2-40 was uniformly negative in all specimens. AVMs were negative for GLUT-1 (11 of 14 [78.6%]) except for 2 cases (2 of 14 [14.3%]) exhibiting focal limited cytoplasmic GLUT-1 immunoreactivity. One case was equivocal for GLUT-1. Masson trichrome highlighted smooth muscle cells, and elastic fibers were identified in thick-walled arteries. AVMs of the jaws generally lack expression of GLUT-1, similar to soft tissue vascular malformations. Clinicoradiographic features of intraosseous AVMs in the present study were consistent with the findings of previous studies, although mean age was higher.