Olive Leaf Polyphenols (OLPs) Stimulate GLUT4 Expression and Translocation in the Skeletal Muscle of Diabetic Rats
Abstract
:1. Introduction
2. Results
2.1. Glucose Tolerance Test (GTT)
2.2. Blood Biochemistry
2.3. Morphological Analysis
2.4. GLUT4 Expression on Muscle Fiber Membrane
2.5. GLUT4/Rab8A, GLUT4/Rab13, and GLUT4/Rab14 Colocalizations on Muscle Fiber Membrane
2.6. GLUT4, Rab8A, Rab13, and Rab14 Expression in Rat Soleus
3. Discussion
3.1. Olive Leaf Polyphenols Reduced Hyperglycemia and Hyperlipidemia
3.2. Histochemical Analysis of Soleus Muscle in Diabetic Rat after Olive Leaf Polyphenols (OLPs) Treatments
3.3. Rab8A, Rab13, and Rab14 in Regulation of GLUT4 Translocation in Rat Skeletal Muscle with Diabetes and Following OLP Therapy
4. Material and Methods
4.1. Materials
4.2. Phenolic Extraction and Analysis
4.2.1. Preparation of the Olea Europaea Leaf Extract (OLE)
4.2.2. UHPLC-DAD Analysis of Oleuropein in the OLE
4.3. Experimental Protocols
4.3.1. Animals Experimental Design and Treatments
4.3.2. Glucose Tolerance Test (GTT)
4.3.3. Blood Biochemistry
4.3.4. Tissue Muscle Homogenization
4.3.5. H&E and Immunofluorescence Staining
4.3.6. SDS-PAGE and Western Blot
4.3.7. Statistical Analysis
5. Conclusions and Future Research
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ACC | Acetyl-CoA carboxylase |
AMPK | 5’ adenosine monophosphate-activated protein kinase |
AS160 (or TBC1D4) | 160 kDa substrate of the Akt Ser/Thr kinase |
C/EBPα | CCAAT/enhancer-binding protein alpha is a transcription factor |
CPT-1 | Carnitine O-palmitoyltransferase 1 |
DM | Diabetes mellitus |
ERK1/2 | Extracellular signal-regulated kinases 1 and 2 |
FASN | Fatty acid synthase gene |
GGT | Glucose tolerance test |
GLUT1 | Glucose transporter 1 |
GLUT4 | Glucose transporter 4 |
GSV | Intracellular storage vesicles |
GTPases | Guanosine triphosphate (GTP) ases |
HbA1c | Glycated hemoglobin A 1c |
HDL-C | High-density lipoprotein cholesterol |
IL-10 | Interleukin-10 |
IL-6 | Interleukin-6 |
IR | Insulin receptor |
iNOS | Nitric oxide synthase, inducible |
IRS-1 | Insulin receptor substrate 1 |
JAK/STAT | Janus kinases/signal transducer and activator of transcription proteins |
LDL-C | Low-density lipoprotein cholesterol |
MAPK3/1 | Mitogen-Activated Protein Kinase 3 and 1 |
MCAD | Medium-chain specific acyl-CoA dehydrogenase |
MCP-1 | Monocyte chemoattractant protein 1 |
MyoVa | Myosin V heavy-chain gene (a class of actin-based motor proteins) |
NEFA | Non-esterified fatty acids |
NF-κB | Nuclear factor NF-kappa-B |
OLE | Olive leaf extract |
p-ACC | Phospho-Acetyl-CoA carboxylase |
p-Akt | Phosphorylated version of AKT |
p-AMPK | Phospho-AMPK |
PARP | Poly (ADP-ribose) polymerase |
PEPCK | Phosphoenolpyruvate carboxykinase |
p-ERα | Phosphorylated estrogen receptor alpha |
PGC-1α | Peroxisome proliferator-activated receptor gamma co-activator 1 alpha |
p-GSK-3β | Phosphorylated glycogen synthase kinase-3 beta |
p-IR | Phosphorylated insulin receptor |
PI3K/AKT | Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway |
p-JNK | Phospho-JNK |
PKC λ/ξ | Protein kinase C λ/ξ |
PLC-PKC | Phospholipase C-protein kinase C |
PM | Plasma membrane |
p-mTOR | Phosphorylated mammalian target of rapamycin (mTOR) |
p-p38 MAPK | Phospho-p38 MAPK |
PPARγ | Peroxisome proliferator-activated receptor gamma |
PPARα | Peroxisome proliferator-activated receptor alpha |
p-PKC | Phosphorylated protein kinase C |
Rab13 | Ras-related protein Rab-13 |
Rab14 | Ras-related protein Rab-14 |
Rab8A | Ras-related protein Rab-8A |
Rac 1 | Ras-related C3 botulinum toxin substrate 1 |
SREBP-1c | Sterol regulatory element-binding protein-1c |
SZT | Streptozotocin |
TNFα | Tumor necrosis factor alpha |
TOL1 | Treatment with 512 mg/kg OLE |
TOL2 | Treatment with 768 mg/kg OLE |
TOL3 | Treatment with 1024 mg/kg OLE |
Appendix A
Compound | Model | Protein Expression | Glucose Uptake (GU)/ Blood Glucose (BG)/ Insulin Sensitivity (IS) | Additional Findings | Treatment | Reference |
---|---|---|---|---|---|---|
Chlorogenic acid | L6 myotubes | GLUT4 | GU | ↑ PPARγ protein | 25 μM for 5 h: cytotoxicity > (50 μM) | [63] |
Cinnamon and extracts | C2C12 myotubes | p-AMPK | GU | 100 or 1000 μg/mL for 3 h | [64] | |
C2C12 myotubes | 30 μg/mL for 4 h | [65] | ||||
Wistar rats (WR) (gastrocnemius muscle) | GLUT4 | ↑ NEFA (serum), ↓ serum creatine ↑ GLUT4 | 30 mg/kg/day for 22 days | [66] | ||
C57BL/6J mice | BG | ↓ NEFA (serum), ↓ LDL-C, ↓ insulin | Overnight fast. 400 mg/kg/day for 21 days | [67] | ||
db/db mice | BG | ↓ NEFA (serum) ↓ fasting blood glucose level | 6 h fast. 400 mg/kg/day for 14 days | |||
C57BL/6J mice | BG | ↑ IRS-1, IR protein | Overnight fast. 150 mg/kg/day for 14 days | [68] | ||
C57BLKS/J db/db mice | BG | ↑ HDL-C levels (serum) ↓ p-Akt, Upregulated mRNA GLUT4 ↑ p-Akt | 20 mg/kg/day (p.o.) for 4 weeks | [69] | ||
Curcumin | C2C12 myotubes | p-Akt, p-AMPK | ↑ p-ACC protein ↑ GU ↑ GLUT4 translocation ↑ p-AMPK ↑ p-ACC ↑ p-Akt (insulin-induced) | 40 μM for 24 h: cytotoxicity > 40 μM 40 µM for 1 h | [70] | |
WR (soleus muscle) | p-AMPK | BG | 1 μM for 30 min or 60 mg/kg | [71] | ||
C2C12 cells | ↑ GU ↓ p-IRS-1 ↓ p-ACC ↑ p-Akt ↑ p-ERK1/2 ↑ p-p38 MAPK | 20 µM for 2 h | [72] | |||
C2 murine myoblasts | ↑ Apoptosis ↓ Cell viability ↑ PARP fragmentation ↑ p-JNK | 50 µM for 24 h | [73] | |||
L6myc skeletal muscle cells | ↑ GLUT4 translocation ↑ p-Akt ↑ p-GSK-3β ↓ TNF-α, IL-6 and MCP-1 levels ↑ IL-10 levels | 25 µM for 16 h | [74] | |||
ECGC | L6 myotubes | p-Akt, p-AMPK | GU | 40 μM for 3 h | [75] | |
SD rats (soleus muscle) | 12 h fast. 75 mg/kg for 1 h, or 100 nM for 15 min | [29] | ||||
C57BL/6 mice (soleus muscle) | 12 h fast. 75 mg/kg for 1 h, or 100 nM for 15 min | |||||
L6 myotubes | GU | 100 nM for 15 min | ||||
C2C12 myotubes | p-Akt, p-AMPK | ↑ p-p38 MAPK, ↑ p-ACC | 20 μM up to 72 h: treatment not cytotoxic up to 48 h | [72] | ||
L6 myotube | GLUT4 | ↑ PI3K, ↓ PKC λ/ξ ↑ GLUT4 RNA, ↑ Rac1 | 1 nM | [76] | ||
ICR mice | GLUT4, PI3K, p-AMPK | ↑ GLUT4, glycogen accumulation in skeletal muscle | Oral administration postprandial hyperglycemia | |||
C2C12 myotubes (ßGlud1−/−) | p-AMPK | ↑ p-AMPK, ↑ GU, ↑ IS | 20 µM EGCG for 10 min | [77] | ||
Ellagic acid | 3T3-L1 adipocytes and C2C12 myotubes | GLUT4, p-AMPK | GU | ↑ GLUT4 ↑ p-AMPK ↑ p-ERK1/2 ↑ p-PKC ζ/λ | 50 μg/mL for 1 h 1, 10, 100, 500 nM | [33] |
Ferulic acid | L6 myotubes | GLUT4 | GU | ↑ PI3K protein | 5 μM for 5 h: cytotoxicity > (50 μM) | [63] |
Gingerol | L6 myotubes | GU | 40 μg/mL for 48 h: treatment not cytotoxic | [78] | ||
Naringenin | L6 myotubes | p-AMPK | GU | 150 μM for 2 h | [79] | |
Quercetin | ob/ob mice (gastrocnemius muscle) | GLUT4 | BG, IS | ↑ GLUT4 RNA, ↓ TNF-α, ↓ iNOS RNA, ↓ NF κB activation | 30 mg/kg alternating days for 10 weeks | [80] |
L6 myotubes | p-Akt | GU | 200 μM for 48 h | |||
Kunming mice (gastrocnemius muscle) | GLUT4, p-AMPK | BG | ↑ p-ACC, ↓ blood triacylglycerol, ↓ total cholesterol, | 12-h fast. 5, 10, 20 mg/kg/day for 13 weeks | [81] | |
C2C12 myotubes | GLUT4, p-AMPK | GU | ↑ PPARα, ACC, MCAD, CPT-1, GLUT4, PGC-1α RNA, p-ACC protein | 10 μM for 24 h: treatment not cytotoxic | ||
C2C12 myotubes | GU | ↑ p-ACC protein | 100 μM for 18 h | [81] | ||
C2C12 myotubes | p-AMPK | GU | enhanced glucose uptake by 38–59% stimulated uptake by 37%, stimulated the AMPK pathway (25–100 mM) inhibited ATP synthase (in mitochondria) by 34 and 79% | quercetin-3-O-glycosides (50 mM; 18 h treatment) in the absence of insulin quercetin aglycone and quercetin glycosides quercetin aglycone by 25 and 100 mM | [82] | |
L6 myotubes | CaMKKβ/AMPK, IRS1/PI3K/Akt JAK/STAT | GU | ↑ GU (0.1 nM and 1 nM quercetin or 1 nM isorhamnetin) ↑ JAK/STAT (1 nM and 10 nM isorhamnetin) ↑ p-AMPK (quercetin) ↑ JAK2/STAT (isorhamnetin) ↑ IRS-1 (at 10 nM) | [34] | ||
ICR mice | GLUT4 | GU | quercetin aglycone form were 4.95 and 6.80 nM (plasma concentration) | 10, 100 and 1000 mg/kg body weight | ||
Resveratrol | L6 myotubes | p-AMPK | GU | 100 μM for 4 h | [83] | |
db/db mice | BG | ↑ Glucose tolerance | 5 mg/mL/100g body weight for 3 weeks † | |||
SD rats (soleus muscle) | GU, BR | Overnight fast. 10 mg/kg/day for 16 weeks | [84] | |||
C2C12 myotubes | GU | 10 μM for 24 h | ||||
L6 myotubes | p-AMPK | GU | 100 μM for 2 h: cell morphology unaltered up to 125 μM | [85] | ||
SD rats (soleus muscle) | GU | ↑ p-ERα, ↑ p-IR, ↓ serum cholesterol, ↓ triglycerides, ↓ uric acid | 1 mg/kg/day for 15 days or 15 weeks | [86] | ||
C2C12 myotubes | p-Akt | GU | ↑ p-ERα, ↑ p-p38 MAPK, ↑ p-ERK, ↑ p-IR | 0.1 μM for 14 h: treatment not cytotoxic | ||
WR (soleus muscle) | GLUT4, p-Akt | BG | ↑ PEPCK | Overnight fast. 0.05–10 mg/kg/day for 7 days | [87] | |
C2C12 myotubes | GU | 30 μM for 30min | ||||
C2C12 myocytes | p-AMPK | ↑ PGC-1α RNA | 50 μM for 24 h: cytotoxicity > (50 μM) | [88] | ||
SIRT1 knockout mice | BG, IS | ↓Mitochondrial content and respiration | 100 mg/kg day for 9 weeks | [89] | ||
Green tea | Wistar rats (WR) | GLUT4 | ↓ Triacylglycerols (plasma) ↓ NEFA, ↓ HbA1c, ↑ GLUT4 | 50 mg/kg body weight for 12 days | [90] | |
KK-Ay mice | GLUT4 | IS | ↓ Triacylglycerols (plasma) | 4 weeks | ||
Procyanidins (dimer to tetramer) from black soybean seeds | ICR mice (soleus muscle) | GLUT4 | GU | ↑ GLUT4 ↑ p-IRS-1 ↑ p-AMPK ↑ plasma insulin level ↑ plasma adiponectin ↓ plasma glucose | EC and C3G in water at 10 μg/kg body weight | [91] |
Procyanidins from cocoa liquor (CLPr) | L6 myoblasts | GLUT4 | GU | ↑ GLUT4 (7 days) GLUT1 unchanged | 250 mg/mL CLPr in DMSO | [92] |
ICR mice (soleus muscle) | GLUT4 | GU | ↑ GLUT4 (7 days) GLUT1 unchanged | 1, 5, 10 μg/mL single oral administration | ||
High-molecular-weight cocoa procyanidins | human primary skeletal muscle cells | GLUT4, PI3K/AKT, p-AMPK | GU | ↑ glycogen synthesis (cocoa extract), ↑ glycogen synthase (GS) (monomers 30% at 10 μM, oligomers 62% at 10 μM, polymers 16% at 10 μM and 32% at 25 μM) ↑ GU (all doses) ↓ PI3K/AKT (CE, 25 μM; oligomer, 25 μM; polymer 10 and 25 μM) | 10 and 25 μM | [93] |
Sinapic acid | SZT-diabetic rats (soleus muscle) | GLUT4 | GU | ↑ reduced glucose infusion rate (GIR) | 5 mg/kg, 10 mg/kg, and 25 mg/kg | [94] |
L6 cells | GU | ↓ PLC-PKC signals ↑ glucose uptake | ||||
Gallic acid | 3T3-L1 cells | GLUT4 | GU | ↑ GLUT4 ↑ PKCζ/λ | 1 µM, 10 µM, 20 µM | [95] |
HFD SZT-diabetic rats (adipose tissue) | GLUT4 | GU | ↑ PPARγ ↑ GLUT4 ↑ PI3K/p-Akt ↑ GU | 20 mg/kg | [96] | |
Black tea polyphenols (theaflavin) | L6 myotubes | GLUT4, p-AMPK | GU | ↑ p-IRS1 ↑ p-AMPK/AMPK ↑ p-GSK-3β ↑ PI3K | 0.1, 1.0, 10 BTP µg/mL | [32] |
Rosemary extract | L6 myotubes | p-AMPK, GLUT4 | GU | ↑ GU (5 µg/mL) ↑ p-AMPK ↑ p-ACC protein ↑ p-PKC | 5 µM RA for 4 h (maximum) | [97] |
Carnosol | L6 myotubes GLUT4myc | p-AMPK, GLUT4, p-Akt | GU | ↑ p-Akt ↑ p-mTOR ↑ p-ACC protein ↑ GLUT4 | 25 µM carnosol (4 h) | [31] |
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Group | |||||
---|---|---|---|---|---|
Control | DM | TOL1 | TOL2 | TOL3 | |
Weight, g | 298.8 ± 21.38 | 241.6 ± 37.45 # | 220.0 ± 20.00 | 240.67 ± 31.88 | 235.3 ± 4.51 |
Glucose, mg/dL | 116 ± 22.3 | 309 ± 40.7 # | 261 ± 8.3 * | 228.2 ± 36.9 * | 257 ± 27.9 * |
Cholesterol, mg/dL | 165 ± 6.2 | 166 ± 4.3 | 163 ± 5.1 | 160 ± 1.1 | 164 ± 6.9 |
Triglycerides, mg/dL | 104 ± 2.1 | 193 ± 114.1 # | 113 ± 7.6 * | 119.5 ± 4.7 | 100 ± 15.5 * |
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Giacometti, J.; Muhvić, D.; Grubić-Kezele, T.; Nikolić, M.; Šoić-Vranić, T.; Bajek, S. Olive Leaf Polyphenols (OLPs) Stimulate GLUT4 Expression and Translocation in the Skeletal Muscle of Diabetic Rats. Int. J. Mol. Sci. 2020, 21, 8981. https://doi.org/10.3390/ijms21238981
Giacometti J, Muhvić D, Grubić-Kezele T, Nikolić M, Šoić-Vranić T, Bajek S. Olive Leaf Polyphenols (OLPs) Stimulate GLUT4 Expression and Translocation in the Skeletal Muscle of Diabetic Rats. International Journal of Molecular Sciences. 2020; 21(23):8981. https://doi.org/10.3390/ijms21238981
Chicago/Turabian StyleGiacometti, Jasminka, Damir Muhvić, Tanja Grubić-Kezele, Marina Nikolić, Tamara Šoić-Vranić, and Snježana Bajek. 2020. "Olive Leaf Polyphenols (OLPs) Stimulate GLUT4 Expression and Translocation in the Skeletal Muscle of Diabetic Rats" International Journal of Molecular Sciences 21, no. 23: 8981. https://doi.org/10.3390/ijms21238981