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Insulin secretion and α-glucosidase inhibitory effects of dicaffeoylquinic acid derivatives
Applied Biological Chemistry volume 65, Article number: 22 (2022)
In this study, we investigated the effects of dicaffeoylquinic acid derivatives, including 1,4-di-O-caffeoylquinic acid (1,4-DCQA), 3,4-di-O-caffeoylquinic acid (3,4-DCQA), 3,5-di-O-caffeoylquinic acid (3,5-DCQA), 4,5-di-O-caffeoylquinic acid (4,5-DCQA), and 1,5-di-O-caffeoylquinic acid (1,5-DCQA) on glucose-stimulated insulin secretion (GSIS) activity and α-glucosidase activity were compared in rat INS-1 pancreatic β-cells. The α-glucosidase inhibitory activities of dicaffeoylquinic acid derivatives were as follows: 1,4-DCQA > 1,5-DCQA > 3,4-DCQA > 4,5-DCQA > 3,5-DCQA. In INS-1 cells, dicaffeoylquinic acid derivatives showed no cytotoxic effect at any concentration (2.5–10 μM). In addition, the GSIS activities of dicaffeoylquinic acid derivatives were as follows: 4,5-DCQA > 3,4-DCQA > 1,4-DCQA > 3,5-DCQA > 1,5-DCQA. Treatment of INS-1 cells with 4,5-DCQA resulted in a marked increase in protein expression of extracellular signal-regulated protein kinases (ERK), insulin receptor substrate-2 (P-IRS-2), Akt, phosphoinositide 3-kinase (P-PI3K), and pancreatic and duodenal homeobox-1 (PDX-1), which might be related to its GSIS activity in INS-1 cells. These findings indicate that the location of the dicaffeoyl functional group influences the anti-diabetic activity of quinic acid.
Diabetes mellitus (DM) is metabolic endocrine disorder in the world associated with abnormal compromised lipid and carbohydrate metabolism. One approach for the treatment of type 2 DM is using α-glucosidase inhibitors as an oral anti-hyperglycemic drug . α-Glucosidase inhibitors has its own mechanism of action that diminish the levels of postprandial blood glucose. It can help in retarding the absorption of carbohydrates by decreasing α-glucosidase activity in the epithelium of small intestine . Acarbose, miglitol, and voglibose are clinically approved as α-glucosidase inhibitors . These three α-glucosidase inhibitors are sugars or its derivatives, which can induce gastrointestinal side effects . A range of chemical compounds isolated from natural products have been reported to be effective in inhibiting the α-glucosidase activity. Most of the chemical compounds reported as α-glucosidase inhibitors in previous studies are secondary metabolites including flavonoids, alkaloids, anthocyanins, terpenoids, and phenolic acids .
Caffeoylquinic acid derivatives have been claimed to have various biological effects including neuroprotective activity [5, 6], anti-oxidant effect [7, 8], anti-inflammatory activity [9, 10], anti-viral effect [11, 12], anti-cancer activity , and anti-hepatotoxic activity . Furthermore, their inhibitory effects on α-glucosidase activity have been scientifically evaluated in the previous many reports [15,16,17]. However, little is known concerning their effect on glucose-stimulated insulin secretion (GSIS). Another approach for the treatment of type 2 DM is an increase in GSIS. GSIS had been considered the exclusive mechanism of insulin regulation . Defective insulin secretion is a characteristic of pancreatic β cell dysfunction, which develops early and gets worse further in T2D . Sulfonylureas known as oral insulinotropic agents to treat T2DM promote insulin secretion by closing K+ATP channels at the plasma membrane, while medicines in this group are known to often lead to hypoglycemia. This is because it continuously stimulates insulin secretion, regardless of plasma glucose levels . Thus, identification of potential compounds that stimulate GSIS is highly desirable. Therefore, in this study, the inhibitory effects of dicaffeoylquinic acid derivatives (Fig. 1) on α-glucosidase inhibitory were compared, and it was also confirmed whether the dicaffeoylquinic acid derivatives enhance insulin secretion in pancreatic β cells using only stimulatory glucose. In addition, the corresponding mechanisms were investigated.
Materials and methods
Plant materials and chemiclas
The dried aerial parts of Saussurea grandifolia were extracted with methanol under reflux. 1,4-Di-O-caffeoylquinic acid (1,4-DCQA) and 1,5-di-O-caffeoylquinic acid (1,5-DCQA) was isolated from S. grandifolia. Dicaffeoylquinic acid derivatives such as 3,4-di-O-caffeoylquinic acid (3,4-DCQA), 4,5-di-O-caffeoylquinic acid (4,5-DCQA), and 3,5-di-O-caffeoylquinic acid (3,5-DCQA) were isolated from Acanthopanax henryi and obtained Natural Product Institute of Science and Technology (www.nist.re.kr, Anseong, Korea).
NMR data of dicaffeoylquinic acid derivatives
1,4-DCQA (purity: 99.7%): 1H-NMR (DMSO-d6, 500 MHz) δ: 7.51 (2H, d, J = 15.5 Hz, H-7ʹ, 7ʹʹ), 7.02 (2H, br s, H-2ʹ, 2ʹʹ), 6.98 (2H, d, H-6ʹ, 6ʹʹ), 6.76 (2H, dd, H-5ʹ, H-5ʹʹ), 6.24 (2H, d, J = 15.5 Hz, H-8ʹ, 8ʹʹ), 5.05 (1H, br s, H-3), 4.75 (1H, br s, H-4), 4.16 (1H, br s, H-5), 2.20 (3H, m, H-6a, 6b, 2a), 1.80 (1H, br s, H-2b).
1,5-DCQA (purity: 99.7%): 1H-NMR (DMSO-d6, 500 MHz) δ: 7.40 (2H, t, J = 16.5 Hz, H-7ʹ,7ʹʹ), 7.00 (2H, br s, H-2ʹ, 2ʹʹ), 6.88 (2H, dd, J = 8.0 Hz, H-6ʹ, 6ʹʹ), 6.66 (2H, d, J = 8.5 Hz, H-5ʹ, H-5ʹʹ), 6.21 (1H, d, J = 16.0 Hz, H-8ʹʹ), 6.06 (1H, d, J = 16.0 Hz, H-8ʹ), 5.28 (1H, dd, J = 7.5 Hz, H-5), 3.99 (1H, br s, H-3), 3.49 (1H, br s, H-4), 1.71–2.51 (4H, m, H2-2, H2-6).
3,4-DCQA (purity: 98.4%): 1H-NMR (DMSO-d6, 500 MHz) δ: 7.45 (2H, m, H-7’, 7’’), 7.03 (2H, dd, J = 10.0 Hz H-2ʹ, 2ʹʹ), 6.95 (2H, m, H-6ʹ, 6ʹʹ), 6.73 (2H, d, J = 8.5 Hz, H-5ʹ, H-5ʹʹ), 6.20 (1H, m, H-8ʹ, H-8ʹʹ), 5.42 (1H, br s, H-3), 4.94 (1H, br s, H-4), 4.05 (1H, br s, H-5), 1.91–2.11 (4H, m, H2-2, H2-6).
3,5-DCQA (purity: 98.7%): 1H-NMR (DMSO-d6, 500 MHz) δ: 7.47 (2H, t, J = 16.5 Hz, H-7ʹ, H-7ʹʹ), 7.05 (2H, dd, J = 8.5 Hz, H-2ʹ, H-2ʹʹ), 6.99 (2H, m, H-6ʹ, 6ʹʹ), 6.77 (2H, dd, J = 8.0 Hz, H-5ʹ, H-5ʹʹ), 6.25 (1H, d, J = 16.0 Hz, H-8ʹʹ), 6.16 (1H, d, J = 15.5 Hz, H- 8ʹ), 5.20 (1H, m, H-3), 5.11 (1H, br s, H-5), 3.84 (1H, br s, H-4), 1.91–2.17 (4H, m, H2-2, H2-6).
4,5-DCQA (purity: 99.9%): 1H-NMR (DMSO-d6, 500 MHz) δ: 7.49 (1H, d, J = 16.0 Hz, H-7ʹʹ), 7.42 (1H, d, J = 16.0 Hz, H-7ʹ), 7.02 (2H, dd, J = 4.5 Hz, H-2ʹ, 2ʹʹ), 6.97 (2H, m, H-6ʹ, 6ʹʹ), 6.74 (2H, dd, J = 8.0 Hz, H-5ʹ, H-5ʹʹ), 6.24 (1H, d, J = 16.0 Hz, H-8ʹʹ), 6.14 (1H, d, J = 16.0 Hz, H-8ʹ), 5.35 (1H, br s, H-5), 4.96 (1H, dd, J = 7.5 Hz, H-4), 4.17 (1H, br s, H-3), 1.87–2.18 (4H, m, H2-2, H2-6).
α-Glucosidase-inhibitory activity assay
Dicaffeoylquinic acid derivatives were assessed for α-glucosidase-inhibitory activity as described previously, with slight modifications [21, 22]. In brief, acarbose and dicaffeoylquinic acid derivatives (80 μL) at varying concentrations (12.5 to 100 μM) in 120 μL of 0.1 M phosphate buffer (pH 6.8) were incubated with 100 μL of 0.5 U/mL α-glucosidase at 37 °C. Enzyme activity was calculated as: α-glucosidase-inhibitory activity (%) = [(Ablank-Asample)/Ablank] × 100.
Cell culture and determination of cell viability
Rat pancreatic INS-1 line (Biohermes, Shanghai, China) was maintained routinely in the Roswell Park Memorial Institute (RPMI) 1640 medium (Cellgro, Manassas, VA, USA) supplemented with 1 mM sodium pyruvate, 0.05 mM 2-mercaptoethanol, 10 mM HEPES, 11 mM D-glucose, 2 mM L-glutamine, and 10% fetal bovine serum (FBS), 1% penicillin/streptomycin (Invitrogen Co., Grand Island, NY, USA) under 5% CO2 and 95% humidity at 37 °C. To determine the non-toxic dose ranges of dicaffeoylquinic acid derivatives, INS-1 cells were seeded at 104 cell per well in 96-well plates. After 24 h of incubation, cells were treated with gliclazide and dicaffeoylquinic acid derivatives (100 μL) at varying concentrations (2.5 to 10 μM) for 24 h. The cells were then incubated for 2 h with 10 μL of Ez-Cytox reagent (Daeil Lab Service Co., Seoul, Korea) as described in published methods .
INS-1 cells plated on 12-well plates for 24 h were used to measure the effects of dicaffeoylquinic acid derivatives on GSIS. To this end, INS-1 cells were kept in Krebs–Ringer bicarbonate HEPES buffer (KRBB) supplemented with 2.8 mM glucose for 2 h. Thereafter the INS-1 cells were incubated for 1 h in the fresh KRBB with the denoted glucose concentrations (2.8 or 16.7 mM glucose) and test agents (gliclazide and dicaffeoylquinic acid derivatives). Glucose stimulated index (GSI) was calculated by dividing the insulin concentration that had accumulated during exposure to 16.7 mM glucose by the insulin accumulated during exposure to 2.8 mM glucose. After incubation a cell culture supernatant was analyzed using a rat insulin ELISA kit (Gentaur, Shibayagi Co. Ltd., Shibukawa, Gunma, Japan) as recommended by the producer to measure the GSIS.
Western blot analysis
In the Western blot analysis, INS-1 cells plated on 12-well plates for 24 h were used to measure the effect of 4,5-DCQA on protein expression changes of PI3K, Akt, P-IRS-2 (Ser731), IRS-2, P-ERK, ERK, P-PI3K, P-Akt (Ser473), and PDX-1. To this end, the cells were treated with 4,5-DCQA for 24 h. The cells were lysed on ice for 20 min in radioimmunoprecipitation assay buffer (Cell Signaling, Danvers, MA, USA) with protease inhibitor. The concentration of protein in the lysates was determined using the Pierce BCA protein assay kit (Thermo Scientific, Rockford, IL, USA). Samples containing 20 μg concentration of protein were subsequently transferred onto polyvinylidene difluoride membranes. The membranes were incubated treated with first and second antibodies against PI3K, Akt, P-IRS-2 (Ser731), IRS-2, P-ERK, ERK, P-PI3K, P-Akt (Ser473), PDX-1, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH).
All analyses were conducted using SPSS Statistics ver. 19.0 (SPSS Inc., Chicago, IL, USA). Nonparametric comparisons of samples were conducted with the Kruskal–Wallis test to analyze the results. Statistical significance was set at p < 0.05.
Identification of dicaffeoylquinic acid derivatives
The dried aerial parts of Saussurea grandifolia were extracted with methanol under reflux. The filterate was concentrated to dryness, suspended in water, and then partitioned and ethyl acetate fraction was further chromatographed on a silica gel to afford 1,5-DCQA with spectra analysis as reported previously . 3,5-DCQA, 4,5-DCQA, 1,4-DCQA, and 3,4-DCQA were identified by spectral analysis  (Fig. 1).
α-Glucosidase inhibitory activities of dicaffeoylquinic acid derivatives
Dicaffeoylquinic acid derivatives were assessed for their α-glucosidase inhibitory activity. It was observed that 3,5-DCQA exhibited 60.65 ± 1.97% inhibitory activity at 50 μΜ (Fig. 2A). The 4,5-DCQA, 1,4-DCQA, 3,4-DCQA, and 1,5-DCQA exhibited 58.83 ± 2.71, 23.66 ± 2.81, 52.18 ± 2.67, 50.92 ± 2.37% activity at 100 μM respectively (Fig. 2B–E). Among the dicaffeoylquinic acid derivatives, 1,4-DCQA exhibited maximum inhibitory activity with IC50 51.75 ± 0.32 μM better than the activity shown by positive control (acarbose) with IC50 60.91 ± 3.85 μM (Fig. 2F).
Effects of dicaffeoylquinic acid derivatives on GSIS
Dicaffeoylquinic acid derivatives were evaluated for their GSIS activity. Since none of dicaffeoylquinic acid derivatives were toxic at all concentrations (2.5 to 10 μM), those concentrations were used in the GSIS assay (Fig. 3A–F). Dicaffeoylquinic acid derivatives led to an increase in GSI in a concentration-dependent manner. The GSI level was 3.59 ± 0.02 for 3,5-DCQA at 10 μM (Fig. 4A). The GSI levels were 4.39 ± 0.08 and 5.42 ± 0.07 for 4,5-DCQA at 5 μM and 10 μM, respectively (Fig. 4B). The GSI levels were 3.84 ± 0.11, 4.28 ± 0.13, and 3.51 ± 0.06 for 1,4-DCQA, 3,4-DCQA, and 1,5-DCQA at 10 μM, respectively (Fig. 4C–E). The GSI levels were 3.71 ± 0.19 and 6.41 ± 0.22 for gliclazide (positive control) at 5 μM and 10 μM, respectively (Fig. 4F). Although the GSIS activity of 4,5-DCQA was not superior to that of the same concentration of gliclazide, it is important that the GSI was increased approximately 5 times compared with control (0 μM).
Effect of 4,5-Dicaffeoylquinic acid on the protein expression of P-IRS-2, IRS-2, P-PI3K, P-ERK, ERK, PI3K, P-Akt (Ser473), and Akt, PDX-1
Treatment with 4,5-DCQA at 5 μM and 10 μM increased the protein expressions of extracellular signal-regulated protein kinases (ERK), insulin receptor substrate-2 (P-IRS-2), Akt, phosphoinositide 3-kinase (P-PI3K), and pancreatic and duodenal homeobox-1 (PDX-1) compared to untreated controls in INS-1 cells (Fig. 5).
Inhibitory effect of dicaffeoylquinic acid derivatives on α-glucosidase activity have been scientifically evaluated in the previous many studies [26,27,28]. In previous studies, 3,4-DCQA (IC50 = 128 μM), 4,5-DCQA (IC50 = 130 μM), and 3,5-DCQA (IC50 = 1166 μM) inhibit the α-glucosidase activity by 50% at a relatively high concentration [26, 28]. Our study showed similar results to previously reported data. In the present study, the effects of dicaffeoylquinic acid derivatives including 3,5-DCQA, 4,5-DCQA, 1,4-DCQA, 3,4-DCQA, and 1,5-DCQA on α-glucosidase activity were compared, and all exhibit inhibitory activity. α-Glucosidase inhibitory activities of dicaffeoylquinic acid derivatives are as follows 1,4-DCQA > 1,5-DCQA > 3,4-DCQA > 4,5-DCQA > 3,5-DCQA. 1,4-DCQA exhibited maximum inhibitory activity with IC50 of 51.75 ± 0.32 μM better than the activity shown by acarbose (positive control) with IC50 of 60.91 ± 3.85 μM. Among the dicaffeoylquinic acid derivatives, less has been reported for effect of 1,4-DCQA on α-glucosidase activity . It has been reported that 1,4-DCQA inhibits production of tumor necrosis factor‑α (TNF-α) and nitric oxide considered as major inflammation marker in lipopolysaccharide‑activated murine macrophage RAW 264.7 cells, whereas 1,5-DCQA and 3,5-DCQA have no inhibitory effect on TNF-α production . The DCQA derivatives used in our study differ only in the arrangement of dicaffeoylquinic acid in the same quinic acid structure. When considering these results, the position of caffeoyl group at the quinic acid moiety might attribute their biological activity.
Little is known about effects of dicaffeoylquinic acid derivatives on insulin secretion compared to their α-glucosidase activities in the in vivo and in vitro models of type 2 DM. Although it has been suggested that Gynura divaricata rich in 4,5-DCQA restore pancreatic function in type 2 DM mice , the effect on 4,5-DCQA itself has not been investigated yet. In the present study, we compared the effects of dicaffeoylquinic acid derivatives including 3,5-DCQA, 4,5-DCQA, 1,4-DCQA, 3,4-DCQA, and 1,5-DCQA on GSIS activity, and all exhibit inhibitory activity without toxicity in INS-1 cells. GSIS activities of dicaffeoylquinic acid derivatives are as follows 4,5-DCQA > 3,4-DCQA > 1,4-DCQA > 3,5-DCQA > 1,5-DCQA. 4,5-DCQA exhibited maximum activity. These findings indicate that the location of the dicaffeoyl functional group influences the anti-diabetic activity of quinic acid. However, we could not speculate the importance of the number of caffeoyl groups at the quinic acid moiety responsible for biological activity of DCQAs, and need for further studies in our future studies.
In addition, treatment with 4,5-DCQA increased protein expressions of ERK, IRS-2, PDX-1, Akt, and PI3K compared to untreated controls in INS-1 cells. These results indicated that GSIS activity of 4,5-DCQA might be partly related to PDX-1 expression via IRS-2/Akt/PI3K signaling pathway and ERK expression. ERK belongs to the mitogen-activated protein kinases (MAPK) family and plays an essential role in regulating not only cellular apoptosis and proliferation, but also differentiation. Earlier study indicates that the MAPK inhibitor PD98059 inhibit ERK phosphorylation and GSIS in β-TC6 mouse pancreatic cells .
Similar results are observed with U0126, a specific MAPK/ERK kinase inhibitor, reduces GSIS in mice pancreatic islets. ERK appears to regulate pancreatic β-cell survival and expression of insulin gene . Many studies have shown that phosphorylated IRS-2 triggers PI3K/Akt pathway activation, and the participation of IRS-2/PI3K/Akt signaling in the regulation of maintenance of β-cell mass and normal pancreatic β‑cell function is demonstrated . In addition, IRS-2/PI3K/Akt signaling is known as the upstream of PDX-1. It has been reported that administration of Gynura divaricata rich in 4,5-DCQA enhances the PDX-1 expression in the pancreatic tissue of diabetic mice, thus retaining mature β-cell function . PDX-1 is a vital transcription factor in the development of pancreas and transactivates insulin gene. Moreover, impaired GSIS is observed in PDX-1-deficient mice [34, 35]. Our current study suggested that treatment with 4,5-DCQA increased the PDX-1 expression via IRS-2/Akt/PI3K signaling pathway and ERK1/2 expression. These results supported the possibility of application of 4,5-DCQA as an antidiabetic agent that can ameliorate GSIS.
Based on the results, we reported the potent α-glucosidase inhibitory potential of dicaffeoylquinic acid derivatives and their GSIS effect. All dicaffeoylquinic acid derivatives exerted promising α-glucosidase inhibitory effects. 1,4-DCQA among dicaffeoylquinic acid derivatives exhibited maximum inhibitory effcets. Further, GSIS assay supported potentiation effect on GSIS shown by the dicaffeoylquinic acid derivatives. In addition, GSIS effect of 4,5-DCQA was supported by increased protein expressions of ERK, IRS-2, Akt, PI3K, and PDX-1. Our study provided partial evidence for the applicability of dicaffeoylquinic acid derivatives as candidates in the treatment of diabetes. However, further study including effect in animal models of T2D and in human islets are necessary.
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This research was supported by UNDBIO Co. Ltd. This research was also supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by Ministry of Science & ICT (2020M3A9E4104380).
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Lee, D., Lee, HD., Kwon, H. et al. Insulin secretion and α-glucosidase inhibitory effects of dicaffeoylquinic acid derivatives. Appl Biol Chem 65, 22 (2022). https://doi.org/10.1186/s13765-022-00688-9
- Dicaffeoylquinic acid derivatives
- Glucose-stimulated insulin secretion