Molecular process of glucose uptake and glycogen storage due to hamamelitannin via insulin signalling cascade in glucose metabolism

Background/Aims: The liver is a vital organ in vertebrates and has a wide range of functions, including glucose absorption, glycogen storage and glucose production. Fibroblast growth factor (FGF)-21 is a metabolic regulator that is primarily produced by the liver. In this paper, we studied the effect of FGF-21 on glucose metabolism in the liver. Methods: The glucose uptake of cells was detected by 2-Deoxy-d-[3H] glucose; the synergy between insulin and FGF-21 was evaluated. The mRNA expression of GLUT1-4, G6Pase and PEPCK was detected by real-time PCR. Glycogen synthesis was examined by the anthrone method. Blood samples to monitor glucose in db/db diabetic mice were obtained by tail snip. Glucose metabolism in the liver and adipose tissues was observed by fluorescence microscopy. Results: In this study, FGF-21 stimulated glucose uptake by liver cells in both a dose and time-dependent manner, and at the same time, FGF-21 specifically stimulated GLUT1 expression in the liver cells. Furthermore, FGF-21 demonstrated a synergistic effect with insulin on glucose absorption, which is in accordance with enhanced GLUT-1 and -4 expression. Treatment with FGF-21 increased glycogen storage in liver cells. Consistent with in vitro results, FGF-21 lowered the plasma glucose level and stimulated GLUT1 expression and glycogen synthesis in db/db diabetic mice. Simultaneously, FGF-21 inhibited the gene expression of G6Pase and PEPCK. Conclusion: Our results suggest that FGF-21 clears up plasma glucose by stimulating glucose absorption in the liver of diabetic animals and decreases glucose release from the liver by inhibiting gluconeogenesis. Overall, these data indicate that the liver is an important target organ of FGF-21 to regulate glucose metabolism.

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Simvastatin profoundly impairs energy metabolism in primary human muscle cells

Endocrine Connections ◽

10.1530/ec-20-0444 ◽

2020 ◽

Vol 9 (11) ◽

pp. 1103-1113

Author(s):

Selina Mäkinen ◽

Neeta Datta ◽

Yen H Nguyen ◽

Petro Kyrylenko ◽

Markku Laakso ◽

...

Keyword(s):

Glucose Metabolism ◽

Glucose Uptake ◽

Human Skeletal Muscle ◽

Insulin Signalling ◽

Glycogen Synthesis ◽

Muscle Cells ◽

Acid Form ◽

Lactone Form ◽

Atp Production ◽

Human Skeletal Muscle Cells

Objectives Simvastatin use is associated with muscular side effects, and increased risk for type 2 diabetes (T2D). In clinical use, simvastatin is administered in inactive lipophilic lactone-form, which is then converted to active acid-form in the body. Here, we have investigated if lactone- and acid-form simvastatin differentially affect glucose metabolism and mitochondrial respiration in primary human skeletal muscle cells. Methods Muscle cells were exposed separately to lactone- and acid-form simvastatin for 48 h. After pre-exposure, glucose uptake and glycogen synthesis were measured using radioactive tracers; insulin signalling was detected with Western blotting; and glycolysis, mitochondrial oxygen consumption and ATP production were measured with Seahorse XFe96 analyzer. Results Lactone-form simvastatin increased glucose uptake and glycogen synthesis, whereas acid-form simvastatin did not affect glucose uptake and decreased glycogen synthesis. Phosphorylation of insulin signalling targets Akt substrate 160 kDa (AS160) and glycogen synthase kinase 3β (GSK3β) was upregulated with lactone-, but not with acid-form simvastatin. Exposure to both forms of simvastatin led to a decrease in glycolysis and glycolytic capacity, as well as to a decrease in mitochondrial respiration and ATP production. Conclusions These data suggest that lactone- and acid-forms of simvastatin exhibit differential effects on non-oxidative glucose metabolism as lactone-form increases and acid-form impairs glucose storage into glycogen, suggesting impaired insulin sensitivity in response to acid-form simvastatin. Both forms profoundly impair oxidative glucose metabolism and energy production in human skeletal muscle cells. These effects may contribute to muscular side effects and risk for T2D observed with simvastatin use.

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Testosterone activates glucose metabolism through AMPK and androgen signaling in cardiomyocyte hypertrophy

Biological Research ◽

10.1186/s40659-021-00328-4 ◽

2021 ◽

Vol 54 (1) ◽

Author(s):

Mayarling Francisca Troncoso ◽

Mario Pavez ◽

Carlos Wilson ◽

Daniel Lagos ◽

Javier Duran ◽

...

Keyword(s):

Glucose Metabolism ◽

Cardiac Hypertrophy ◽

Glucose Uptake ◽

Male Rats ◽

Cardiomyocyte Hypertrophy ◽

Mrna Levels ◽

Elevated Glucose ◽

Amp Activated Protein Kinase ◽

Cultured Cardiomyocytes

Abstract Background Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptake—via AMP-activated protein kinase (AMPK)—after acute treatment in cardiomyocytes. However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR). Methods Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of β-myosin heavy chain (β-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR). Results Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated β-mhc, Hk2 and Pfk2 mRNA levels. Conclusion These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.

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LncRNA HOTAIR regulates glucose transporter Glut1 expression and glucose uptake in macrophages during inflammation

Scientific Reports ◽

10.1038/s41598-020-80291-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Monira Obaid ◽

S. M. Nashir Udden ◽

Prasanna Alluri ◽

Subhrangsu S. Mandal

Keyword(s):

Immune Response ◽

Glucose Metabolism ◽

Glucose Uptake ◽

Immune Cells ◽

Glucose Transporter ◽

Energy Needs ◽

Glut1 Expression ◽

Lncrna Hotair ◽

Upstream Regulators ◽

Glucose Transporter Glut1

AbstractInflammation plays central roles in the immune response. Inflammatory response normally requires higher energy and therefore is associated with glucose metabolism. Our recent study demonstrates that lncRNA HOTAIR plays key roles in NF-kB activation, cytokine expression, and inflammation. Here, we investigated if HOTAIR plays any role in the regulation of glucose metabolism in immune cells during inflammation. Our results demonstrate that LPS-induced inflammation induces the expression of glucose transporter isoform 1 (Glut1) which controls the glucose uptake in macrophages. LPS-induced Glut1 expression is regulated via NF-kB activation. Importantly, siRNA-mediated knockdown of HOTAIR suppressed the LPS-induced expression of Glut1 suggesting key roles of HOTAIR in LPS-induced Glut1 expression in macrophage. HOTAIR induces NF-kB activation, which in turn increases Glut1 expression in response to LPS. We also found that HOTAIR regulates glucose uptake in macrophages during LPS-induced inflammation and its knockdown decreases LPS-induced increased glucose uptake. HOTAIR also regulates other upstream regulators of glucose metabolism such as PTEN and HIF1α, suggesting its multimodal functions in glucose metabolism. Overall, our study demonstrated that lncRNA HOTAIR plays key roles in LPS-induced Glut1 expression and glucose uptake by activating NF-kB and hence HOTAIR regulates metabolic programming in immune cells potentially to meet the energy needs during the immune response.

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Low-Dose Acrolein, an Endogenous and Exogenous Toxic Molecule, Inhibits Glucose Transport via an Inhibition of Akt-Regulated GLUT4 Signaling in Skeletal Muscle Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22137228 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7228

Author(s):

Ching-Chia Wang ◽

Huang-Jen Chen ◽

Ding-Cheng Chan ◽

Chen-Yuan Chiu ◽

Shing-Hwa Liu ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Metabolism ◽

Glucose Tolerance ◽

Protein Expression ◽

Glucose Uptake ◽

Glucose Transport ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Type 2 Diabetic

Urinary acrolein adduct levels have been reported to be increased in both habitual smokers and type-2 diabetic patients. The impairment of glucose transport in skeletal muscles is a major factor responsible for glucose uptake reduction in type-2 diabetic patients. The effect of acrolein on glucose metabolism in skeletal muscle remains unclear. Here, we investigated whether acrolein affects muscular glucose metabolism in vitro and glucose tolerance in vivo. Exposure of mice to acrolein (2.5 and 5 mg/kg/day) for 4 weeks substantially increased fasting blood glucose and impaired glucose tolerance. The glucose transporter-4 (GLUT4) protein expression was significantly decreased in soleus muscles of acrolein-treated mice. The glucose uptake was significantly decreased in differentiated C2C12 myotubes treated with a non-cytotoxic dose of acrolein (1 μM) for 24 and 72 h. Acrolein (0.5–2 μM) also significantly decreased the GLUT4 expression in myotubes. Acrolein suppressed the phosphorylation of glucose metabolic signals IRS1, Akt, mTOR, p70S6K, and GSK3α/β. Over-expression of constitutive activation of Akt reversed the inhibitory effects of acrolein on GLUT4 protein expression and glucose uptake in myotubes. These results suggest that acrolein at doses relevant to human exposure dysregulates glucose metabolism in skeletal muscle cells and impairs glucose tolerance in mice.

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High glucose and insulin in combination cause insulin receptor substrate-1 and -2 depletion and protein kinase B desensitisation in primary cultured rat adipocytes: possible implications for insulin resistance in type 2 diabetes

Acta Endocrinologica ◽

10.1530/eje.0.1480157 ◽

2003 ◽

Vol 148 (1) ◽

pp. 157-167 ◽

Cited By ~ 43

Author(s):

J Buren ◽

HX Liu ◽

J Lauritz ◽

JW Eriksson

Keyword(s):

Glucose Uptake ◽

High Glucose ◽

Insulin Treatment ◽

Insulin Signalling ◽

Binding Capacity ◽

Insulin Binding ◽

Rat Adipocytes ◽

Glucose Levels ◽

High Insulin ◽

The Right

OBJECTIVE: The purpose of this study was to investigate the cellular effects of long-term exposure to high insulin and glucose levels on glucose transport and insulin signalling proteins. DESIGN AND METHODS: Rat adipocytes were cultured for 24 h in different glucose concentrations with 10(4) microU/ml of insulin or without insulin. After washing, (125)I-insulin binding, basal and acutely insulin-stimulated d-[(14)C]glucose uptake, and insulin signalling proteins and glucose transporter 4 (GLUT4) were assessed. RESULTS: High glucose (15 and 25 mmol/l) for 24 h induced a decrease in basal and insulin-stimulated glucose uptake compared with control cells incubated in low glucose (5 or 10 mmol/l). Twenty-four hours of insulin treatment decreased insulin binding capacity by approximately 40%, and shifted the dose-response curve for insulin's acute effect on glucose uptake 2- to 3-fold to the right. Twenty-four hours of insulin treatment reduced basal and insulin-stimulated glucose uptake only in the presence of high glucose (by approximately 30-50%). At high glucose, insulin receptor substrate-1 (IRS-1) expression was downregulated by approximately 20-50%, whereas IRS-2 was strongly upregulated by glucose levels of 10 mmol/l or more (by 100-400%). Insulin treatment amplified the suppression of IRS-1 when combined with high glucose and also IRS-2 expression was almost abolished. Twenty-four hours of treatment with high glucose or insulin, alone or in combination, shifted the dose-response curve for insulin's effect to acutely phosphorylate protein kinase B (PKB) to the right. Fifteen mmol/l glucose increased GLUT4 in cellular membranes (by approximately 140%) compared with 5 mmol/l but this was prevented by a high insulin concentration. CONCLUSIONS: Long-term exposure to high glucose per se decreases IRS-1 but increases IRS-2 content in rat adipocytes and it impairs glucose transport capacity. Treatment with high insulin downregulates insulin binding capacity and, when combined with high glucose, it produces a marked depletion of IRS-1 and -2 content together with an impaired sensitivity to insulin stimulation of PKB activity. These mechanisms may potentially contribute to insulin resistance in type 2 diabetes.

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Differential glycolytic and glycogenogenic transduction pathways in male and female bovine embryos produced in vitro

Reproduction Fertility and Development ◽

10.1071/rd11080 ◽

2012 ◽

Vol 24 (2) ◽

pp. 344 ◽

Cited By ~ 10

Author(s):

M. Garcia-Herreros ◽

I. M. Aparicio ◽

D. Rath ◽

T. Fair ◽

P. Lonergan

Keyword(s):

Glucose Metabolism ◽

Protein Expression ◽

Glucose Uptake ◽

Glucose Transporter ◽

Glycogen Synthase ◽

Bovine Embryos ◽

High Concentration ◽

Glucose Transporter 1 ◽

Male And Female ◽

Glut 1

Previous studies have shown that developmental kinetic rates following IVF are lower in female than in male blastocysts and that this may be related to differences in glucose metabolism. In addition, an inhibition of phosphatidylinositol 3-kinase (PI3-K) inhibits glucose uptake in murine blastocysts. Therefore, the aim of this study was to identify and compare the expression of proteins involved in glucose metabolism (hexokinase-I, HK-I; phosphofructokinase-1, PFK-1; pyruvate kinase1/2, PK1/2; glyceraldehyde-3-phosphate dehydrogenase, GAPDH; glucose transporter-1, GLUT-1; and glycogen synthase kinase-3, GSK-3) in male and female bovine blastocysts to determine whether PI3-K has a role in the regulation of the expression of these proteins. Hexokinase-I, PFK-1, PK1/2, GAPDH and GLUT-1 were present in bovine embryos. Protein expression of these proteins and GSK-3 was significantly higher in male compared with female blastocysts. Inhibition of PI3-K with LY294002 significantly decreased the expression of HK-I, PFK-1, GAPDH, GSK-3 A/B and GLUT-1. Results showed that the expression of glycolytic proteins HK-I, PFK-1, GAPDH and PK1/2, and the transporters GLUT-1 and GSK-3 is regulated by PI3-K in bovine blastocysts. Moreover, the differential protein expression observed between male and female blastocysts might explain the faster developmental kinetics seen in males, as the expression of main proteins involved in glycolysis and glycogenogenesis was significantly higher in male than female bovine embryos and also could explain the sensitivity of male embryos to a high concentration of glucose, as a positive correlation between GLUT-1 expression and glucose uptake in embryos has been demonstrated.

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TXNIP links anticipatory unfolded protein response to estrogen reprogramming glucose metabolism in breast cancer cells

Endocrinology ◽

10.1210/endocr/bqab212 ◽

2021 ◽

Author(s):

Yuanzhong Wang ◽

Shiuan Chen

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Glucose Metabolism ◽

Glucose Uptake ◽

Unfolded Protein Response ◽

Cancer Cells ◽

Warburg Effect ◽

Breast Cancer Cells ◽

Unfolded Protein ◽

Protein Response

Abstract Estrogen and estrogen receptor (ER) play a fundamental role in breast cancer. To adapt the rapid proliferation of ER+ breast cancer cells, estrogen increases glucose uptake and reprograms glucose metabolism. Meanwhile, estrogen/ER activates the anticipatory unfolded protein response (UPR) preparing cancer cells for the increased protein production required for subsequent cell proliferation. Here, we report that thioredoxin-interacting protein (TXNIP) is an important regulator of glucose metabolism in ER+ breast cancer cells, and estrogen/ER increases glucose uptake and reprograms glucose metabolism via activating anticipatory unfolded protein response (UPR) and subsequently repressing TXNIP expression. By using two widely used ER+ breast cancer cell lines MCF7 and T47D, we showed that MCF7 cells express high TXNIP levels and exhibit mitochondrial oxidative phosphorylation (OXPHOS) phenotype, while T47D cells express low TXNIP levels and display aerobic glycolysis (Warburg effect) phenotype. Knockdown of TXNIP promoted glucose uptake and Warburg effect, while forced overexpression of TXNIP inhibited glucose uptake and Warburg effect. We further showed that estrogen represses TXNIP expression and activates UPR sensor inositol-requiring enzyme 1 (IRE1) via ER in the breast cancer cells, and IRE1 activity is required for estrogen suppression of TXNIP expression and estrogen-induced cell proliferation. Together, our study suggests that TXNIP is involved in estrogen-induced glucose uptake and metabolic reprogramming in ER+ breast cancer cells, and links anticipatory UPR to estrogen reprogramming glucose metabolism.

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Effect of training on the dose-response relationship for insulin action in men

Journal of Applied Physiology ◽

10.1152/jappl.1989.66.2.695 ◽

1989 ◽

Vol 66 (2) ◽

pp. 695-703 ◽

Cited By ~ 71

Author(s):

K. J. Mikines ◽

B. Sonne ◽

P. A. Farrell ◽

B. Tronier ◽

H. Galbo

Keyword(s):

Glucose Uptake ◽

Insulin Action ◽

Glycogen Synthase ◽

Vastus Lateralis ◽

Training Session ◽

Glycogen Storage ◽

Whole Body ◽

Vastus Lateralis Muscle ◽

Trained Subjects ◽

Insulin Responsiveness

Seven endurance-trained subjects [maximal O2 consumption (VO2max) 64 +/- 1 (SE) ml.min-1.kg-1] were subjected to three sequential hyperinsulinemic euglycemic clamps 15 h after having performed their last training session (T). Results were compared with findings in seven untrained subjects (VO2max 44 +/- 2 ml.min-1.kg-1) studied both at rest (UT) and after 60 min of bicycle exercise at 150 W (UT-ex). In T and UT-ex compared with UT, sensitivity for insulin-mediated whole-body glucose uptake was higher [insulin concentrations eliciting half-maximal glucose uptake being 44 +/- 2 (T) and 43 +/- 4 (UT-ex) vs. 52 +/- 3 microU/ml (UT), P less than 0.05] and responsiveness was higher [13.4 +/- 1.2 (T) and 10.9 +/- 0.7 (UT-ex) vs. 9.5 +/- 0.7 mg.min-1.kg-1 (UT), P less than 0.05]. Furthermore, responsiveness was higher (P less than 0.05) in T than in UT-ex. Insulin-stimulated O2 uptake and maximal glucose oxidation rate were higher in T than in UT and UT-ex. Insulin-stimulated conversion or glucose to glycogen and muscle glycogen synthase was higher in T than in UT and UT-ex. However, glycogen storage in vastus lateralis muscle was found only in UT-ex. No change in any glucoregulatory hormone or metabolite could explain the increased insulin action in trained subjects. It is concluded that physical training induces an adaptive increase in insulin responsiveness of whole-body glucose uptake, which does not reflect increased glycogen deposition in muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

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Effect of calorie restriction on in vivo glucose metabolism by individual tissues in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.276.4.e728 ◽

1999 ◽

Vol 276 (4) ◽

pp. E728-E738 ◽

Cited By ~ 14

Author(s):

Thomas J. Wetter ◽

Annie C. Gazdag ◽

David J. Dean ◽

Gregory D. Cartee

Keyword(s):

Glucose Metabolism ◽

Glucose Uptake ◽

Calorie Restriction ◽

The Other ◽

Index Formula ◽

Tracer Technique ◽

Ad Libitum ◽

White Fat ◽

Fat Pads

We evaluated the effects of 8 mo of calorie restriction [CR: 60% of ad libitum (AL) food intake] on glucose uptake by 14 tissues in unanesthetized, adult (12 mo) F344×BN rats. Glucose metabolism was assessed by the 2-[3H]deoxyglucose tracer technique at 1500 or 2100. Despite an ∼60% decline in insulinemia with CR, plasma 2-[3H]deoxyglucose clearance for CR was greater than for AL at both times. A small, CR-related decrease in glucose metabolic index ([Formula: see text]) occurred only at 1500 in the spleen and heart, and this decrease was reversed at 2100. In some tissues (cerebellum, lung, kidney, soleus, and diaphragm),[Formula: see text] was unaffected by diet, regardless of time. In the other tissues (brown fat, 3 white fat pads, epitrochlearis, plantaris, and gastrocnemius),[Formula: see text] was higher or tended to be higher for CR vs. AL at one or both times. These findings indicate that 8 mo of CR did not cause a continuous reduction in in vivo glucose uptake by any tissue studied, and, in several insulin-sensitive tissues, glucose uptake was at times greater for CR vs. AL rats.

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