Glucose Transport Activity Research Articles

Anthocyanins as Antidiabetic Agents-In Vitro and In Silico Approaches of Preventive and Therapeutic Effects.

Many efforts have been made in the past two decades into the search for novel natural and less-toxic anti-diabetic agents. Some clinical trials have assigned this ability to anthocyanins, although different factors like the food source, the amount ingested, the matrix effect and the time of consumption (before or after a meal) seem to result in contradictory conclusions. The possible mechanisms involved in these preventive or therapeutic effects will be discussed—giving emphasis to the latest in vitro and in silico approaches. Therapeutic strategies to counteract metabolic alterations related to hyperglycemia and Type 2 Diabetes Mellitus (T2DM) may include: (a) Inhibition of carbohydrate-metabolizing enzymes; (b) reduction of glucose transporters expression or activity; (c) inhibition of glycogenolysis and (d) modulation of gut microbiota by anthocyanin breakdown products. These strategies may be achieved through administration of individual anthocyanins or by functional foods containing complexes of anthocyanin:carbohydrate:protein.

Tacrolimus Induced Diabetes Presenting As Recurrent Pyelonephritis – A Rare Clinical Presentation

Tacrolimus is immunosuppressive agent used in a variety of skin disorders including vitiligo. Systemic Tacrolimus has been known to cause diabetes by inducing insulin resistance and increasing the activity and expression of glucose transporter , SGLT1 . In addition to this Tacrolimus has direct beta cell toxicity and subsequent insulin secretory defects. Although systemic absorption of tropical Tacrolimus is minimal but cases have been reported where tropical use of Tacrolimus has been associated with the blood levels above therapeutic range causing potential toxicity . Here we highlight a interesting case of a 22 year old female who was on treatment with Tacrolimus ointment for Segmental Vitiligo presented with features of pyelonephritis with past history of similar recurrent episodes and on further investigations was diagnosed to have New Onset Diabetes Mellitus with elevated serum Tacrolimus levels suggesting Tacrolimus induced beta cell dysfunction and insulin resistance thus making it an interesting and rare presentation of potential toxicity.

Effects of sterol-type elicitors on biochemical characterization of polysaccharides from Antrodia cinnamomea

Sterols play crucial roles in the physiological functions of organisms. In this study, we examined the chemical and biological effects of sterol type elicitors, including squalene, cholesterol and stigmasterol, on polysaccharides (PSs) of Antrodia cinnamomea. Characteristic studies revealed that squalene and stigmasterol effectively increased the glucose contents in PSs. Specifically, squalene not only induced glucose content but also increased fucose and mannose levels in PSs. However, cholesterol did not induce changes in sugar content in PSs. We further identified that high dose squalene significantly promoted 20% yield (w/w) of PSs as well as significantly increased the glucose, galactose and fucose contents. In addition, the major PSs species had a molecular weight of 21 kDa, and squalene significantly increased its area percentage to 43.54. The biological effects of PSs (squalenePS) from squalene treated A. cinnamomea presented anticancer activities by inhibiting lung cancer cell viability and colony formation. Functional studies revealed that squalenePS reduced the glucose uptake and lactate secretion may correlate to inhibition of AKT activity and downregulation of glucose transporter (GLUT1) expression. Our findings suggested squalene may play vital roles in regulating the PSs assembling and bioactivities of A. cinnamomea. Moreover, squalene may be a potential supplement for adding the culture medium of A. cinnamomea.

Early Signs of Impaired Gut Function Affect Daily Functioning in Patients With Advanced Cancer Undergoing Chemotherapy.

Gastrointestinal symptoms are common during chemotherapy, but underlying disturbances in gut function and their impact on daily life are unclear. This study investigates gut function in a heterogenous group of cancer patients with gastrointestinal symptoms during chemotherapy and its relation to anabolic response, muscle health, and daily functioning. In 16 patients with solid tumors (mostly stage III+IV) undergoing chemotherapy (T) and 16 healthy (H) matched controls, small-intestinal membrane integrity was measured by urine sugar tests. Protein digestion, absorption, and anabolic response to a conventional protein supplement were analyzed by stable-tracer methods. Muscle mass and strength and daily functioning were assessed. Eighty-one percent of T patients reported gastrointestinal symptoms. Small-intestinal membrane permeability was similar, but active glucose transport was lower in the T group (T, 35.5% ± 3.4% vs H, 48.4% ± 4.7%; P=.03). Protein digestion and absorption tended to be lower in the T group (0.67 ± 0.02 vs 0.80 ± 0.04; P=.08). Net protein anabolic response to feeding was comparable, although lower in cancer patients with recent weight loss. Gut permeability negatively correlated to hand grip strength, global health, and physical functioning, and active-transport capacity positively correlated to global health in the T group. Advanced cancer patients with gastrointestinal symptoms during chemotherapy, particularly those with recent weight loss, show signs of impaired gut function negatively affecting muscle health, daily functioning, and anabolic response to feeding.

Erythroid glucose transport in health and disease.

Glucose transport is intimately linked to red blood cell physiology. Glucose is the unique energy source for these cells, and defects in glucose metabolism or transport activity are associated with impaired red blood cell morphology and deformability leading to reduced lifespan. In vertebrate erythrocytes, glucose transport is mediated by GLUT1 (in humans) or GLUT4 transporters. These proteins also account for dehydroascorbic acid (DHA) transport through erythrocyte membrane. The peculiarities of glucose transporters and the red blood cell pathologies involving GLUT1 are summarized in the present review.

20-Hydroxyecdysone ameliorates metabolic and cardiovascular dysfunction in high-fat-high-fructose-fed ovariectomized rats

BackgroundEcdysteroids are polyhydroxylated steroids present in invertebrates and plants. 20-Hydroxyecdysone (20E) is the most common and the main biologically active compound of ecdysteroids. Previous studies have demonstrated anabolic and metabolic effects of 20E in mammals. However, it is unknown whether 20E has a positive effect on all aspects of cardiometabolic syndrome. The aims of this study were to investigate the favorable effect and possible underlying mechanisms of 20E in a rat model of cardiometabolic syndrome (CMS) induced by a high-calorie diet combined with female sex hormone deprivation.Methods20E (5 mg/kg, 10 mg/kg, or 20 mg/kg) or pioglitazone (PIO) (10 mg/kg) was intragastrically administered to sham-operated Sprague-Dawley female rats and ovariectomized rats fed a high-fat-high-fructose diet (OHFFD) for 8 weeks. The phenotypic characteristics of CMS, including central adiposity, blood pressure, serum lipid profile, glucose tolerance, insulin action on skeletal muscle glucose transport activity and hepatic protein expression, were determined.ResultsSome CMS characteristics were improved by 20E treatment. Rats treated with 20E had lower body weight, abdominal fat accumulation than rats treated with vehicle control without changes in total caloric intake and fat-free mass. OHFFD rats exhibited high blood pressure, but 20E-treated rats maintained normal blood pressure with a lower level of low-density lipoprotein (LDL)-cholesterol. Although 20E showed no positive effect on inducing insulin-mediated glucose transport in the skeletal muscle of OHFFD rats, 20E improved whole body glucose homeostasis. Analysis of protein expression in livers from 20E-treated rats revealed significantly increased expression of pAkt Ser473, pFOXO1 Ser256, pAMPKα Thr172, and FGF21.Conclusion20E treatment can alleviate cardiometabolic disorder caused by a high-fat-high-fructose diet and female sex hormone deprivation. In particular, 20E helps improve whole body insulin sensitivity in OHFFD rats, and the mechanisms that underlie this favorable effect are potentially mediated by the activation of AMPK and FGF21. The present study indicates that 20E could be an alternative therapeutic option for the prevention and alleviation of cardiometabolic syndrome.

Functional Expression of Sodium-Dependent Glucose Transporter in Amelogenesis

Glucose is an essential source of energy for mammalian cells and is transported into the cells by glucose transporters. There are 2 types of glucose transporters: one is a passive glucose transporter, GLUT (SLC2A), and the other is a sodium-dependent active glucose transporter, SGLT (SLC5A). We previously reported that the expression of GLUTs during tooth development is precisely and spatiotemporally controlled and that the glucose uptake mediated by GLUT1 plays a crucial role in early tooth morphogenesis and tooth size determination. This study aimed to clarify the localization and roles of SGLT1 and SGLT2 in murine ameloblast differentiation by using immunohistochemistry, immunoelectron microscopy, an in vitro tooth organ culture experiment, and in vivo administration of an inhibitor of SGLT1/2, phloridzin. SGLT1, which has high affinity with glucose, was immunolocalized in the early secretory ameloblasts and the ruffle-ended ameloblasts in the maturation stage. However, SGLT2, which has high glucose transport capacity, was observed in the stratum intermedium, papillary layer, and ameloblasts at the maturation stage and colocalized with Na+-K+-ATPase. The inhibition of SGLT1/2 by phloridzin in the tooth germs induced the disturbance of ameloblast differentiation and enamel matrix formation both in vitro (organ culture) and in vivo (mouse model). The expression of SGLT1 and SGLT2 was significantly upregulated in hypoxic conditions in the ameloblast-lineage cells. These findings suggest that the active glucose uptake mediated by SGLT1 and SGLT2 is strictly regulated and dependent on the intra- and extracellular microenvironments during tooth morphogenesis and that the appropriate passive and active glucose transport is an essential event in amelogenesis.

Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control.

Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical antipsychotic drug olanzapine increases body weight include central dysregulations leading to hyperphagia and direct peripheral impairment of fat cell lipolysis. Several investigations have reproduced in vitro direct actions of antipsychotics on rodent adipocytes, cultured preadipocytes, or human adipose tissue-derived stem cells. However, to our knowledge, no such direct action has been described in human mature adipocytes. The aim of the present study was to compare in human adipocytes the putative direct alterations of lipolysis by antipsychotics (haloperidol, olanzapine, ziprazidone, risperidone), antidepressants (pargyline, phenelzine), or anxiolytics (opipramol). Lipolytic responses to the tested drugs, and to recognized lipolytic (e.g., isoprenaline) or antilipolytic agents (e.g., insulin) were determined, together with glucose transport and amine oxidase activities in abdominal subcutaneous adipocytes from individuals undergoing plastic surgery. None of the tested drugs were lipolytic. Surprisingly, only opipramol exhibited substantial antilipolytic properties in the micromolar to millimolar range. An opipramol antilipolytic effect was evident against isoprenaline-, forskolin-, or atrial natriuretic peptide-stimulated lipolysis. Opipramol did not impair insulin activation of glucose transport but inhibited monoamine oxidase (MAO) activity to the same extent as antidepressants recognized as MAO inhibitors (pargyline, harmine, or phenelzine), whereas antipsychotics were inefficient. Considering its unique properties, opipramol, which is not associated with weight gain in treated patients, is a good candidate for drug repurposing because it limits exaggerated lipolysis, prevents hydrogen peroxide release by amine oxidases in adipocytes, and is thereby of potential use to limit lipotoxicity and oxidative stress, two deleterious complications of diabetes and obesity.

Changes in Placental Nutrient Transporter Protein Expression and Activity Across Gestation in Normal and Obese Women.

Fetal growth and development are dependent on placental nutrient transport. The syncytiotrophoblast (ST) and its two polarized plasma membranes, the maternal-facing microvillous membrane (MVM) and fetal-facing basal membrane (BM), represent the primary barrier in the human placenta, controlling transplacental transfer of small solutes. MVM and BM nutrient transporter expression and activity are increased in obese mothers delivering large babies. However, placental nutrient transporter expression and activity in early gestation in normal and obese women are largely unknown. Placentas from normal BMI and obese women at 6-24weeks of gestation, and term placentas from normal BMI women, were collected and ST plasma membranes isolated. The activity and protein expression of amino acid, glucose, and fatty acid transporters was assessed. No significant differences were observed in placental nutrient transporter protein expression between normal BMI and obese women in early pregnancy. In the MVM, system A amino acid activity (p = 0.02), SNAT2 (p < 0.0001), SNAT4 (p < 0.001), and GLUT1 (p = 0.01) protein expression were higher at term compared with early gestation. In contrast, MVM system L activity (p = 0.001), FATP4 (p = 0.03), and FATP6 (p = 0.009) protein expression were lower at term compared with early pregnancy. In the BM, there was no change in system L activity across gestation; however, BM FATP6 (p = 0.002) protein expression was lower at term compared with early pregnancy. These results suggest that placental transport of amino acids, glucose, and fatty acids are subjected to coordinated regulation across gestation to meet a fetal nutrient demand that changes with advancing pregnancy.

Beta-sitosterol attenuates insulin resistance in adipose tissue via IRS-1/Akt mediated insulin signaling in high fat diet and sucrose induced type-2 diabetic rats

In our previous study, we have shown that β-sitosterol (SIT) enhances glycemic control by increasing the activation of insulin receptor (IR) and glucose transporter 4 (GLUT4) proteins in adipose tissue. However, the possible role of SIT on the regulation of post-receptor insulin signal transduction is not known. Hence, the study was aimed to assess the effects of SIT on IRS-1/Akt mediated insulin signaling molecules in high-fat diet and sucrose induced type-2 diabetic rats. An oral effective dose of SIT (20 mg/kg b.wt) was given for 30 days to high fat-fed type-2 diabetic rats to find out whether SIT regulates IRS-1/Akt pathway of insulin signaling. The results showed that SIT attenuated the insulin receptor substrate-1 serine phosphorylation (p-IRS-1Ser636) (P = 0.0003). However, it up-regulated the mRNA expression of IR (P = 0.0036) and post-receptor insulin signaling molecules such as IRS-1 (P < 0.0001), β-arrestin-2 (P < 0.0058), Akt (P = 0.0008), AS160 (P = 0.0030) and GLUT4 (P < 0.0001) with a concomitant increase in the levels of IRS-1(P < 0.0001), p-IRS1-1Tyr632 (P = 0.0014), Akt (P < 0.0001), p-AktSer473/Thr308 (P = 0.0006; P < 0.0001), AS160 and p-AS160Thr642 (P < 0.0001) compared with type-2 diabetic rats. In Silico analysis was also performed and it showed that SIT possesses the greater binding affinity with β-arrestin-2, c-Src, and IRS-1 as well as Akt proteins and proved to attenuate insulin resistance as this study coincides with in vivo findings. Our present study clearly shows that SIT attenuates high fat diet-induced detrimental changes in adipose tissue. Therefore, it is concluded from the present findings that, SIT could be used as potential therapeutic phytomedicine for the management of type-2 diabetes.

Amino acid-based compound activates atypical PKC and leptin receptor pathways to improve glycemia and anxiety like behavior in diabetic mice

Differences in glucose uptake in peripheral and neural tissues account for the reduced efficacy of insulin in nervous tissues. Herein, we report the design of short peptides, referred as amino acid compounds (AAC) with and without a modified side chain moiety. At nanomolar concentrations, a candidate therapeutic molecule, AAC2, containing a 7-(diethylamino) coumarin-3-carboxamide side-chain improved glucose control in human peripheral adipocytes and the endothelial brain barrier cells by activation of insulin-insensitive glucose transporter 1 (GLUT1). AAC2 interacted specifically with the leptin receptor (LepR) and activated atypical protein kinase C zeta (PKCς) to increase glucose uptake. The effects induced by AAC2 were absent in leptin receptor-deficient predipocytes and in Leprdb mice. In contrast, AAC2 established glycemic control altering food intake in leptin-deficient Lepob mice. Therefore, AAC2 activated the LepR and acted in a cytokine-like manner distinct from leptin. In a monogenic Ins2Akita mouse model for the phenotypes associated with type 1 diabetes, AAC2 rescued systemic glucose uptake in these mice without an increase in insulin levels and adiposity, as seen in insulin-treated Ins2Akita mice. In contrast to insulin, AAC2 treatment increased brain mass and reduced anxiety-related behavior in Ins2Akita mice. Our data suggests that the unique mechanism of action for AAC2, activating LepR/PKCς/GLUT1 axis, offers an effective strategy to broaden glycemic control for the prevention of diabetic complications of the nervous system and, possibly, other insulin insensitive or resistant tissues.

AVE0991, a Nonpeptide Angiotensin 1-7 Receptor Agonist, Improves Glucose Metabolism in the Skeletal Muscle of Obese Zucker Rats: Possible Involvement of Prooxidant/Antioxidant Mechanisms.

Angiotensin 1-7 (Ang 1-7) enhances insulin signaling and glucose transport activity in the skeletal muscle. The aim of our study was to evaluate the effect of AVE0991, a nonpeptide Mas receptor agonist, on the metabolic parameters, expression of RAS components and markers of oxidative stress, and insulin signaling in the skeletal morbidly obese rats. 33-week-old male obese Zucker rats were treated with vehicle and AVE0991 (0.5 mg/kg BW/day) via osmotic minipumps for two weeks. Gene expressions were determined by qPCR and/or Western blot analysis in musculus quadriceps. The enzymatic activities were detected flourometrically (aminopeptidase A) or by colorimetric assay kit (protein tyrosine phosphatase 1B). Administration of AVE0991 enhanced insulin signaling cascade in the skeletal muscle, reflected by improved whole-body glucose tolerance. It has been shown that reactive oxygen species (ROS) have insulin-mimetic action in muscle. The expression of renin receptor, transcription factor PLZF, and prooxidant genes was upregulated by AVE0991 accompanied by elevated expression of genes coding enzymes with antioxidant action. Our results show that AVE0991 administration activates genes involved in both ROS generation and clearance establishing a new prooxidant/antioxidant balance on a higher level, which might contribute to the improved insulin signaling pathway and glucose tolerance of obese Zucker rats.

TRIM32 Promotes the Growth of Gastric Cancer Cells through Enhancing AKT Activity and Glucose Transportation.

Tripartite motif protein 32 (TRIM32), an E3 ubiquitin ligase, is a member of the TRIM protein family. However, the underlying function of TRIM32 in gastric cancer (GC) remains unclear. Here, we aimed to explore the function of TRIM32 in GC cells. TRIM32 was induced silencing and overexpression using RNA interference (RNAi) and lentiviral-mediate vector in GC cells, respectively. Moreover, the PI3K/AKT inhibitor LY294002 was used to examine the relationship between TRIM32 and AKT. Quantitative reverse-transcription PCR (qRT-PCR) and western blot were used to determine the mRNA and protein contents. The glucose analog 2-NBDG was used as a fluorescent probe for determining the activity of glucose transport. An annexin V-fluorescein isothiocyanate apoptosis detection kit was used to stain NCI-N87, MKN74, and MKN45 cells. Cell counting kit-8 (CCK-8) assay was used to examine cell proliferation. Our results indicated that TRIM32 was associated with poor overall survival of patients with GC. Moreover, TRIM32 was a proproliferation and antiapoptosis factor and involved in the AKT pathway in GC cells. Furthermore, TRIM32 possibly mediated the metabolism of glycolysis through targeting GLUT1 and HKII in GC cells. Importantly, TRIM32 silencing deeply suppressed the tumorigenicity of GC cells in vivo. Our findings not only enhanced the understanding of the function of TRIM32 but also indicated its potential value as a target in GC treatment.

Impact of viral disease hypophagia on pig jejunal function and integrity.

Pathogen challenges are often accompanied by reductions in feed intake, making it difficult to differentiate impacts of reduced feed intake from impacts of pathogen on various response parameters. Therefore, the objective of this study was to determine the impact of Porcine Reproductive and Respiratory Syndrome virus (PRRSV) and feed intake on parameters of jejunal function and integrity in growing pigs. Twenty-four pigs (11.34 ± 1.54 kg BW) were randomly selected and allotted to 1 of 3 treatments (n = 8 pigs/treatment): 1) PRRSV naïve, ad libitum fed (Ad), 2) PRRSV-inoculated, ad libitum fed (PRRS+), and 3) PRRSV naïve, pair-fed to the PRRS+ pigs’ daily feed intake (PF). At 17 days post inoculation, all pigs were euthanized and the jejunum was collected for analysis. At days post inoculation 17, PRRS+ and PF pigs had decreased (P < 0.05) transepithelial resistance compared with Ad pigs; whereas fluorescein isothiocyanate-dextran 4 kDa permeability was not different among treatments. Active glucose transport was increased (P < 0.05) in PRRS+ and PF pigs compared with Ad pigs. Brush border carbohydrase activity was reduced in PRRS+ pigs compared with PF pigs for lactase (55%; P = 0.015), sucrase (37%; P = 0.002), and maltase (30%; P = 0.015). For all three carbohydrases, Ad pigs had activities intermediate that of PRRS+ and PF pigs. The mRNA abundance of the tight junction proteins claudin 2, claudin 3, claudin 4, occludin, and zonula occludens-1 were reduced in PRRS+ pigs compared with Ad pigs; however, neither the total protein abundance nor the cellular compartmentalization of these tight junction proteins differed among treatments. Taken together, this study demonstrates that the changes that occur to intestinal epithelium structure, function, and integrity during a systemic PRRSV challenge can be partially explained by reductions in feed intake. Further, long term adaptation to PRRSV challenge and caloric restriction does reduce intestinal transepithelial resistance but does not appear to reduce the integrity of tight junction protein complexes.

Hypoxia preconditioning protects neuronal cells against traumatic brain injury through stimulation of glucose transport mediated by HIF-1\u03b1/GLUTs signaling pathway in rat

Hypoxia preconditioning (HPC), a well-established preconditioning model, has been shown to protect the brain against severe hypoxia or ischemia caused by traumatic brain injury (TBI), but the mechanism has not been well elucidated. Anaerobic glycolysis is the major way for neurons to produce energy under cerebral ischemia and hypoxia after TBI, and it requires large amounts of glucose. We hypothesized that glucose transport, as a rate-limiting step of glucose metabolism, may play key roles in the neuroprotective effects of HPC on cerebral cortex tissue against TBI. The aim of this study was to investigate the effect of HPC on glucose transport activity of rat cerebral cortex tissue after TBI through examining the gene expression of two major glucose transporters (GLUT1 and GLUT3) and their upstream target gene hypoxia-inducible factor-1α (HIF-1α). Sprague-Dawley rats were treated with HPC (50.47 kPa, 3 h/d, 3d). Twenty-four hours after the last treatment, the rats were injured using the Feeney free falling model. Cortex tissues of injured rats were removed at 1 h, 4 h, 8 h, 12 h, 1 day, 3 days, 7 d, and 14 days post-injury for histological analysis. Compared with TBI alone, HPC before TBI resulted in the expression of HIF-1α, GLUT1, and GLUT3 to increase at 1 h; they were markedly increased at 4 h, 8 h, 12 h, 1 day, and 3 days and decreased thereafter (p < 0.05). HPC before TBI could improve neuronal survival in rats by examining NeuN staining and observing reduced apoptosis by examining TUNEL staining. The result showed that HPC before TBI could increase the expression of GLUT1 and GLUT3. And through double immunofluorescence staining for GLUT3 and NeuN, the results strongly suggest that HPC improved glucose transport activity of neurons in rats with TBI. In summary, our results further support that HPC can improve hypoxia tolerance and attenuate neuronal loss of cerebral cortex in rats after TBI. The mechanism is mainly related to the increase of glucose transport activity through inducing GLUT1 and GLUT3 expression through upregulating HIF-1α expression.

Age-related Regulation of Active Amino Acid Transport in the Ileum of Broiler Chickens.

Broiler chickens grow rapidly within a short period; in this regard, our group had previously reported a decrease in the active transport of glucose in the intestines of broiler chickens with their growth. Therefore, in this study, we compared the active transport process of amino acids in the intestines between 1- and 5-week-old broilers using everted sac, Ussing chamber techniques, and real-time quantitative polymerase chain reaction (RT-PCR). The everted sac experiment showed that amino acids were absorbed from all segments of the small intestine in both age groups. There were no significant differences in the serosal to mucosal ratio between 1- and 5-week-old broilers. The Ussing chamber experiment showed that amino acid-induced short-circuit current (ΔIsc) in the ileal epithelium was significantly greater in the 5-week-old chickens than in the 1-week-old chicks (P=0.035). Membrane conductance, an indicator of ion permeability, showed no significant difference between the two groups. Moreover, the mRNA expression levels of amino acid transporters (ASCT1, EAAT3, B0AT1, and y+LAT1) were significantly elevated in the distal ileum of the 5-week-old broilers compared to those in the 1-week-old broilers (P<0.05), while no significant differences were observed in the mRNA levels of ATB0'+, B0/+AT, rBAT, CAT1, and CAT2 in both groups. Our study provides clear evidence that age-dependent increase in the active transport of amino acid across the ileal epithelium is caused by the high expression of Na+-dependent amino acid transporters in broiler chickens.

Glucose transporter expression and regulation following a fast in the ruby-throated hummingbird, Archilochus colubris.

Hummingbirds, subsisting almost exclusively on nectar sugar, face extreme challenges to blood sugar regulation. The capacity for transmembrane sugar transport is mediated by the activity of facilitative glucose transporters (GLUTs) and their localisation to the plasma membrane (PM). In this study, we determined the relative protein abundance of GLUT1, GLUT2, GLUT3 and GLUT5 via immunoblot using custom-designed antibodies in whole-tissue homogenates and PM fractions of flight muscle, heart and liver of ruby-throated hummingbirds (Archilochus colubris). The GLUTs examined were detected in nearly all tissues tested. Hepatic GLUT1 was minimally present in whole-tissue homogenates and absent win PM fractions. GLUT5 was expressed in flight muscles at levels comparable to those of the liver, consistent with the hypothesised uniquely high fructose uptake and oxidation capacity of hummingbird flight muscles. To assess GLUT regulation, we fed ruby-throated hummingbirds 1 mol l-1 sucrose ad libitum for 24 h followed by either 1 h of fasting or continued feeding until sampling. We measured relative GLUT abundance and concentration of circulating sugars. Blood fructose concentration in fasted hummingbirds declined (∼5 mmol l-1 to ∼0.18 mmol l-1), while fructose-transporting GLUT2 and GLUT5 abundance did not change in PM fractions. Blood glucose concentrations remained elevated in fed and fasted hummingbirds (∼30 mmol l-1), while glucose-transporting GLUT1 and GLUT3 in flight muscle and liver PM fractions, respectively, declined in fasted birds. Our results suggest that glucose uptake capacity is dynamically reduced in response to fasting, allowing for maintenance of elevated blood glucose levels, while fructose uptake capacity remains constitutively elevated promoting depletion of blood total fructose within the first hour of a fast.

Brain glucose and ketone utilization in brain aging and neurodegenerative diseases.

To meet its high energy demands, the brain mostly utilizes glucose. However, the brain has evolved to exploit additional fuels, such as ketones, especially during prolonged fasting. With aging and neurodegenerative diseases (NDDs), the brain becomes inefficient at utilizing glucose due to changes in glia and neurons that involve glucose transport, glycolytic and Krebs cycle enzyme activities, and insulin signaling. Positron emission tomography and magnetic resonance spectroscopy studies have identified glucose metabolism abnormalities in aging, Alzheimer's disease (AD) and other NDDs in vivo. Despite glucose hypometabolism, brain cells can utilize ketones efficiently, thereby providing a rationale for the development of therapeutic ketogenic interventions in AD and other NDDs. This review compares available ketogenic interventions and discusses the potential of the potent oral Ketone Ester for future therapeutic use in AD and other NDDs characterized by inefficient glucose utilization.

Role of LXR alpha in regulating expression of glucose transporter 4 in adipocytes — Investigation on improvement of health of diabetic patients

BackgroundThe insulin-responsive glucose transporter 4 (GLUT4) plays prominent role in insulin-mediated facilitated glucose uptake into most of the cell types, majorly muscle, liver and adipose tissue. Impaired expression of GLUT4 has been linked to insulin resistance and diabetes. In adipocytes, excess lipids that are generated from liver and by de novo lipogenesis utilizing blood sugar, are stored. There are various nuclear factors, co-factors and signaling mechanisms that directly and indirectly regulate glucose transporter activity in adipocytes. Molecular mechanism behind the regulation of GLUT4 in adipocytes has not elucidated well. ObjectiveTherefore, the present study focuses to explore the role of Liver X receptor- alpha (LXRα) on GLUT4 expression and the possible co-factors involved during in vitro adipogenesis and is assessed by modulating the activity of LXRα with specific agonist and antagonist ligands in 3T3L1 differentiated cells. ResultsThe results demonstrate that SR 9238 (300nM), a strong inhibitor of LXRα, decreased the rate of adipogenesis through reduced lipid droplet formation in adipocytes without affecting the cell morphology. The FMOC-l-Leucine (FLL), a known partial ligand of PPARγ, enhanced the expression of LXRα. Thus, it can be concluded that LXRα has a significant role in adipocyte differentiation and FLL interaction promoted the transcription of LXRα, thereby promotes GLUT4 expression. The results in this study identified the role of LXRα in regulating the expression of GLUT4 through SRC1. ConclusionThe study is of much relevance in treatment of diabetes and also opens the possibility of identifying new drug molecules that target LXRα.

Analysis of the Expression of Genes Related to Lipidic and Glycogenic Metabolism in Pleomorphic Adenomas and Carcinomas Ex Pleomorphic Adenomas

Abstract Introduction The carcinoma ex pleomorphic adenoma (CXPA) arises from a pleomorphic adenoma (PA) and is supposed to gain lipogenesis and glycogenesis during its malignant transformation. Increased lipogenesis is a characteristic of cancer cells, consisting of increased fatty acid synthesis by the enzyme fatty acid synthase (FASN) and by the accumulation of cytoplasmic lipid droplets, which express adipophilin. The increase in glycolytic metabolism has been associated with the activity of glycolytic enzymes and glucose transporters (GLUTs), whose expression is induced by HIF-1 (inducing factor of hypoxia 1). Objectives To analyze the gene expression of FASN, adipophilin, HIF-1α, and GLUT-1 in PA and CXPA samples. Methodology Gene expression analysis of the FASN, adipophilin, HIF1-α, and GLUT-1 genes was performed by the real-time PCR (qPCR) method. Fourteen cases of PA and 14 cases of CXAP were evaluated. Results FASN, adipophilin, HIF-1α, and GLUT-1 were more expressed in CXAP than in AP, although there was no significant difference between levels of adipophilin expression in CXPA and PA. Conclusion Increased expression of FASN, HIF1-α, and GLUT-1 in CXAP may be associated with malignant transformation of PA, while additional studies are needed to understand the role of adipophilin in PA carcinogenesis. Moreover, this is the first study to investigate the role of these genes in the malignant transformation of PA.