2941
Views & Citations1941
Likes & Shares
Phytol,
which is a product of chlorophyll degradation, is known to possess diverse
biological functions, including anti-obesity and anti-diabetes. Long-term
intake of phytol has beneficial effects on insulin resistance, obesity, and
diabetes via improvement of lipid metabolism. However, the exact mechanisms
involved and effects of immediate action such as single intake of phytol on
postprandial hyperglyceamia remain poorly understood. In present study, the
effects of phytol on glucose uptake and associated mechanisms were investigated
both in vitro and in vivo. We found that phytol induced insulin secretion by
RIN-5Fand directly stimulated glucose uptake via the activation of 5’
adenosine-monophosphate-activated protein kinase (AMPK) and phospatidylinositol-3
kinase/AKTin L6 myo tubes. Phytol also significantly suppressed the increase of
postprandial blood glucose levels via AMPK activation, not AKT, of skeletal
muscle and improved the abnormal patterns of insulin secretion in obese mice.
These findings confirm the glucose uptake mechanism, specifically in skeletal
muscle, by intake of dietary phytol and the immediate effects of phytol’s
health promoting ability.
Keywords: Phytol, Postprandial hyperglycemia, Obesity,
Insulin secretion, Glucose uptake
Abbreviations: AKT: Protein Kinase B; AMPK: 5’
Adenosine-monophosphate-activated Protein Kinase; AUC: Areas Under the Curve;
DMEM: Dulbecco’s Modified Eagle’s Medium; ELISA: Enzyme-linked Immunosorbent
Assay; FBS: Fetal Bovine Serum; GLUT4: Glucose Transporter 4; HFD: High-fat
Diet; IRS: Insulin Receptor Substrates; KHH: Krebs-Henseleit-Hepes; LFD:
Low-fat Diet; NAD: Nicotineamide Adenine Dinucleotide; OGTT: Oral Glucose
Tolerance Test; PI3K: Phosphatidylinositol-3 Kinase; PPARs: Peroxisome
Proliferator-activated Receptors; RPMI: Roswell Park Memorial Institute; RXR:
Retinoid-X-Receptor; SE: Standard Errors;T2D: Type 2 Diabetes
INTRODUCTION
Several
lifestyle factors affect the incidence of type 2 diabetes (T2D), while obesity
and weight gain dramatically increase the risk of developing this disease. As
an individual becomes more obese, they enter a more insulin-resistant state,
leading to impaired glucose tolerance that can potentially lead to the onset of
T2D [1]. Humans with T2D have normal or high insulin levels, but tissues, such
as the liver, skeletal muscle, and adipose tissue, become resistant to this
insulin. The pancreas compensate for this by producing large amounts of
insulin, which can result in impaired glucose transport into these tissue
[2,3].
The
skeletal muscle tissue accounts for up to 80% of insulin-mediated glucose
uptake in the postprandial state. The insulin signaling pathway that leads to
increased glucose uptake into muscle involves the binding of insulin to its
receptor, phosphorylation of downstream insulin receptor substrates (IRS), and
activation of phosphatidylinositol-3 kinase (PI3K) and protein kinase B (AKT),
which promotes the translocation of glucose transporter 4 (GLUT4) from an
intracellular pool to the plasma membrane [4]. In addition, 5′
adenosine-monophosphate-activated protein kinase (AMPK) also contributes to
enhanced glucose uptake.
This heterotrimeric
ser/thr kinase responds to an increase in the cellular AMP/ATP ratio [5], and
therefore, is activated by exercise/contraction, metformin, and
thiazolidinedione [6,7]. Consequently, AMPK has become an attractive
pharmacological target for the treatment of insulin resistance, obesity, and
T2D.
Phytol
(3,7,11,15-tetramethylhexaded-2-en-1-ol), is a plastidial isoprenoid that forms
part of the chlorophyll molecule [8,9]. It has previously been shown that
phytol is a precursor for vitamin E and vitamin K1 [10]. In addition, phytol is
a type of phytochemical-a bioactive, non-nutrient compound that is found in
plant foods such as fruits, vegetables, and grains. Many phytochemicals are
potent effectors of biological processes and are able to influence disease risk
via several complementary, overlapping mechanisms [11]. Because almost all
phytosynthetic organisms contain chlorophyll, phytol is abundant in various
plant foods, including green leafy vegetables, for example, spinach is known to
contain 62 mg phytol per 100 g wet weight [12]. It has been suggested that
chlorophyll is only partially digested, with the phytol moiety being released
into the body. However, chlorophyllase, which catalyzes the hydrolysis of
chlorophyll to form chlorophyllide and phytol, actually promotes chlorophyllide
formation upon disruption of leaf cells or when it is artificially mistargeted
to the chloroplast [13]. Therefore, it is possible that humans could readily
digest the phytol that is contained in green leafy vegetables.
Previous
animal studies have indicated that phytol may have anticancer and antoxidative
effects [14,15]. In addition, long-term intake of phytol may help with the
management of insulin resistance and metabolic disorders, which accompany
diabetes and/or obesity, by activating the major regulators of lipid
metabolism, including retinoid-X-receptor (RXR) and peroxisome
proliferator-activated receptors (PPARs) [16,17]. We previously reported that
phytol increased the level of human blood nicotineamide adenine dinucleotide
(NAD), strongly linked to diabetes, in the rat liver [18,19]. However, the
effects of immediate action such as single intake of phytol on postprandial
hyperglyceamia via enhancing glucose uptake and insulin secretion have not
previously been reported. Thus, the present study investigated the promotional
effects of phytol on glucose uptake, its mechanisms in myotubes, insulin
secretion in pancreatic β-cells, and the effects of a single administration of
phytol on increases in postprandial blood glucose and insulin levels in obese
mice fed a high-fat diet.
MATERIALS AND METHODS
In vitro studies
In vitro
cell culture of RIN-5F and L6 myotubes: RIN-5F cells from the RIN-m rat islet
cell line were purchased from the American Type Culture Collection (VA, USA).
The cells were maintained in Roswell Park Memorial Institute (RPMI) 1640
supplemented with 10% (v/v) heat-inactivated fetal bovine serum (FBS) (Biowest,
Nuaillé, France), streptomycin (100 μg/mL), and penicillin G (100 U/mL) (10%
FBS/RPMI 1640) at 37°C in a 5% CO2 atmosphere. L6 myoblast cells were purchased
from the European Collection of Animal Cell Culture (Wiltshire, UK) and
cultured in Dulbecco’s modified Eagle’s medium (DMEM) with L-glutamine,
streptomycin, penicillin G, and 10% FBS (10% FBS/DMEM) at 37°C in a humidified
5% CO2 incubator.
Assay of
insulin secretion activity: The RIN-5F cells had been derived from rat
pancreatic β-cells and were used to evaluate insulin secretion activity
[20-22]. The cells were cultured on 24-well plates at a cell density of 4 × 105
cells/mL. After 72 h incubation, the medium in each well was replaced with 1 mL
fresh medium, and the cells were incubated for a further 24 h. The medium was
then removed from each well, and the cells were washed with fresh medium
supplemented with 1% FBS.
Various
concentrations of phytol (Wako, Osaka, Japan)or insulin (wako)were added to the
wells, and the cells were incubated for 3h. An aliquot was then withdrawn from
each well and centrifuged to separate the cells. The concentration of insulin
in the medium was determined using an enzyme-linked immunosorbent assay (ELISA)
(Morinaga Institute of Biological Science, Yokohama, Japan). The phytol was
dissolved in dimethyl sulfoxide (DMSO) at a final concentration of 0.1% (v/v),
and the insulin secretion level of samples with and without phytol were then
compared.
Determination
of glucose consumption by cultured L6 myotubes: A glucose consumption assay was
performed on the L6 myotubes using the modified method of Doi et al. [23]. The
L6 myoblasts (1 × 105 cells/mL)were maintained under subconfluent conditions in
24-well plates, and were cultured in 10% FBS/DMEM containing 5.5 mM glucose.
The cells were differentiated over 8 days by reducing the serum concentration
to 1% FBS containing either 5.5 mM glucose or 25 mM high glucose [20,24]. The
myotubes were then maintained in filter-sterilized Krebs-Henseleit-Hepes buffer
(KHH buffer; pH 7.4, 0.164 g/L KH2PO4, 0.192 g/L CaCl2 – 2H2O, 0.298 g/L MgSO4
– 7H2O, 0.36 g/L KCl, 2.38 g/L Hepes, 6.9 g/L NaCl, and 2.1 g/L NaHCO3)
containing 0.1% bovine serum albumin, 2 mM pyruvate sodium, 5mM glucose, and
18mM mannitol for 2 h. The medium was then
removed and replaced with 5 mMglucose and 17.5mM mannitol containing various
concentration of phytol or insulin. The medium was collected at time zero and 4
h, and the glucose concentration was measured using the glucose oxidase method
with the glucose CII-test (Wako). Glucose consumption was then calculated by
subtracting the remaining glucose at the 4 h time point from that in the medium
at time zero.
Immunoblot
analysis: Using a similar method to the glucose consumption assay, L6 myoblasts
(1 × 105 cells/mL) were seeded in 100 mm dishes and were maintained under
subconfluent conditions in 10% FBS/DMEM containing 5.5 mM glucose. The cells
were differentiated over8 days, following which the myotubes were placed in KHH
buffer containing 0.1% bovine serum albumin, 2 mM sodium pyruvate, 5 mM
glucose, and 18 mM mannitol for 2 h. The medium was then removed and replaced
with 5 mM glucose, 17.5mM mannitol, and various concentration of phytol. After
3 h, the cells were collected and stored at– 80oC until further
analysis.
The cells
were rinsed with Ca2+/Mg2+ free phosphate-buffered saline,scraped from the
100mm dishes, and collected in a total volume of 100 μL of lysate buffer (50mM
Tris (pH 8.0), 10mM NaF, 1mM Na3VO4, 0.5 mM 2-mercaptoethanol, 0.1% Triton X-100,
1% protease inhibitor cocktail (Calbiochem, CA, USA)) [25].The cells were then
immediately homogenized. The protein concentration of the samples for
immuoblotting was determined using the PierceTM BCA Protein Assay Kit (Thermo
Scientific, MA, USA). Immunoblot detection was performed using Ez-Capture MG
(ATTO, Tokyo, Japan). An anti-rat AKT antibody (#9272), anti-rat phosphorylated
AKT antibody (#9271), anti-rat AMPK antibody (#2532),anti-rat phosphorylated
AMPK antibody (#2531), and anti-rat β-actin (#4967) were obtained from Cell
Signaling Technology (MA, USA). Anti-rabbit (W4011) IgG was purchased from
Promega Corporation (WI, USA).
In vivo studies
Animals: Four-week-old male C57BL/6J mice were
purchased from SLC Japan (Shizuoka,
Japan)and fed a commercial CE-2 pellet diet (Clea Japan, Tokyo, Japan) for 7
days. The mice were then assigned to one of five experimental groups (n = 6),
each of which contained mice of equal weights. The animals in four of these
groups were fed a 45% high-fat diet (HFD) (D12451; Research Diets, NJ, USA),
while the fifth group received a low-fat diet (LFD) (D12450B; Research Diets).
The animals were placed in individual cages, maintained in a
temperature-controlled room (23 ± 2°C) on a 12 h light/dark cycle, and water and
food were provided ad libitum. The study was approved by the Institution Animal
Care and Use Committee of the Tokyo University of Marine Science and
Technology, Japan.
Oral glucose tolerance test: An oral glucose tolerance test
(OGTT) was performed on mice fed HDF or LFD fed for 4 months [26]. The
administration solutions were prepared with glucose solutions containing 0.5%
carboxymethyl-cellulose and 0 mg/kg body weight (bw) phytol (HFD or LFD
groups), or 12.5, 25, or 50 mg/kg bw phytol (HFD + phy 12.5, HFD + phy 25, or
HFD + 50 mg/kg bw groups, respectively), and were orally administered at 2 g/kg
body weight glucose following overnight fasting. Blood samples were collected
from the tail vein before, and 15, 30, 60, and 90 min after the administration.
Serum glucose levels were determined using the glucose CII-test (Wako), and
serum insulin was measured using ELISA kits (Morinaga Institute of Biological
Science). All kits were used in accordance with the manufacturer’s protocols.
At the
end of the treatment period, the mice were anesthetized and sacrificed with
isoflurane (Wako) following overnight fasting. Subsequently, subcutaneous and
visceral fat samples were collected, with visceral fat defined as the sum of
the mesenteric, epididymal, and retroperitoneal fat pad weight.
Immunoblot analysis: Using a similar method to OGTT,
each groups (LFD, HFD, HFD + phy 12.5, HFD + phy 25, and HFD + 50 mg/kg bw)
were orally administered at 2 g/kg body weight glucose with/without phytol
following overnight fasting. Then mice were anesthetized and sacrificed with
isoflurane 15-20 min after the administration and skeletal muscle samples were
obtained. The tissues were snap-frozen in liquid nitrogen and stored – 80oC
until needed for further analysis.
The
protein concentration of the samples for immunoblotting, which was homogenized
with lysate buffer, was determined by using the Pierce TM BCA Protein Assay
Kit.
Statistical analysis
Values
were expressed as the means± standard errors (SE) of the mean. Differences
between the treatment groups were identified using Dunnett’s multiple
comparison tests and were considered significant when p was < 0.05 and <
0.01.Calculations of areas under the curve (AUC) for plasma glucose and insulin
responses were based on the trapezoid rule.
RESULTS AND DISCUSSION
In vitro,
phytol stimulates insulin secretion and glucose uptake via activation of AKT
and AMPK
To
investigate the effect of phytol on insulin secretion, we examined insulin
secretion by RIN-5F cells, a rat islet tumor cell line. Phytol significantly
stimulated insulin secretion in a dose dependent manner (Figure 1).
In
animals, phytol is converted to phytanic acid in several tissues [9,27]. The
finding suggests that the insulin sensitizing/anti-diabetic effect of phytol is
not only mediated by partly from activation of nuclear receptors and
heterodimerization of RXR with PPARγ by phytanic acid [16], specifically in
human skeletal muscle and adipocytes, but also act directly to pancreatic
β-cells. Furthermore, because phytol is known to have antioxidantive effects
[15], it may reduce oxidant stress in RIN-5F cells.
The
effect of phytol on glucose uptake under normal glucose (5.5 mM) and high
glucose (25mM) conditions was examined in L6 cells. These glucose conditions
mimicked the normoglycemic condition and the hyperglycemic condition in
diabetes, respectively [20,24]. Under normal glucose conditions, phytol
concentrations of 50–200 μM significantly stimulated glucose uptake in a
dose-independent manner (Figure 2A).
In contrast, under high glucose conditions, maximum increase in glucose uptake
was observed at 50 μM phytol (Figure
2B).
Therefore,
it can be concluded that 50 μM is the optimal phytol concentration for normal
glucose conditions, while < 50 μM is optimal for high glucose conditions.
Importantly, these data showed that phytol had the same effect on glucose
uptake in myotubes as observed with maximum insulin stimulation. A further
investigation was performed to examine whether phytol increases glucose uptake
in myoblasts with low GLUT4 expression, which are known not to respond to insulin
[28]. In these L6 myoblasts, glucose uptake was not significantly increased by
phytol, indicating that it may act by modulating GLUT4 translocation and/or
activity (data not shown).
The
effect of phytol on AKT phosphorylation was examined. Insulin stimulates the
phosphorylation of both residues associated with AKT activation (Thr308 and
Ser473), but200 μM phytol also activated Ser473 in L6 cells (Figure 3A).A previous study showed that
phytol strongly activates PPARα and also acts as a ligand, binding to this
transcriptional factor [17]. PPARα expresses in skeletal muscle as well as
heart and liver [29] and increases fatty acid oxidation by inducing AMPK
activation [30]. Furthermore, several other phytochemicals have also been found
to activate AMPK [31]. Therefore, we hypothesized that phytol would also
activate AMPK in skeletal muscle. Supporting this, treatment of the cells with
phytol resulted in a significant increase in AMPK-Thr172 phosphorylation, which
is a known indicator of AMPK activation (Figure
3B), whereas AMPK was not activated by insulin. These phenomena by phytol
were indicated in a dose-dependent manner. These results suggest that phytol
enhance glucose uptake in the skeletal muscle by inducing GLUT4 translocation
through activation of weak AKT and strong AMPK. Furthermore, activation of both
AKT and AMPK in skeletal muscle by phytol may contribute to the
insulin-sensitizing/anti-diabetic effect following its intake.
Abnormal glucose metabolism in diet-induced
obesity mice is improved by a single administration of phytol
Mice
which were fed the HFD for four months became obese, exhibiting higher final
body weights, and more subcutaneous and visceral fat than normal mice that
received the LFD over the same period (Table
1).
The OGTT
showed that the administration of a glucose solution without phytol resulted in
the serum glucose levels in the HFD group becoming significantly higher than
those in the LFD group for 90 min after administration (Figure 4A), indicating that the diet-induced obese mice had abnormal
glucose metabolism. In contrast, a single administration of a glucose solution
containing 12.5 or 50 mg/kg bw phytol to obese mice significantly suppressed
postprandial hyperglycemia compared with the HFD group. The serum glucose level
in obese mice that were administered 25 mg/kg bw phytol was not significantly
higher than the HFD group after 15 min. However, the AUC for serum glucose
levels was significantly lower in all phytol groups compared with the HFD group
(Figue 4B). This in vivo phenomenon
may be similar to the earlier finding that phytol enhances glucose uptake in L6
myoblasts in vitro.
Additionally,
the obese mice that administrated 25 and 50 mg/kg phytol in a single
administration tended to be suppressed rapidly increasing and reducing of serum
insulin secretion from 15 min to 30 min after administration (Figure 5A). However, the AUC for serum
insulin levels in these phytol groups was not significantly different, compared
with that in HFD group (Figure 5B).Thus,
a single administration of phytol improved the abnormal pattern of insulin
secretion in obese mice without affecting the amount of insulin secretion. This
in vivo phenomenon did not agree with the finding that phytol promotes insulin
secretion in cultured RIN-5F cells in vitro. We hypothesize that phytol has
different mechanisms acting on the pancreas depending on intake period. It has
been reported that Asian patients with T2D are physiologically characterized by
lower β-cell function and a lesser degree of insulin resistance, compared with
their Caucasian counterparts [32]. A once-daily intake of phytol could
contribute much to enhance β-cell function in T2D patients of the world,
specifically many Asian countries. Moreover, the improvement mechanism of
insulin secretion by phytol may be similar to the results of vitamin E, one of
phytol metabolites [33].
We also
examined that the effects of phytol on AKT and AMPK phosphorylation in skeletal
muscle of obese mice. In mice administered phytol, only AMPK-Thr172
phosphorylation was drastically increased (Figure
6A and B). This in vivo phenomenon did not agree with the finding that
phytol induced activation of AKT-Ser473.In order to clarify whether phytol
induce directly AMPK activation in skeletal muscle and L6 cell, we demonstrated
by using one of A MPK inhibitors, dolsomolphin, in L6 cell and found that
co-adding dorsomolphin inhibited AMPK phosphorylation by phytol at 50−200μM
(data not shown).It is possible that phytol activates strongly AMPK
phosphorylation over AKT in vivo and enhances glucose uptake, especially in
skeletal muscle.
High-fat diets
have been shown to result in increased body weight and diabetes in various
strains of mice and rats. Indeed, C57BL/6J mice are a particularly good model mimicking
human metabolic derangements that are observed in obesity because when fed ad
libitum with a HFD, these mice develop obesity, hyperinsulinemia,
hyperglycemia, and hypertension, but when fed ad libitum to chow diet, they
remain lean without metabolic abnormalities [34]. The single administration of
phytol to obese mice that were fed a HFD for four months suppressed the
increases in postprandial blood glucose levels that occurred in the HFD group.
Previous studies have shown that phytol is rapidly converted into phytanic acid
in the tissues of mammals such as rats and humans [9,27]. However, Golerich et
al. [35] reported that phytol accumulated in the liver of rats that were fed a
phytol-enriched diet for 7 days. Thus, these in vivo results are likely to be
caused by the administration of phytol.
CONCLUSIONS
The present study demonstrates, for the
first time, that phytol improves the abnormal pattern of insulin secretion in
pancreatic β-cells and directly stimulates muscle glucose uptake independent of
insulin via AMPK activation in vivo. Moreover, a single administration of
phytol improved glucose tolerance in obese mice that were exhibiting abnormal
insulin secretion. Besides previous studies on the effects of the long-term
intake of phytol in rodents, these data confirmed the glucose uptake mechanism
by intake of dietary phytol and the immediate effects of phytol’s health
promoting ability.
ACKNOWLEDGEMENTS
The authors are thankful to KENKO Mayonnaise
Co., Ltd. for the financial support.
FUNDING RESOURCE
This research did not receive any specific grant
from funding agencies in the public, commercial, or not-for-profit sectors.
- Hu FB, Manson JE, Stampfer MJ, Colditz G, Liu S, et al. (2001)
Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. The N
Engl J Med 345: 790-797.
- DeFronzo
RA, Tripathy D (2009) Skeletal muscle insulin resistance is the primary
defect in type 2 diabetes. Diabetes Care 32: 157-163.
- Stanford
KI, Goodyear LJ (2014) Exercise and type 2 diabetes: molecular mechanisms
regulating glucose uptake in skeletal muscle. Advan Physiol Educat 38:
308-314.
- Saltiel
AR, Kahn CR (2001) Insulin signaling and the regulation of glucose and
lipid metabolism. Nature 414: 799-806.
- Towler
MC, Hardie DG (2007) AMP-activated protein kinase in metabolic control and
insulin signaling. Circ Res 10: 328-341.
- Fryer
LG, Parbu-Patel A, Carling D (2002) The Anti-diabetic drugs rosiglita zone
and metformin stimulate AMP-activated protein kinase through distinct
signaling pathways. J Biol Chem 277: 25226-25232.
- Musi
N, Goodyear LJ (2003) AMP-activated protein kinase and muscle glucose
uptake. Acta Physiol Scand 178: 337-345.
- Swiezewska
E, Danikiewicz W (2005) Polyisoprenoids: structure, biosynthesis and
function. Prog Lipid Res 44: 235-258.
- van
den Brink DM, Wanders RJ (2006) Phytanic acid: production from phytol, its
breakdown and role in human disease. Cell Mol Life Sci 63: 1752-1765.
- Valentin
HE, Lincoln K, Moshiri F, Jensen PK, Qi Q, et al. (2006) The Arabidopsis
vitamin E pathway gene5-1 mutant reveals a critical role for phytol kinase
in seed tocopherol biosynthesis. Plant cell 18: 212-224.
- Lampe
JW, Chang JL (2007) Interindividual differences in phytochemical
metabolism and disposition. Semin Cancer Biol 17: 347-353.
- Baxter
JH (1968) Absorption of chlorophyll phytol in normal man and in patients
with Refsum's disease. J Lipid Res 9: 636-641.
- Hu X, Makita S, Schelbert S, Sano S, Ochiai M, et al. (2015)
Reexamination of chlorophyllase function implies its involvement in
defense against chewing herbivores. Plant Physiol 167: 660-670.
- Lee
KI, Rhee SH, Park KY (1999) Anticancer Activity of Phytol and
Eicosatrienoic Acid Identified from Perilla Leaves. J Kor Soc Food Sci
Nutr 28: 1107-1112.
- Santos CC, Salvadori MS, Mota VG, Costa LM, de Almeida AA, et al. (2013)
Antinociceptive and Antioxidant Activities of Phytol In Vivo and In Vitro
Models. Neurosci J.
- Elmazar
MM, El-Abhar HS, Schaalan MF, Farag NA (2013) Phytol/Phytanic acid and
insulin resistance: potential role of phytanic acid proven by docking
simulation and modulation of biochemical alterations. PLoS ONE 8: e45638.
- Goto
T, Takahashi N, Kato S, Egawa K, Ebisu S, et al. (2005) Phytol directly
activates peroxisome proliferator-activated receptor α (PPARα) and
regulates gene expression involved in lipid metabolism in PPARα-expressing
HepG2 hepatocytes. Biochem Biophys Res Commun 337: 440-445.
- Matsuda
H, Gomi RT, Hirai S, Egashira Y (2013) Effect of dietary phytol on the
expression of α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase, a
key enzyme of tryptophan-niacin metabolism, in rats. Biosci Biotechnol
Biochem 77: 1416-1419.
- Yoshino
J, Mills KF, Yoon MJ, Imai S (2011) Nicotinamide mononucleotide, a key
NAD(+) intermediate, treats the pathophysiology of diet- and age-induced
diabetes in mice. Cell Metab 14: 528-536.
- Ha BG, Nagaoka M, Yonezawa T, Tanabe R, Woo JT, et al. (2012)
Regulatory mechanism for the stimulatory action of genistein on glucose
uptake in vitro and in vivo. J Nutr Biochem 23: 501-509.
- Mujića
A, Grdovićb N, Mujićc I, Mihailovićb M, Živkovićd J, et al. (2011)
Antioxidative effects of phenolic extracts from chestnut leaves, catkins
and spiny burs in streptozotocin-treated rat pancreatic β-cells. Food
Chem. 125: 841-849.
- Nomura
E, Kashiwada A, Hosoda A, Nakamura K, Morishita H, et al. (2003) Synthesis
of amide compounds of ferulic acid, and their stimulatory effects on
insulin secretion in vitro. Bioorg Med Chem 11: 3807-3813.
- Doi
M, Yamaoka I, Fukunaga T, Nakayama M (2003) Isoleucine, a potent plasma
glucose-lowering amino acid, stimulates glucose uptake in C2C12 myotubes.
Biochem Biophys Res Commun 312: 1111-1117.
- Zhang
W, Liu J, Tian L, Liu Q, Fu Y, Garvey WT (2013) TRIB3 mediates
glucose-induced insulin resistance via a mechanism that requires the
hexosamine biosynthetic pathway. Diabetes 62: 4192-4200.
- Nishiumi
S, Ashida H (2007) Rapid preparation of a plasma membrane fraction from
adipocytes and muscle cells: application to detection of translocated
glucose transporter 4 on the plasma membrane. Biosci Biotechnol Biochem
71: 2343-2346.
- Kim
YI, Hirai S, Goto T, Ohyane C, Takahashi H, et al. (2012) Potent PPARα
activator derived from tomato juice, 13-oxo–9,11-octadecadienoic acid,
decreases plasma and hepatic triglyceride in obese diabetic mice. PLoS ONE
7: e31317.
- Steinberg
D (1996) The Metabolic and Molecular Bases of Inherited Disease. (7th edn),
McGraw-Hill, NY.
- Mitsumoto
Y, Burdett E, Grant A, Klip A (1991) Differential expression of the GLUT1
and GLUT4 glucose transporters during differentiation of L6 muscle cells.
Biochem Biophys Res Commun. 175: 652-659.
- Burri
L, Thoresen GH, Berge RK (2010) The Role of PPARα Activation in Liver and
Muscle. PPAR Res 1-11.
- Lee WJ, Kim M, Park HS, Kim HS, Jeon MJ, et al. (2006)
AMPK activation increases fatty acid oxidation in skeletal muscle by
activating PPARα and PGC-1. Biochem Biophys Res Commun 340: 291295.
- Lee
CG, Koo JH, Kim SG (2015) Phytochemical regulation of Fyn and AMPK
signaling circuitry. Arch Pharm Res 38: 2093-2105.
- Kim
YG, Hahn S, Oh TJ, Park KS, Cho YM (2014) Differences in the
HbA1c-lowering efficacy of glucagon-like peptide-1 analogues between
Asians and non-Asians: a systematic review and meta-analysis. Diabetes
Obes Metab 16: 900-909.
- Ihara
Y, Yamada Y, Toyokuni S, Miyawaki K, Ban N, et al. (2000) Antioxidant
α-tocopherol ameliorates glycemic control of GK rats, a model of type 2
diabetes. FEBS Lett 473: 24-26.
- Collins
S, Martin TL, Surwit RS, Robidoux J (2004) Genetic vulnerability to
diet-induced obesity in the C57BL/6J mouse: physiological and molecular
characteristics. Physiol Behav 81: 243-248.
- Gloerich J, van Vlies N, Jansen GA, Denis S, Ruiter JP, et al. (2005)
A phytol-enriched diet induces changes in fatty acid metabolism in mice
both via PPARalpha-dependent and -independent pathways. J Lipid Res 46:
716-726.
QUICK LINKS
- SUBMIT MANUSCRIPT
- RECOMMEND THE JOURNAL
-
SUBSCRIBE FOR ALERTS
RELATED JOURNALS
- Journal of Astronomy and Space Research
- Advances in Nanomedicine and Nanotechnology Research (ISSN: 2688-5476)
- Journal of Microbiology and Microbial Infections (ISSN: 2689-7660)
- Proteomics and Bioinformatics (ISSN:2641-7561)
- Journal of Biochemistry and Molecular Medicine (ISSN:2641-6948)
- Journal of Agriculture and Forest Meteorology Research (ISSN:2642-0449)
- Journal of Veterinary and Marine Sciences (ISSN: 2689-7830)