Abstract
We previously demonstrated that an aspalathin-enriched green rooibos extract (GRE) reversed palmitate-induced insulin resistance in C2C12 skeletal muscle and 3T3-L1 fat cells by modulating key effectors of insulin signalling such as phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and AMP-activated protein kinase (AMPK). However, the effect of GRE on hepatic insulin resistance is unknown. The effects of GRE on lipid-induced hepatic insulin resistance using palmitate-exposed C3A liver cells and obese insulin resistant (OBIR) rats were explored. GRE attenuated the palmitate-induced impairment of glucose and lipid metabolism in treated C3A cells and improved insulin sensitivity in OBIR rats. Mechanistically, GRE treatment significantly increased PI3K/AKT and AMPK phosphorylation while concurrently enhancing glucose transporter 2 expression. These findings were further supported by marked stimulation of genes involved in glucose metabolism, such as insulin receptor (Insr) and insulin receptor substrate 1 and 2 (Irs1 and Irs2), as well as those involved in lipid metabolism, including Forkhead box protein O1 (FOXO1) and carnitine palmitoyl transferase 1 (CPT1) following GRE treatment. GRE showed a strong potential to ameliorate hepatic insulin resistance by improving insulin sensitivity through the regulation of PI3K/AKT, FOXO1 and AMPK-mediated pathways.
Keywords:
AKT; AMPK; PI3K; diabetes mellitus; green rooibos extract; insulin resistance; metabolic syndrome; obesity; therapeutic target.
MeSH terms
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3T3 Cells
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AMP-Activated Protein Kinases / genetics*
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AMP-Activated Protein Kinases / metabolism
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Animals
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Aspalathus / chemistry
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Carnitine O-Palmitoyltransferase / genetics
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Carnitine O-Palmitoyltransferase / metabolism
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Cell Line
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Chalcones / isolation & purification
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Chalcones / pharmacology*
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Diet, High-Fat / adverse effects
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Dietary Sugars / adverse effects
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Gene Expression Regulation
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Hepatocytes / cytology
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Hyperglycemia / drug therapy*
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Hyperglycemia / etiology
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Hyperglycemia / genetics
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Hyperglycemia / metabolism
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Hypoglycemic Agents / isolation & purification
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Hypoglycemic Agents / pharmacology*
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Insulin Receptor Substrate Proteins / genetics
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Insulin Receptor Substrate Proteins / metabolism
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Insulin Resistance*
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Male
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Mice
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Muscle Fibers, Skeletal / cytology
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Muscle Fibers, Skeletal / drug effects
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Muscle Fibers, Skeletal / metabolism
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Palmitic Acid / pharmacology
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Phosphatidylinositol 3-Kinases / genetics*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Plant Extracts / chemistry
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Proto-Oncogene Proteins c-akt / genetics*
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Proto-Oncogene Proteins c-akt / metabolism
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Rats
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Rats, Wistar
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Receptor, Insulin / genetics
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Receptor, Insulin / metabolism
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Signal Transduction
Substances
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Chalcones
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Dietary Sugars
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Hypoglycemic Agents
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Insulin Receptor Substrate Proteins
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Irs1 protein, rat
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Irs2 protein, rat
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Nerve Tissue Proteins
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Plant Extracts
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aspalathin
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Foxo1 protein, rat
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Palmitic Acid
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Carnitine O-Palmitoyltransferase
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carnitine palmitoyltransferase-1a, rat
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Phosphatidylinositol 3-Kinases
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Receptor, Insulin
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Proto-Oncogene Proteins c-akt
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AMP-Activated Protein Kinases