The Effects and Mechanism of Saponins of Panax notoginseng on Glucose Metabolism in 3T3-L1 Cells

This study was carried out to determine the effect of saponins of Panax notoginseng (SPN), a naturally occurring cardiovascular agent, on: (1) glucose uptake, (2) GLUT4 translocation and (3) glycogen synthesis in 3T3-L1 adipocytes. Electrospray ionization-Mass spectrometry (ESI-MS) was used to determine the structural characterization of the major active components of SPN. 3T3-L1 adipocytes were cultured and treated with 100 nM insulin alone or with 10, 50 and 100 μg/ml of SPN. [3H]2-deoxyglucose glucose uptake, GLUT4 immunofluorescence imaging and glycogen synthesis assay were carried out to determine the effects of SPN on glucose metabolism. Under insulin stimulation, SPN significantly increased glucose uptake in a dose-dependent manner; 50 μg/ml of SPN increased glucose uptake by 64% (p < 0.001). Immunofluorescence imaging and analysis have revealed that 50 and 100 μg/ml of SPN increased GLUT4 in the plasma membrane by 3-fold and 6-fold respectively (p < 0.001). Furthermore, the incorporation of D-[U-14C] glucose into glycogen was enhanced by 53% in 3T3-L1 cells treated with 100 μg/ml of SPN (p < 0.01 vs. insulin stimulation alone). SPN, a naturally occurring agent used to treat ischemic cardio-cerebral vascular disease in China, enhanced insulin-stimulated glucose uptake and glycogen synthesis in adipocytes. The results of this study indicate that SPN may have a therapeutic potential for hyperglycaemia in type 2 diabetes.

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Liver Plays a Major Role in FGF-21 Mediated Glucose Homeostasis

Cellular Physiology and Biochemistry ◽

10.1159/000487568 ◽

2018 ◽

Vol 45 (4) ◽

pp. 1423-1433 ◽

Cited By ~ 8

Author(s):

Mingyao Liu ◽

Hongwei Cao ◽

Yuting Hou ◽

Guopeng Sun ◽

Deshan Li ◽

...

Keyword(s):

Glucose Metabolism ◽

Glucose Uptake ◽

Plasma Glucose ◽

Glycogen Synthesis ◽

Glycogen Storage ◽

Glucose Absorption ◽

Liver Cells ◽

Dependent Manner ◽

Diabetic Mice ◽

Glut1 Expression

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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Muscle glucose uptake during and after exercise is normal in insulin-resistant rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.264.2.e167 ◽

1993 ◽

Vol 264 (2) ◽

pp. E167-E172 ◽

Cited By ~ 2

Author(s):

M. Kusunoki ◽

L. H. Storlien ◽

J. MacDessi ◽

N. D. Oakes ◽

C. Kennedy ◽

...

Keyword(s):

Glucose Uptake ◽

Glucose Transporter ◽

Treadmill Exercise ◽

Glycogen Synthesis ◽

Insulin Stimulation ◽

Adult Rats ◽

Insulin Resistant ◽

Glucose Levels ◽

Hindlimb Muscles ◽

Postexercise Recovery

It is not generally known whether impaired stimulation of muscle glucose metabolism in insulin-resistant states is specific to insulin stimulation. Our aim was to examine whether glucose uptake responded normally to exercise and postexercise recovery in insulin-resistant high-fat-fed (HFF) rats. Three-week HFF or Chow-fed [control (Con)] adult rats were studied 5 days after cannulation. Before, during, or immediately after (recovery) 50 min of treadmill exercise, bolus 2-deoxy-[3H]glucose and [14C]glucose were administered to estimate muscle glucose uptake (R'g) and glycogen incorporation rates. Mean exercise and recovery plasma glucose levels were similar in HFF and Con rats. In hindlimb muscles sampled, exercise and recovery R'g were similar in HFF and Con (e.g., red quadriceps exercise 104 +/- 13 vs. 113 +/- 8, recovery 45.3 +/- 3.9 vs. 47.7 +/- 4.5 mumol.100 g-1.min-1, respectively). Moreover, muscle glucose transporter (GLUT-4) content was not reduced in HFF rats. Glycogen resynthesis accounted almost entirely for R'g during recovery and was equivalent between groups. We conclude that impaired muscle glucose uptake and glycogen synthesis in HFF rats are characteristic of insulin but not of exercise or postexercise stimulation.

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Glucose metabolism in epitrochlearis muscle of acutely exercised and trained rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1986.250.2.e137 ◽

1986 ◽

Vol 250 (2) ◽

pp. E137-E143 ◽

Cited By ~ 2

Author(s):

T. A. Davis ◽

S. Klahr ◽

E. D. Tegtmeyer ◽

D. F. Osborne ◽

T. L. Howard ◽

...

Keyword(s):

Insulin Sensitivity ◽

Glucose Metabolism ◽

Glucose Uptake ◽

Acute Exercise ◽

Glycogen Synthesis ◽

Prior Training ◽

Glycogen Stores

Effects of insulin on glycogen synthesis (GS), glycolytic utilization (GU), and glucose uptake (GT) were studied in isolated epitrochlearis muscles from exercise-trained or sedentary rats during recovery from acute exercise or at rest. During the 1st h after acute exercise, the enhanced basal and insulin-stimulated GT was directed mainly toward replenishment of glycogen but basal GU was also increased. During the second through third hours after exercise, basal GS decreased but remained greater than rest and basal GU and GT returned to normal. Insulin sensitivity of these parameters was enhanced. Training alone reduced basal GS but enhanced insulin sensitivity of GT and GU. Training reduced the acute exercise-stimulated increase in basal and insulin sensitivity of GS during recovery from acute exercise, probably due to elevated glycogen stores. Thus recovery from acute exercise or training, either alone or in combination, enhances insulin stimulated GT in muscle; however, the increased glucose is primarily channeled toward GS after acute exercise, which is reduced by prior training and is directed to GU in trained animals either at rest or after acute exercise.

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Hepatic glucose metabolism during intraduodenal glucose infusion: impact of infection

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.279.1.e108 ◽

2000 ◽

Vol 279 (1) ◽

pp. E108-E115

Author(s):

Owen P. McGuinness ◽

Joseph Ejiofor ◽

D. Brooks Lacy ◽

Nancy Schrom

Keyword(s):

Glucose Metabolism ◽

Glucose Uptake ◽

Glycogen Synthesis ◽

Fibrin Clot ◽

Glucose Absorption ◽

Glucose Infusion ◽

Hepatic Glucose Metabolism ◽

Hepatic Glucose ◽

Glycogen Deposition ◽

Hepatic Glucose Uptake

We previously reported that infection decreases hepatic glucose uptake when glucose is given as a constant peripheral glucose infusion (8 mg · kg−1· min−1). This impairment persisted despite greater hyperinsulinemia in the infected group. In a normal setting, hepatic glucose uptake can be further enhanced if glucose is given gastrointestinally. Thus the aim of this study was to determine whether hepatic glucose uptake is impaired during an infection when glucose is given gastrointestinally. Thirty-six hours before study, a sham (SH, n = 7) or Escherichia coli-containing (2 × 109organisms/kg; INF; n = 7) fibrin clot was placed in the peritoneal cavity of chronically catheterized dogs. After the 36 h, a glucose bolus (150 mg/kg) followed by a continuous infusion (8 mg · kg−1· min−1) of glucose was given intraduodenally to conscious dogs for 240 min. Tracer ([3-3H]glucose and [U-14C]glucose) and arterial-venous difference techniques were used to assess hepatic and intestinal glucose metabolism. Infection increased hepatic blood flow (35 ± 5 vs. 47 ± 3 ml · kg−1· min−1; SH vs. INF) and basal glucose rate of appearance (2.1 ± 0.2 vs. 3.3 ± 0.1 mg · kg−1· min−1). Arterial insulin concentrations increased similarly in SH and INF during the last hour of glucose infusion (38 ± 8 vs. 46 ± 20 μU/ml), and arterial glucagon concentrations fell (62 ± 14 to 30 ± 3 vs. 624 ± 191 to 208 ± 97 pg/ml). Net intestinal glucose absorption was decreased in INF, attenuating the increase in blood glucose caused by the glucose load. Despite this, net hepatic glucose uptake (1.6 ± 0.8 vs. 2.4 ± 0.9 mg · kg−1· min−1; SH vs. INF) and consequently tracer-determined glycogen synthesis (1.3 ± 0.3 vs. 1.0 ± 0.3 mg · kg−1· min−1) were similar between groups. In summary, infection impairs net glucose absorption, but not net hepatic glucose uptake or glycogen deposition, when glucose is given intraduodenally.

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Prolonged suppression of glucose metabolism causes insulin resistance in rat skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.272.2.e288 ◽

1997 ◽

Vol 272 (2) ◽

pp. E288-E296 ◽

Cited By ~ 6

Author(s):

J. K. Kim ◽

J. H. Youn

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Glucose Metabolism ◽

Glucose Uptake ◽

Skeletal Muscles ◽

Glycogen Synthesis ◽

Whole Body ◽

Metabolic Fluxes ◽

Phosphate Inhibition ◽

Intracellular Glucose

To determine whether an impairment of intracellular glucose metabolism causes insulin resistance, we examined the effects of suppression of glycolysis or glycogen synthesis on whole body and skeletal muscle insulin-stimulated glucose uptake during 450-min hyperinsulinemic euglycemic clamps in conscious rats. After the initial 150 min to attain steady-state insulin action, animals received an additional infusion of saline, Intralipid and heparin (to suppress glycolysis), or amylin (to suppress glycogen synthesis) for up to 300 min. Insulin-stimulated whole body glucose fluxes were constant with saline infusion (n = 7). In contrast, Intralipid infusion (n = 7) suppressed glycolysis by approximately 32%, and amylin infusion (n = 7) suppressed glycogen synthesis by approximately 45% within 30 min after the start of the infusions (P < 0.05). The suppression of metabolic fluxes increased muscle glucose 6-phosphate levels (P < 0.05), but this did not immediately affect insulin-stimulated glucose uptake due to compensatory increases in other metabolic fluxes. Insulin-stimulated whole body glucose uptake started to decrease at approximately 60 min and was significantly decreased by approximately 30% at the end of clamps (P < 0.05). Similar patterns of changes in insulin-stimulated glucose fluxes were observed in individual skeletal muscles. Thus the suppression of intracellular glucose metabolism caused decreases in insulin-stimulated glucose uptake through a cellular adaptive mechanism in response to a prolonged elevation of glucose 6-phosphate rather than the classic mechanism involving glucose 6-phosphate inhibition of hexokinase.

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COMP-Ang-1 Improves Glucose Uptake in db/db Mice with Type 2 Diabetes

Hormone and Metabolic Research ◽

10.1055/a-1126-4402 ◽

2020 ◽

Vol 52 (09) ◽

pp. 685-688

Author(s):

Petra Baum ◽

Sabine Paeschke ◽

Nora Klöting ◽

Matthias Blüher ◽

Matthias Kern ◽

...

Keyword(s):

Glucose Metabolism ◽

Glucose Uptake ◽

Matrix Protein ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Vascular Endothelial ◽

Euglycemic Hyperinsulinemic Clamp ◽

Hba1c Levels ◽

Angiopoietin 1

AbstractCartilage oligomeric matrix protein (COMP)-Angiopoietin-1 is a potent angiopoietin-1 (Ang-1) variant that possesses therapeutic potential in angiogenesis and vascular endothelial dysfunction. Noteworthy, we have shown that COMP-Ang-1 improves hyperglycemia and neuroregeneration in ob/ob mice. However, the mechanism of the antidiabetic effect of COMP-Ang-1 is completely unknown. Therefore, we elucidated the diabetes protective molecular mechanisms of COMP-Ang-1 in diabetic db/db mouse model. COMP-Ang-1 (0.5 ng/g body weight) or aqueous NaCl solution was injected intraperitoneally per day in 21 consecutive days into 3-month old, male db/db mice (n=10 per group). Blood glucose and HbA1c levels were determined at baseline and 21 days after COMP-Ang-1 or NaCl treatment. The effect of COMP-Ang-1 on glucose uptake was investigated by euglycemic-hyperinsulinemic clamp studies and key genes of glucose metabolism were studied by Western blot analysis. Our findings indicate that COMP-Ang-1 improves glucose metabolism in a tissue specific manner by regulating HIF-1α transcriptional genes of GLUT-1 expression.

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Histone deacetylase 5 regulates glucose uptake and insulin action in muscle cells

Journal of Molecular Endocrinology ◽

10.1530/jme-12-0095 ◽

2012 ◽

Vol 49 (3) ◽

pp. 203-211 ◽

Cited By ~ 29

Author(s):

Suryaprakash Raichur ◽

Song Hooi Teh ◽

Kenji Ohwaki ◽

Vidhi Gaur ◽

Yun Chau Long ◽

...

Keyword(s):

Glucose Metabolism ◽

Glucose Uptake ◽

Histone Deacetylases ◽

Insulin Action ◽

Metabolic Flux ◽

Muscle Development ◽

Glycogen Synthesis ◽

Hdac Inhibitors ◽

Muscle Cells ◽

Histone Deacetylation

The class IIa histone deacetylases (HDACs) act as transcriptional repressors by altering chromatin structure through histone deacetylation. This family of enzymes regulates muscle development and phenotype, through regulation of muscle-specific genes including myogenin and MyoD (MYOD1). More recently, class IIa HDACs have been implicated in regulation of genes involved in glucose metabolism. However, the effects of HDAC5 on glucose metabolism and insulin action have not been directly assessed. Knockdown of HDAC5 in human primary muscle cells increased glucose uptake and was associated with increased GLUT4 (SLC2A4) expression and promoter activity but was associated with reduced GLUT1 (SLC2A1) expression. There was no change in PGC-1α (PPARGC1A) expression. The effects of HDAC5 knockdown on glucose metabolism were not due to alterations in the initiation of differentiation, as knockdown of HDAC5 after the onset of differentiation also resulted in increased glucose uptake and insulin-stimulated glycogen synthesis. These data show that inhibition of HDAC5 enhances metabolism and insulin action in muscle cells. As these processes in muscle are dysregulated in metabolic disease, HDAC inhibition could be an effective therapeutic strategy to improve muscle metabolism in these diseases. Therefore, we also examined the effects of the pan HDAC inhibitor, Scriptaid, on muscle cell metabolism. In myotubes, Scriptaid increased histone 3 acetylation, GLUT4 expression, glucose uptake and both oxidative and non-oxidative metabolic flux. Together, these data suggest that HDAC5 regulates muscle glucose metabolism and insulin action and that HDAC inhibitors can be used to modulate these parameters in muscle cells.

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Glucose metabolism and recycling by hepatocytes of OB/OB and ob/ob mice.

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1990.259.3.e389 ◽

1990 ◽

Vol 259 (3) ◽

pp. E389

Author(s):

J T Lahtela ◽

P A Wals ◽

J Katz

Keyword(s):

Glucose Metabolism ◽

Glucose Uptake ◽

Glycogen Synthesis ◽

Diabetic Mice ◽

Obese Mice ◽

Glucose Carbon ◽

Glucose Phosphorylation ◽

Total Utilization ◽

Mouse Hepatocytes ◽

Hydrolysis Of

Hepatocytes were prepared from livers of ob/ob (obese diabetic) mice and their lean (OB/OB) siblings that had been fasted for 24 h. The hepatocytes were incubated with [U-14C, 2-3H]-, [U-14C, 3-3H]-, and [U-14C, 6-3H]glucose at concentrations from 20 to 120 mM. 14C was recovered mainly in CO2, glycogen, and lactate. Tritium was recovered in water and glycogen. The yield in labeled products from [2-3H]glucose ranged from two to three times that from [U-14C]glucose. The yields from [3-3H]- and [6-3H]glucose were similar, and 1.3-1.7 times that from [U-14C]glucose. At 40 mM, total utilization of glucose by obese mice was about twice that for lean mice, but there was little difference at 120 mM. The rate of recycling between glucose and glucose 6-phosphate was calculated. An equation to calculate the rate of recycling of glucose from the 2-3H/U-14C ratio in glycogen is derived in the APPENDIX. Our results show that 1) the utilization of glucose by hepatocytes from obese diabetic mice exceeds that of their lean controls, 2) the rate of glucose phosphorylation in both groups greatly exceeds glucose uptake and the rate of glycogen synthesis, 3) glucose phosphorylation represents a difference between a high glucokinase rate and hydrolysis of glucose 6-phosphate, and 4) recycling of glucose carbon between glucose 6-phosphate and pyruvate occurs within mouse hepatocytes.

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Resveratrol Ameliorates High-Fat-Diet-Induced Abnormalities in Hepatic Glucose Metabolism in Mice via the AMP-Activated Protein Kinase Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/6616906 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Caiping Lu ◽

Hanying Xing ◽

Linquan Yang ◽

Kaiting Chen ◽

Linyi Shu ◽

...

Keyword(s):

Insulin Resistance ◽

Protein Kinase ◽

Glucose Metabolism ◽

Glucose Uptake ◽

High Fat Diet ◽

Blood Glucose Concentration ◽

Glycogen Synthesis ◽

Liver Fat ◽

High Fat ◽

Amp Activated Protein Kinase

Diabetes mellitus is highly prevalent worldwide. High-fat-diet (HFD) consumption can lead to liver fat accumulation, impair hepatic glycometabolism, and cause insulin resistance and the development of diabetes. Resveratrol has been shown to improve the blood glucose concentration of diabetic mice, but its effect on the abnormal hepatic glycometabolism induced by HFD-feeding and the mechanism involved are unknown. In this study, we determined the effects of resveratrol on the insulin resistance of high-fat-diet-fed mice and a hepatocyte model by measuring serum biochemical indexes, key indicators of glycometabolism, glucose uptake, and glycogen synthesis in hepatocytes. We found that resveratrol treatment significantly ameliorated the HFD-induced abnormalities in glucose metabolism in mice, increased glucose absorption and glycogen synthesis, downregulated protein phosphatase 2A (PP2A) and activated Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ), and increased the phosphorylation of AMP-activated protein kinase (AMPK). In insulin-resistant HepG2 cells, the administration of a PP2A activator or CaMKKβ inhibitor attenuated the effects of resveratrol, but the administration of an AMPK inhibitor abolished the effects of resveratrol. Resveratrol significantly ameliorates abnormalities in glycometabolism induced by HFD-feeding and increases glucose uptake and glycogen synthesis in hepatocytes. These effects are mediated through the activation of AMPK by PP2A and CaMKKβ.

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Requirement of Atypical Protein Kinase Cλ for Insulin Stimulation of Glucose Uptake but Not for Akt Activation in 3T3-L1 Adipocytes

Molecular and Cellular Biology ◽

10.1128/mcb.18.12.6971 ◽

1998 ◽

Vol 18 (12) ◽

pp. 6971-6982 ◽

Cited By ~ 269

Author(s):

Ko Kotani ◽

Wataru Ogawa ◽

Michihiro Matsumoto ◽

Tadahiro Kitamura ◽

Hiroshi Sakaue ◽

...

Keyword(s):

Protein Kinase ◽

Glucose Uptake ◽

Glucose Transporter ◽

Dominant Negative ◽

Dominant Negative Mutant ◽

Pleckstrin Homology Domain ◽

Dependent Manner ◽

Insulin Stimulation ◽

Negative Effects ◽

Stimulation Of

ABSTRACT Phosphoinositide (PI) 3-kinase contributes to a wide variety of biological actions, including insulin stimulation of glucose transport in adipocytes. Both Akt (protein kinase B), a serine-threonine kinase with a pleckstrin homology domain, and atypical isoforms of protein kinase C (PKCζ and PKCλ) have been implicated as downstream effectors of PI 3-kinase. Endogenous or transfected PKCλ in 3T3-L1 adipocytes or CHO cells has now been shown to be activated by insulin in a manner sensitive to inhibitors of PI 3-kinase (wortmannin and a dominant negative mutant of PI 3-kinase). Overexpression of kinase-deficient mutants of PKCλ (λKD or λΔNKD), achieved with the use of adenovirus-mediated gene transfer, resulted in inhibition of insulin activation of PKCλ, indicating that these mutants exert dominant negative effects. Insulin-stimulated glucose uptake and translocation of the glucose transporter GLUT4 to the plasma membrane, but not growth hormone- or hyperosmolarity-induced glucose uptake, were inhibited by λKD or λΔNKD in a dose-dependent manner. The maximal inhibition of insulin-induced glucose uptake achieved by the dominant negative mutants of PKCλ was ∼50 to 60%. These mutants did not inhibit insulin-induced activation of Akt. A PKCλ mutant that lacks the pseudosubstrate domain (λΔPD) exhibited markedly increased kinase activity relative to that of the wild-type enzyme, and expression of λΔPD in quiescent 3T3-L1 adipocytes resulted in the stimulation of glucose uptake and translocation of GLUT4 but not in the activation of Akt. Furthermore, overexpression of an Akt mutant in which the phosphorylation sites targeted by growth factors are replaced by alanine resulted in inhibition of insulin-induced activation of Akt but not of PKCλ. These results suggest that insulin-elicited signals that pass through PI 3-kinase subsequently diverge into at least two independent pathways, an Akt pathway and a PKCλ pathway, and that the latter pathway contributes, at least in part, to insulin stimulation of glucose uptake in 3T3-L1 adipocytes.

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