Identification of baicalin from Bofutsushosan and Daisaikoto as a potent inducer of glucose uptake and modulator of insulin signaling-associated pathways

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by hyperglycemia that can lead to long-term complications including heart diseases, stroke, retinopathy, and renal failure. Treatment strategies include stimulating glucose uptake and controlling blood glucose level. Bofutsushosan (BOF) and Daisaikoto (DAI) are two herb-based kampo medicines that have been demonstrated to improve metabolism-associated disorders including obesity, hyperlipidemia, and nonalcoholic fatty liver. Given their bioactivities against metabolic syndromes, we explored in this study the effect of BOF and DAI extracts on glucose absorption and used them as source to identify phytochemical stimulator of glucose absorption. Glucose uptake and mechanistic studies were evaluated in differentiated C2C12 skeletal muscle cells, and HPLC analysis was used to determine the molecular bioactive constituents. Our results indicated that the ethanolic extracts of BOF and DAI (BOFEE and DAIEE, respectively) enhanced the glucose uptake ratio in the differentiated C2C12 cells, and further analysis identified the flavone baicalin as a major constituent capable of efficiently stimulating glucose absorption. Mechanistic studies revealed that the effect from baicalin involved the activation of IRS-1 and GLUT-4, and implicated the AMPK, PI3K/Akt, and MAPK/ERK signaling cascades. Due to its potency, we suggest that baicalin merit further evaluation as a potential candidate anti-hyperglycemic agent for the treatment and management of T2DM.

Natural Polyphenols in Metabolic Syndrome: Protective Mechanisms and Clinical Applications

“…In human umbilical vein endothelial cells cultured with high glucose (HG), baicalin was shown to alleviate cellular oxidative stress by enhancing the nuclear factor erythroid 2 (NRF2)-mediated transcriptional activation of heme oxygenase 1 (HO-1), superoxide dismutase (SOD), and catalase (CAT) [ 81 ], which is expected to relieve aortic vascular injury in diabetic patients. Meanwhile, in differentiated C2C12 skeletal muscle cells, baicalin can also activate insulin receptor substrate 1 (IRS-1) and glucose transporter 4 (GLUT4), as well as AMPK, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), and MAPK/extracellular signal-regulated kinase (ERK) signaling cascades, to enhance the glucose uptake and utilization of muscle cells [ 82 ]. Corresponding animal experiments also showed that baicalin has the potential to reverse HFD-induced hyperglycemia and systemic insulin resistance in mice, which might be attributed to the activation of the AKT/AKT substrate of 160 kD (AS160)/GLUT4 and MAPK/PPARγ coactivator 1α (PGC-1α)/GLUT4 pathways [ 83 ].…”

Pharmacological properties of baicalin on liver diseases: a narrative review

“…Baicalin possesses potential therapeutic effects on systemic diseases, including ocular disorders [ 5 ], periodontal diseases [ 6 ], inflammatory disorders [ 7 ], metabolic disorders [ 8 ] and even nervous system diseases [ 9 , 10 ], thanks to its anti-inflammatory, anti-oxidative, anti-angiogenesis, and immunoregulatory effect. Moreover, baicalin possesses anti-obese, anti-viral, and anti-dyslipidemia effect, thus playing a critical role in improving liver function after injury or alleviating liver diseases [ 7 , 11 – 13 ]. Since baicalin has a very wide range of pharmacological effects, more and more in-depth studies have been conducted.…”

Integrated Analysis of the Mechanisms of Da-Chai-Hu Decoction in Type 2 Diabetes Mellitus by a Network Pharmacology Approach

“…Baicalin is the main active component of Scutellaria root. Experiment by Kuo et al proved that the alcohol extract of DCHD can promote the absorption of glucose to reduce blood sugar, primarily by baicalin activating the IRS-1 and glut4 genes and the signaling cascade of 5′ AMP-activated protein kinase (AMPK), PI3K/Akt, and MAPK/ERK [16]. Naringin, the active component of immature bitter orange, combined with berberine can reduce liver lipid by activating AMPK and inhibiting Notch signaling pathway, thereby enhancing insulin sensitivity and improving resistance and remarkably improving oral glucose tolerance test (OGTT) [17].…”