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. 2022 Jul 28;31(12):1583–1591. doi: 10.1007/s10068-022-01146-4

Monascus-fermented grain vinegar enhances glucose homeostasis through the IRS-1/PI3K/Akt and AMPK signaling pathways in HepG2 cell and db/db mice

Ye-Won Lee 1, Young-Hee Pyo 1,✉
PMCID: PMC9582056  PMID: 36278136

Abstract

MV was reported to have beneficial effects in ameliorating insulin resistance in db/db mice, but the intrinsic mechanisms for glucose homeostasis are unclear. This study examined the anti-diabetic mechanism of MV using HepG2 cells and C57BL/KsJ-db/db mice. MV increased insulin sensitivity by promoting insulin-dependent glucose uptake and activating glycogen accumulation in HepG2 cells. Furthermore, the glucose homeostasis was enhanced in db/db mice administered 1 mg/kg/day of MV for eight weeks by activating the IRS-1/PI3K/Akt and AMPK pathways in the skeletal muscle and liver tissue. In addition, MV promoted glycogen synthesis by regulating the key enzymes, including GSK-3β and GS, and suppressed gluconeogenesis by inhibiting the mRNA expressions of G6pase and PEPCK. These findings show that MV regulates both signaling pathways and improves the glucose metabolism disorder. Thus, MV might be an alternative functional food or nutraceutical in ameliorating T2DM.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10068-022-01146-4.

Keywords: Monascus-vinegar, T2DM, Glucose homeostasis, Db/db mouse

Introduction

T2DM is the most prevalent endocrine disease globally and a major global health problem with a significant economic burden in many countries (Burke et al., 2012). The World Health Organization (WHO) predicted 366 million individuals with T2DM in 2030, giving a diabetes prevalence of 5% (Lu et al., 2008). Various anti-diabetic medicines have been developed, but the long-term using of synthetic drugs is limited. Therefore, there has been increasing interest in anti-diabetic functional foods made from natural ingredients without side effects (Zhang et al., 2018).

Vinegar is used extensively as an antibiotic agent, but recently, the metabolic effects of vinegar have attracted increasing interest (Petsiou et al., 2020). Several studies have examined how vinegar affects the glucose metabolism in vivo and in vitro. Some vinegars, such as tomato (Seo et al., 2014), mangosteen (Karim et al., 2019), Zhenjiang aromatic (Xia et al., 2021), and apple vinegars (Ousaaid et al., 2022), increase insulin sensitivity, regulate the glucose metabolism, and decrease the level of lipid profile parameters.

MV is produced from grain fermented with Monascus pilosus, and has antioxidant, anti-obesity, and anti-diabetic properties (Hwang et al., 2016; Noh and Pyo, 2021; Pyo et al., 2022). For example, it modulates the blood glucose, insulin, and glycosylated hemoglobin levels and improves the serum leptin levels in db/db mice. These diverse bioactive actions of MV have been attributed to the abundance of organic acids, polyphenols, isoflavones, ubiquinones, free amino acids, and γ-aminobutyric acid (GABA) (Hwang and Pyo, 2018). On the other hand, the effects of MV on the hypoglycemic activity and the precise mechanism underlying its contribution are unclear. This study investigated the effects of MV on the diabetes-related changes in the glucose metabolism in vitro using HepG2 cells. Furthermore, this study assessed whether dietary supplementation with MV could improve glucose metabolism disorders associated with glycogen synthesis and gluconeogenensis by activating the IRS-1/PI3K/Akt and AMPK signaling pathways in the skeletal muscle and liver of C57BL/KsJ-db/db mice, the most widely used model for T2DM studies.

Materials and methods

Reagents

The glucose uptake colorimetric assay kit and glycogen assay kit were provided by Biovision (Milpitas, CA, USA). Fetal bovine serum (FBS) was supplied by Capricorn Scientific (Ebsdorfergrund, Germany). Minimum Essential Medium Eagle (MEM) and penicillin were obtained from Welgene (Gyeongsan, Korea). The primary antibodies to IRS-1 (2382S), p-PI3K (Tyr199) (4228S), AMPK (2532S), p-AMPK (Thr172) (2531S), GSK-3β (9315S), p-GSK-3β (Ser9) (9323S), GS (3886S), and p-GS (Ser641) (3891S) were procured from Cell Signaling Technology (Danvers, MA, USA). The primary antibody to p-IRS1 (Tyr612) (44-816G) was acquired from Thermo Fisher Scientific (Waltham, MA, USA). The primary antibodies to PI3K (R12-2307), Akt (B0817), and p-Akt (Ser473) (A7004) were procured from Assay Biotechnology (Fremont, CA, USA). The primary antibodies to GLUT4 (sc-53566) and β-actin (sc-47778) were purchased from Santa Cruz Biotechnology (Dallas, Texas, USA). The secondary antibodies were obtained from GeneTex (Irvine, CA, USA). AccuPower® CycleScript RT PreMix and AccuPower® PCR PreMix were supplied by Bioneer (Daejeon, Korea). G6pase, PEPCK, and GAPDH primers were procured from Bioneer (Daejeon, Korea).

Preparation of MV

The Monascus-fermented grain vinegar (MV) was prepared using Monascus pilosus (KCCM 60084) purchased from KCCM (Seoul, Korea). The procedure for preparing MV was the same as that in a previous study (Hwang et al., 2016) (Supplementary Fig. 1). Briefly, brown rice and black beans were fermented with M. pilosus for 20 days at 28 °C. After alcohol fermentation for four days, acetic acid fermentation was performed for four weeks at 30 °C. The samples for HepG2 cells were extracted by adding butanol to MV and concentrated. Concentrate was dissolved in dimethyl sulfoxide (DMSO) and stored at − 80 °C.

Cell culture and cytotoxicity assay

HepG2 cells were supplied by the Korean Cell Line Bank (Seoul, Korea). The HepG2 cells were cultured in 25 mM HEPES, 25 mM NaHCO3, 90% MEM supplemented with 10% FBS, and 1% penicillin–streptomycin at 37 °C in an incubator containing 5% CO2. The cells were seeded at 5.0 × 104 cells/mL and cultured for 24 h. The cells were treated with different concentrations of MV extract (0.5, 5, 50, and 500 µg/mL) for 24 h and 48 h. After removing the medium, 20 µL of MTT (Duchefa, Haarlem, Netherlands) at a concentration of 5 mg/mL was added. Finally, 200 µL of DMSO was used to dissolve the formazan complex. The absorbance at 550 nm was read by a microplate reader (Bio-Rad Laboratories, Hercules, CA, USA).

Glucose uptake and glycogen content

The glucose uptake was measured using a glucose uptake colorimetric assay kit. Cells with a density of 5.0 × 104 cells/mL were seeded and incubated for 24 h. After starving for glucose, the MV extract was treated with various concentrations, and 10 mM of 2-deoxyglucose was added. The cells were suspended with 80 µL of extraction buffer and heated at 85 °C for 40 min. The extract was neutralized by using 10 µL of buffer and centrifuged (16,000×g for 5 min). The supernatant was applied to glucose uptake assay. The glycogen contents were calculated using a glycogen assay kit. The cells were prepared at 1.0 × 106 cells/mL and incubated with MV extract of different concentrations for 24 h. After discarding the medium, 200 µL of distilled water was used to homogenize the cells. The homogenates were boiled and centrifuged at 16,000×g for 5 min. The supernatant was used to assess the glycogen content. The OD values were then measured using a microplate reader.

Animal experiments

Male C57BL/KsJ-db/db mice (2 weeks old) were purchased from Jung-Ang Lab Animal, Inc. (Seoul, Korea). The Institutional Animal Care and Use Committee at Sungshin Women’s University, Seoul, Korea approved the care and use of laboratory animals in this study, which complied with all institutional and national guidelines (Reference No.: SSWIACUC-2020-009). All animals were raised in individual cages with a light/dark cycle for 12 h at 25 °C. The mice were then assigned to the db/db group (n = 9) and MV group (n = 9). The db/db group was administered distilled water orally (1 mL/kg/day), and the MV group was administered MV orally (1 mL/kg/day) for eight weeks. During the experiment, food (sterile feed, SAFE + 40, Central Lab, Animal Inc., Seoul, Korea) and water were provided freely. After eighth weeks, the liver and skeletal muscle were obtained and stored at − 80 °C until analysis.

Western blot

The appropriate amounts of tissue samples and HepG2 cells were taken and lysed with a lysis buffer (LPS solution, Daejeon. Korea), including 1% protease and phosphatase inhibitors. Equivalent proteins were loaded on 10% sodium dodecyl sulfate–polyacrylamide gels and transferred to a polyvinylidene fluoride membrane (Bio-Rad, Hercules, CA, USA). After blocking with 5% non-fat milk, the membranes were incubated overnight with various primary antibodies. The membranes were then washed and incubated with the secondary antibodies for 1 h. The protein bands were detected using a chemiluminescence detection kit (DYNEBIO, Seongnam, Gyeonggi-do, Korea). Image J software (NIH, Bethesda, USA) was used to quantify the band intensity of Western blot.

Reverse-transcription PCR (RT-PCR)

The total RNA in the liver tissue was isolated with TRIzol reagent (Invitrogen, Carlsbad, CA, USA). The RNA quantity and purity was determined using Nanodrop 2000 (Thermo Fischer Scientific Inc., Waltham, MA, USA). The cDNA was synthesized using the AccuPower® CycleScript RT PreMix in a 20 µL reaction volume at 45 °C for 45 min and 95 °C for 5 min. The primer sequences are given in Table 1. The synthesized cDNA was used in RT-PCR using an AccuPower® PCR PreMix. Image J software was used to analyze the data.

Table 1.

PCR primer sequences

Gene Primer Sequence (5′ → 3′)
G6pase Forward TGT GTC TGT GAT TGC TGA CC
Reverse CGG AGC TGT TGC TGT AGT AG
PEPCK Forward TGT TTA CTG GGA AGG CAT CG
Reverse ACG GCC ACC AAA GAT GAT AC
GAPDH Forward CGT GCC GCC TGG AGA AAC C
Reverse TGG AAG AGT GGG AGT TGC TGT TG
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Statistical analysis

SPSS 16.0 software (SPSS, Chicago, IL, USA) was performed for statistical analyses. All data are reported as mean ± SD. A two-tailed Student’s t-test or one-way analysis of variance (ANOVA) was conducted to assess the significant differences between the means; p values < 0.05 were considered significant.

Results and discussion

Effect of MV on glucose metabolism in HepG2 cells

Supplementary Fig. 2 presents the cytotoxicity data of MV extracts tested at 0.5–500 μg/mL. There was no significant cytotoxicity up to the maximum concentration of 500 μg/mL. Thus, further treatments of HepG2 cells were performed at the highest dose of 50 μg/mL. As presented in Fig. 1A, insulin increased the intracellular glucose uptake by 87.50% and 11.80%, respectively in control and MV group, compared to the normal group. Treatment with 50 μg/mL of MV increased the glucose uptake by 82.95% compared to the control (0.88 ± 0.02 pmol). Hence, MV can enhance the glucose uptake in HepG2 cells. Park et al. (2019) reported that reduced glucose uptake is a feature of T2DM, suggesting it is essential to promote glucose uptake via glucose transporter (GLUT). Among the GLUTs family, GLUT4 is one of the major regulators of glucose transport, stimulated by insulin. It can also facilitate glucose uptake and glycogen synthesis (Chen et al., 2021; Kou et al., 2021). Thus, the levels of GLUT4 protein expression was examined by western blot. As presented in Fig. 1B, MV at 0.5, 5, and 50 μg/mL increased the level of GLUT4 protein expression by 3.0-, 4.2-, and 5.4-fold, respectively, indicating that the MV treatment evoked a significant dose-dependent increase in the GLUT4 protein expression compared to the control, which concurs with a previous study. According to Beh et al. (2017), Nipa vinegar upregulated GLUT4 expression, possibly because of the presence of organic acids, including acetic acid. The effect of MV on the glycogenesis was examined in HepG2 cells. Glycogen participates in the glucose metabolism related to glucose homeostasis (Wang et al., 2018). As presented in Fig. 1C, the glycogen contents in the MV group increased dose-dependently except for the highest concentration of 50 μg/mL compared to the control group. At 50 μg/mL, the glycogen contents increased by 806.2% compared to the control group (5.16 ± 2.06 ng/µg protein). Morgan and Mosawy (2016) reported that the hypoglycemic effect might be due to acetic acid, the primary organic acid of vinegar. They suggested that acetic acid increases glycogen synthesis by impeding glycolysis and accumulating glucose-6-phosphate. These results indicate that MV regulated glucose metabolism by stimulating insulin-dependent glucose uptake and enhancing glycogen accumulation in HepG2 cells.

Fig. 1.

Fig. 1

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Measurement of glucose uptake, GLUT4 protein expression, and glycogen contents in HepG2 cells. (A) Effect of MV on glucose uptake. (B) Effect of MV on GLUT4 protein expression. (C) Effect of MV on glycogen contents. The data are reported as the means ± standard deviation derived from three independent experiments. Means with the same letter above the bars are not significantly different at the 5% level

Effect of MV on insulin resistance in skeletal muscle of T2DM mice

Insulin resistance is caused by a dysfunction of the insulin-signaling pathway in the skeletal muscle and the liver (He et al., 2022; Ye, 2013). The insulin-dependent IRS-1/PI3K/Akt signaling pathway is activated when insulin binds to the insulin receptor. Phosphorylated IRS-1 (IRS-1Tyr612) phosphorylates PI3K, which then phosphorylates Akt (AktSer473), ultimately increasing GLUT4 translocation. This signaling pathway raises glucose absorption into skeletal muscle and lowers the blood glucose level (Huang et al., 2021). Activated AMPK, an insulin-independent signaling pathway, also promotes GLUT4 translocation and glucose absorption (Lee et al., 2020). Thus, the activity of both signaling pathways were measured to assess the potential mechanisms related to the glucose metabolism of MV in the skeletal muscle of db/db mice. The activation of the IRS-1/PI3K/Akt and AMPK were downregulated remarkably in the db/db group but upregulated after MV intervention (Fig. 2). This is consistent with the evidence showing that the activation of PI3K/Akt and AMPK in the skeletal muscle reduces blood glucose by enhancing the glucose absorption (Kim et al., 2019). Furthermore, the GLUT4 expression was upregulated markedly in the MV group compared to the db/db group, as shown in Fig. 2. These findings suggest that the MV treatment may increase insulin sensitivity by activating both signaling pathways and glucose absorption in the skeletal muscle of T2DM mice.

Fig. 2.

Fig. 2

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Effect of MV on p-IRS-1, IRS-1, p-PI3K, PI3K, p-Akt, Akt, GLUT4, p-AMPK, and AMPK protein expression in the skeletal muscle of db/db mice. The data are reported as mean ± S.D. (n = 3). *p < 0.05, **p < 0.01 versus db/db group

Effect of MV on insulin resistance in liver of T2DM mice

The liver is a major organ in maintaining glucose homeostasis. When the insulin resistance increases, the glucose metabolism in the liver is abnormal, resulting in excessive gluconeogenesis and hyperglycemia (Bao et al., 2020). As presented in Fig. 3 A and B, the activation of the IRS-1/PI3K/Akt and AMPK enhanced in the liver after the MV treatment. These findings are coherent with the conversions in the skeletal muscle. Both signaling pathways regulate glycogen synthesis by controlling key enzymes, such as GSK-3β and GS (Lv et al., 2019). Thus, the mechanisms of MV on glycogen synthesis were examined by measuring the phosphorylation of the GSK-3β and GS in the liver. The protein expressions of p-GSK-3β and GS were remarkably higher in the MV group than in the db/db group (Fig. 3C), while GSK-3β and p-GS were lower (Fig. 3D). These findings are coherent with Xia et al. (2021), who reported that the Zhenjiang aromatic vinegar regulated glycogen synthesis through the IRS-1/PI3K/Akt signaling pathways in HepG2 cells. Hence, both signaling pathways may affect the MV-mediated anti-diabetic effect, promoting glycogen synthesis by modulating GSK-3β and GS protein expression in the liver of T2DM mice.

Fig. 3.

Fig. 3

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Effect of MV on p-IRS-1, IRS-1, p-PI3K, PI3K, p-Akt, Akt, p-AMPK, AMPK, p-GSK-3β, GSK-3β, p-GS, and GS protein expression in the liver of db/db mice. The data are presented as mean ± S.D. (n = 3). *p < 0.05, **p < 0.01 versus the db/db group

Effect of MV on the mRNA expression of glucose metabolism in the liver of T2DM mice

G6pase and PEPCK are key enzymes in liver gluconeogenesis, the reverse pathway of glycolysis (Wang and Dong, 2019). The presence of these enzymes in T2DM patients has been debated (Zhang et al., 2019). Hence, these enzymes are therapeutic targets to control glucose homeostasis. The effect of MV on the mRNA expression of G6pase and PEPCK were examined in the liver of T2DM mice. RT-PCR analysis showed that the mRNA levels of these enzymes were remarkably lower in the MV group than in the db/db group (Fig. 4). Hence, the oral administration of MV may inhibit gluconeogenesis by suppressing the mRNA expression of these enzymes in the liver. Previous studies reported that activation of the PI3K/Akt and AMPK signaling pathways could regulate the gene expression related to gluconeogenesis (Han et al., 2008; Liu et al., 2021; Zhang et al., 2019). This result explains why MV stimulated glucose absorption and metabolism under insulin-limited conditions. In the current study, MV improved the glucose metabolism disorders by regulating the signaling pathways -mediated glycogen synthesis and glucose absorption in T2DM mice, as summarized in Fig. 5.

Fig. 4.

Fig. 4

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Effects of MV on gluconeogenesis in liver tissue of db/db mice. The mRNA expression levels of G6pase (A) and PEPCK (B) were determined by RT-PCR. The data are shown as mean ± S.D. (n = 3). *p < 0.05 versus the db/db group

Fig. 5.

Fig. 5

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MV regulates glucose homeostasis via the IRS-1/PI3K/Akt and AMPK signaling pathways

In conclusion, MV ameliorated insulin resistance by stimulating insulin-dependent glucose uptake and enhancing glycogen accumulation in HepG2 cells. Furthermore, MV activated the IRS-1/PI3K/Akt and AMPK signaling pathways, which upregulated glucose transportation and glycogen synthesis and down-regulated gluconeogenesis in T2DM mice. Hence, MV may enhance glucose homeostasis via both signaling pathways, inducing glycogen synthesis and suppressing gluconeogenesis in T2DM mice. The results highlight the potential of MV as a functional food for preventing and treating T2DM.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 103 KB) (102.6KB, docx)

Acknowledgements

This study was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2019R1F1A1054590).

Abbreviations

MV

Monascus-fermented grain vinegar

IRS-1

Insulin receptor substrate-1

PI3K

Phosphatidylinositol 3-kinase

Akt

Protein kinase B

AMPK

AMP-activated protein kinase

GLUT4

Glucose transporter type 4

GSK-3β

Glycogen synthase kinase-3β

GS

Glycogen synthase

G6pase

Glucose-6-phosphatase

PEPCK

Phosphoenolpyruvate carboxykinase

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

T2DM

Type 2 diabetes mellitus

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Ye-Won Lee, Email: fifi1229@naver.com.

Young-Hee Pyo, Email: rosapyo@sungshin.ac.kr.

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Supplementary Materials

Supplementary file1 (DOCX 103 KB) (102.6KB, docx)

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