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ABSTRACT

Increasingly westernized eating habits and insufficient physical activity have increased prevalence of type 2 diabetes in Korea. Green tea extracts (GTE) obtained from Camellia sinensis have shown beneficial effects particularly on glucose metabolism and transport. Thus, many studies have been done on GTE for its actions on glucose control and insulin sensitivity. However, most of them were performed on cells and animals and not so many were on humans. Therefore, we conducted an open-label, crossover clinical study using AP GTE provides by AmorePacific Corporation R&D Center and investigated its effects on postprandial blood glucose after a high-fat/high-carbohydrate meal. Twenty subjects (men and women) aged ≥ 19 years with a body mass index (BMI) of 18.5–29.9 kg/m2 and fasting glucose of 100–139 mg/dL were enrolled. First, the control study was performed, where all subjects were fasted for 12 hours and blood (35 mL) was collected from before (0 hours) they consumed a high-fat/high-carbohydrate meal and at 0.5, 1, 2, 3, 4, and 5 hours after the meal. After at least a week of washout period, AP GTE study was performed in the same way except taking 4 tablets of AP GTE after ingesting the same high-fat/high-carbohydrate meal. The blood samples were used for assessment of glucose and insulin concentrations. AP GTE-treated subjects had significantly lower plasma concentrations of glucose and insulin over 5 hours than the subjects not treated with AP GTE. During the experiment, no adverse effects were reported from the clinical laboratory testing, vital signs, and physical examinations. These results suggest that AP GTE supplementation may give beneficial effects to subjects who need glycemic control.

Trial Registration: ClinicalTrials.gov Identifier: NCT04850326

Keywords: Green Tea Extracts; Glucose; Insulin; Clinical Study

INTRODUCTION

Diabetes mellitus is a significant public health problem affecting 7.7% of the world adult population older than 20 years.1 In Korea, the prevalence of diabetes has increased 5 to 6 times from 1.5% to 7%–9% during the past 30 years.2 Increasingly westernized eating habits and insufficient physical activity have a large influence on the increasing incidence of diabetes in Korea.3

Food Suppl Biomater Health. 2021 Sep;1(3):e32https://doi.org/10.52361/fsbh.2021.1.e32pISSN 2765-4362·eISSN 2765-4699

Original Article

Received: Aug 13, 2021Revised: Sep 27, 2021Accepted: Sep 27, 2021

Correspondence:Jae-Heon Kang, MD, PhDDepartment of Family Medicine, Sungkyunkwan University Kangbuk Samsung Hospital, 29 Saemunan-ro, Jongno-gu, Seoul 03181, Korea.E-mail: jhkang100495@gmail.com

© 2021 Health Supplements Future ForumThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

ORCID iDsJae-Heon Kang https://orcid.org/0000-0002-5209-0824Hyun-Jin Nam https://orcid.org/0000-0002-6368-883XKyoungmi Jung https://orcid.org/0000-0002-4453-5096Gyeyoung Choi https://orcid.org/0000-0002-9679-8779Ji-Hae Lee https://orcid.org/0000-0002-5708-8336Hyun Woo Jeong https://orcid.org/0000-0003-1815-166XJonghwa Roh https://orcid.org/0000-0001-9899-6640Wangi Kim https://orcid.org/0000-0001-9687-1545

Jae-Heon Kang ,1 Hyun-Jin Nam ,2 Kyoungmi Jung ,2 Gyeyoung Choi ,2 Ji-Hae Lee ,2 Hyun Woo Jeong ,2 Jonghwa Roh ,2 Wangi Kim 2

1Department of Family Medicine, Sungkyunkwan University Kangbuk Samsung Hospital, Seoul, Korea2Laboratory of Healthcare, AmorePacific Corporation R&D Center, Yongin, Korea

Clinical Study on the Effects of AmorePacific Green Tea Extract (AP GTE) on Postprandial Blood Glucose and Insulin after a High-Fat/High-Carbohydrate Meal

https://e-fsbh.org

Trial RegistrationClinicalTrials.gov Identifier: NCT04850326

FundingThis research was supported by AmorePacific Corporation.

DisclosureKang JH received a research grant from AmorePacific Corporation. The other authors have no potential conflicts of interest to disclose.

Author ContributionsConceptualization: Kang JH, Kim W. Data curation: Jung K, Lee JH. Formal analysis: Jung K. Methodology: Nam HJ, Jung K, Kang JH. Software: Jung K, Lee JH. Validation: Nam HJ, Choi G, Jeong HW, Rho JH. Investigation: Kang JH. Writing-original draft: Nam HJ, Jung K. Writing-review & editing: Kang JH, Roh J, Lee JH, Choi G, Jeong HW, Kim W.

As the incidence of diabetes increases, the prevalence of prediabetes is increasing worldwide, and the importance of prediabetes management continues to be emphasized. According to the Centers of Disease Control and Prevention National Diabetes Statistics Report, 37% of adults aged older than 20 years from 2009 through 2012 in the United States had prediabetes,4 and more than 470 million people will have prediabetes by 2030.5 Prediabetes is a condition characterized by blood glucose levels that are above the normal range, but still fall below the diagnostic threshold for type 2 diabetes (T2D). According to the Korea Diabetes Association, it can be diagnosed through the following means: fasting plasma glucose of 100–125 mg/dL, glucose level of 140–199 mg/dL 2 hours after a 75 g oral glucose load, and/or 5.7%–6.4% hemoglobin A1c (HbA1c).6 In addition, prediabetes is related to other health risks, including nephropathy, kidney disease, neuropathies, retinopathy, and macrovascular disease.7 People with prediabetes have an increased risk of developing T2D but can return to normal blood glucose with proper diet and lifestyle adjustments.8 Accordingly, management of prediabetes remains an essential part of public health.

Green tea extracts (GTE) originating from Camellia sinensis have shown beneficial effects, including antioxidant, anti-inflammatory, anticarcinogenic, and hypoglycemic effects. In particular, epigallocatechin gallate (EGCG), the most abundant catechin in GTE, is involved in blood sugar control and represses hepatic glucose production.9 Co-consumption of polysaccharides and GTE inhibited intestinal transport of glucose in Caco-2 cells.10 Intake of catechin-rich GTEs with polysaccharides and flavonols derived from green tea delayed absorption of added sugars in an in vitro gastrointestinal digestion model system with Caco-2 cells.11 In addition, GTE improved glucose and insulin tolerance in high-fat diet-fed C57/BL6 mice.12

A meta-analysis of 17 randomized controlled trials suggested that green tea showed favorable effects on glucose control and insulin sensitivity by reducing fasting glucose and HbA1c levels.13 Daily supplementary intake of GTE containing 560 mg polyphenols reduced fasting glucose in overweight women, and supplementation with 400 or 800 mg EGCG showed statistically significant differences in glucose and insulin levels compared to supplementation with a placebo in healthy postmenopausal women.14,15 Moreover, intake of EGCG (300 mg) also significantly reduced plasma glucose concentration in subjects with impaired glucose tolerance compared to placebo intake.16

Acute GTE ingestion increased fat oxidation and improved glucose tolerance compared to placebo ingestion in healthy humans.17 Using the oral glucose tolerance test, reductions in blood glucose levels were observed in healthy humans after drinking green tea (1.5 g) compared with drinking a placebo.18

The present clinical study (NCT04850326) investigated the effects of AP GTE on postprandial blood glucose after a high-fat/high-carbohydrate meal in semi-healthy humans over 5 hours.

METHODS

Study designThis study was conducted as an open-label, cross-over clinical trial at a single center in the Republic of Korea between July 2020 and January 2021 (NCT04850326). Informed consent was submitted by all subjects when they were enrolled. This trial was performed in compliance with the provisions of the Declaration of Helsinki, International Conference on Harmonization

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Good Clinical Practice guidelines, and applicable regulatory requirements. The Institutional Review Board (IRB) of Kangbuk Samsung Hospital approved all study protocols, informed consent forms, and relevant supporting data (IRB No. KBSMC 2019-09-037-001).

Subject selectionThe inclusion criteria were as follows: male or female subjects aged ≥ 19 years; body mass index (BMI), 18.5–29.9 kg/m2; and fasting glucose, 100–139 mg/dL. Subjects with a fasting glucose level of 126–139 mg/dL and were under medication or needed medication according to the investigator's medical opinion were excluded. Subjects voluntarily decided to participate in this clinical study and signed an informed consent form on their own or through their representatives.

Participants with the following conditions were also excluded: obesity, diabetes, dyslipidemia, cardiovascular diseases (heart failure, angina pectoris, and myocardial infarction), uncontrolled chronic internal medical diseases (liver disease, renal failure, hypertension, etc.), hyper/hypothyroidism, active malignant tumor, acute or chronic hepatitis (an alanine aminotransferase/aspartate aminotransferase ratio of ≥ 3 × the upper limit of the normal range), and renal failure (creatinine level of ≥ 1.5 × the upper limit of the normal range). In addition, subjects could be deemed ineligible to participate in this clinical study according to the investigator's medical opinion.

Assays for glucose and insulinAssessment for concentrations of glucose (mg/dL) and insulin (µIU/mL) were performed at the Department of Diagnostic Laboratory Medicine in Kangbuk Samsung Hospital.

Preparation of AP GTEAP GTE was formulated with green tea extracts and crude tea polysaccharides (CTP) and fractions rich in flavonol glycosides (FLGs). In brief, the dried green tea leaves (Camellia sinensis produced from Osulloc farm, Jeju, Korea) were first extracted with 50% ethanol for 1 hour at 70°C, and the reaction was centrifuged. The supernatants were concentrated using a vacuum evaporator and dried with a spray dryer. The precipitate obtained was called GTE. The content of catechins in GTE was determined by HPLC (Waters Alliance 2695; Waters, Milford, MA, USA).The residue was further extracted with water, concentrated and dried. The resulting residue was called CTP. The GTE was treated with approximately 1% of celluose for 30 minutes at 70°C and dried out. The obtained residue was called FLGs. The mixture of GTE, CTP and FLGs (10:1:1) was called AP GTE which was used in this experiment.

Treatment planThis was an open-label, crossover study. A total of 20 eligible subjects were recruited to participate in two one-day studies separated by a washout period of at least one week. First, all subjects were allocated to the control group. After a 12-hour fast, baseline blood (0 hours) was collected from the peripheral vein in the forearm. Subjects then consumed a high-fat/high-carbohydrate meal (1,074 kcal: carbohydrate ~123 g, fat ~49 g, and protein ~34.4 g). Subsequently, blood samples were collected at 0.5, 1, 2, 3, 4, and 5 hours after meal completion. No food was allowed until the end of the study (5 hours). After the wash-out period (7–11 days), all subjects were allocated to the AP GTE treatment group. After fasting for 12 hours, the subjects took four AP GTE tablets immediately after ingesting the same high-fat/high-carbohydrate meal under the same conditions. The AP GTE tablets were provided by the AmorePacific R&D Center (Yongin, Korea). One AP GTE tablet contains 0.5 g of GTE consisting of 122.31 mg catechins.

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Efficacy and safety evaluationsThe efficacy evaluations were based on changes in concentrations of glucose (mg/dL), insulin (µIU/mL), and triglycerides (mg/dL) at 0, 0.5, 1, 2, 3, 4, and 5 hours. Safety and tolerability were evaluated by adverse event (AE) reporting, clinical laboratory testing, vital signs, and physical examinations.

Statistical analysisThe full analysis set (FAS) population was used for all efficacy analyses using JMP® software (Version 15.1.0, SAS Institute, Cary, NC, USA). For efficacy analysis, differences between the control and AP GTE treatment groups were analyzed using t-test. The safety population included all patients who were administered the investigational product at least once. Differences between the groups in terms of treatment-emergent AEs, adverse drug reactions, and serious AEs were analyzed using Pearson's χ2 test or Fisher's exact test and coded using the system organ classes and MedDRA version 21.0. P < 0.05 was considered statistically significant.

RESULTS

Study design and subject dispositionA total of 39 subjects were screened, and 20 were assigned to the control and AP GTE treatment groups (n = 20) consecutively, separated by at least a one-week washout period (Fig. 1A and B). Twenty subjects received AP GTE and were analyzed for safety of the materials tested and completed the study treatment. Of these subjects, 55.0% were female, with a mean age of 39.80 ± 13.66 years. Mean fasting glucose and BMI levels were 102.63 ± 8.65 mg/dL and 24.72 ± 3.72 kg/m2, respectively (Table 1).

EfficacyThe baseline glucose plasma concentrations of the control (102.9 ± 8.9 mg/dL) and AP GTE treatment (102.4 ± 8.6 mg/dL) groups were similar. We observed larger reductions of glucose

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Excluded (n = 19)• Screening failure (n = 19)

Randomized (n = 20)Control and AP GTE treatment group

Completed (n = 20)• Analyzed (n = 20), full analysis set

Assessed for eligibility (n = 39)

Visit 1

A

B

~10 days

ScreeningVisit 2

0 0.5 1 2 3 4 5 hr

Visit 3

7–11 days0 0.5 1 2 3 4 5 hr

Control AP GTE

Wash-outperiod

Fig. 1. Study design and subject disposition. (A) Study design. (B) Subject disposition. GTE = green tea extract.

plasma concentrations in the AP GTE treatment group at 0.5 hour after consuming a high-fat/high-carbohydrate meal. Statistically significant differences in glucose between the 2 groups were observed at 1 hour (control: 133.4 ± 27.8 mg/dL vs. AP GTE: 120.4 ± 28.0 mg/dL) and maintained for 4 hours (Fig. 2A). Similarly, AP GTE-treated subjects had a greater reduction in plasma concentrations of insulin compared to the control group over 5 hours (Fig. 2B). There were no significant differences in triglyceride concentrations (data not shown). In addition, significant differences were observed in the area under the curve (AUC) for glucose and insulin between the two groups (Fig. 3A and B). We also observed a decreasing tendency of the maximum concentration (Cmax) values for glucose and insulin in the AP GTE treatment group compared to the control group (data not shown).

SafetyThe AP GTE group showed a favorable safety profile, and the incidence of AEs was 0.0% in both the control and treatment groups. No adverse drug reactions or serious AEs were observed. Additionally, no clinically significant abnormalities were found in the subjects' clinical laboratory values, vital signs, or physical examinations.

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Table 1. Baseline demographics (n = 20)Subjects ValuesAge (yr) 39.80 ± 13.66

19–29 6 (30.0)30–39 6 (30.0)40–49 2 (10.0)50–59 5 (25.0)60–70 1 (5.0)

Sex, male 9 (45.0)Height (cm) 165.22 ± 7.62Weight (kg) 67.85 ± 13.33Fasting glucose (mg/dL) 102.63 ± 8.65BMI (kg/m2) 24.72 ± 3.75Values are expressed as mean ± standard deviation or number (%).

80

150

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Plas

ma

gluc

ose

(mg/

dL)

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80

70

60

50

40

30

10

20

B

Plas

ma

insu

lin (µ

IU/m

L)

0 0.5 1 2 3 4 5Time (hr)

ControlAP-GTE

*

** **

0 0.5 1 2 3 4 5Time (hr)

ControlAP-GTE

**

*

Fig. 2. Effects of AP GTE on plasma concentrations of glucose (A) and insulin (B) after a high-fat/high-carbohydrate meal. In the control study, all subjects were fasted for 12 hours and blood (35 mL) was collected from before (0 hours) they consumed a high-fat/high-carbohydrate meal and at 0.5, 1, 2, 3, 4, and 5 hours after the meal. After at least a week of washout period, AP GTE study was performed in the same way except taking 4 tablets of AP GTE after taking the same high-fat/high-carbohydrate meal. The blood samples were used for assessment of glucose and insulin concentrations. Differences between the two groups were determined by using a paired t-test. GTE = green tea extract. *P < 0.05, **P < 0.01 vs. control.

DISCUSSION

This clinical study demonstrated that treatment with AP GTE consisting of catechins, CTP, and fractions rich in FLGs in subjects with a BMI of 18.5–29.9 kg/m2 and fasting glucose of 100–139 mg/dL aged ≥ 19 years, resulted in a greater reduction in the concentrations of glucose and insulin when compared with the control group. These results indicate that consuming AP GTE after a high-fat/high-carbohydrate meal may improve glucose control and insulin sensitivity.

The molecular mechanisms of GTE in glycemic control have been studied throughout the world. EGCG, a major component of GTE, acts as a trigger for metabolic switch favoring energy catabolism. It activates adenosine monophosphate-activated protein kinase to enhance fatty acid oxidation and repress lipogenesis.19,20 It also induces autophagic lipolysis to reduce intracellular lipid content.21,22 GTE also relieves lipid dysregulation and glucose intolerance by regulating inflammatory responses and compositional changes in the gut microbiota.12 Considering the role of extra lipids (e.g., free fatty acids) in the development of chronic inflammation, a major causal factor for insulin resistance and related metabolic complications, amelioration of lipid dysregulation by EGCG and GTE would be beneficial in glycemic control measures.

Conversely, GTE and EGCG can act directly in the gastrointestinal tract through the regulation of digestion and absorption of carbohydrates to maintain glucose homeostasis. EGCG can bind to α-amylase and α-glucosidase to inhibit its enzymatic activity through the induction of their conformational change, respectively.23,24 Besides, flavonols are also proposed to interact with α-amylase to suppress starch digestion.25 Considering the amount of EGCG in AP GTE, it is feasible that AP GTE exerts inhibitory effects on carbohydrate-digesting enzymes.

In an in vitro digestion-mimicking system using CaCo-2 cells, polysaccharides in combination with GTE reduced the digestion of rich starch and intestinal glucose transport.10,26 The expression of the sodium-dependent glucose cotransporter which

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400

700

650

600

550

500

450

A

Glu

cose

AUC

(mg/

dL/h

r)

Control AP-GTE100

250

200

150

B

Insu

lin A

UC (µ

IU/m

L/hr

)

Control AP-GTE

**

*

Fig. 3. AUC for (A) glucose and (B) insulin over the 5 hours period in both control and AP GTE groups. The experimental conditions were the same as in Fig. 2. Differences between the 2 groups were determined by using a paired t-test. AUC = area under the curve, GTE = green tea extract. *P < 0.05, **P < 0.01 vs. control.

mediates the intestinal transport of glucose was decreased by co-treatment with GTE and polysaccharides from green tea,10 indicating that AP GTE is able to control glucose metabolism through the regulation of glucose transporters in the gastrointestinal tract. Absorbed glucose is further transported to skeletal muscle cells by EGCG and GTE-mediated glucose transporter 4 translocation, thereby decreasing circulating glucose level.27,28 Through the multi-step regulation of glucose metabolism, AP GTE could effectively alleviate glucose intolerance. Recently evidence indicates that green tea-derived polysaccharides form resistant starch which interferes with carbohydrate digestion (Oh et al., unpublished data). In combination with catechins, polysaccharides are expected to boost the anti-hyperglycemic effect of AP GTE.

In this clinical study, we proved that AP GTE improves glycemic control after a high-fat/high-carbohydrate meal. Consumption of AP GTE resulted in immediate reduction in plasma glucose and insulin levels, in accordance with the AUC and Cmax values trends which indicated reductions, confirming the ability of the AP GTE to control postprandial blood glucose. Regarding the experimental design, the effect of AP GTE on glycemic control is primarily mediated by the regulation of digestion and absorption of carbohydrates. There is supporting evidence that each component of the AP GTE boosts the hypoglycemic effect of green tea, and according to these results, it is recommended to serve GTE in combination with CTP and FLGs to treat metabolic disorders, including hyperglycemia and insulin resistance.

Treatment with AP GTE exerted a favorable safety profile and improved glycemic control over a 5-hour treatment after a high-fat/high-carbohydrate meal. Our study is meaningful because this is first time to prove the GTE's postprandial glycaemia-lowering effects in human, although GTE's anti-glycemic effects are previously well studied, and the potential for blood glucose control by insulin resistance studied in vivo was confirmed through this clinical study.

However, our study had several limitations, including a small sample size and a short treatment period. In addition, this study was not a double-blind, randomized-controlled trial. Therefore, further clinical studies to evaluate the efficacy of AP GTE on glucose metabolism with a longer treatment period and a double-blinded, randomized controlled study design with a larger sample size are needed. Long-term administration of AP GTE would provide greater efficacy to glycemic and lipidemic control through short-term and long-term regulatory mechanisms.

In conclusion, AP GTE supplementation in subjects with a BMI of 18.5–29.9 kg/m2 and fasting glucose of 100–139 mg/dL had beneficial effects on glycemic control by reducing plasma levels of glucose and insulin. These results show that AP GTE may be a beneficial dietary supplement to enhance public health in subjects who need glycemic control.

ACKNOWLEDGMENTS

The authors are grateful to the subjects for their participation in this study and the investigator and study team (AmorePacific Corporation R&D Center) for their contributions.

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