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. 2022 Mar 25;31(8):1073–1080. doi: 10.1007/s10068-022-01068-1

Capsicum annuum L. cv. DANGJO ameliorated hyperglycemia in type 2 diabetes animal model induced by high-fat diet and streptozotocin

Jin Tae Kim 1, Yimeng Zhou 1, Shuai Qiu 1, Seung Beom Lee 1, Ho Jin Park 1, Min Jeong Kim 2, Sung Keun Jung 2, Eunbin Seo 3, Young-Jun Kim 3, Hong Jin Lee 1,✉
PMCID: PMC9300795  PMID: 35873370

Abstract

In this study, it was evaluated the effect of freeze-dried powder of Capsicum annuum L. cv. DANGJO (DJ) on ameliorating hyperglycemia in type 2 diabetes rat model induced by high-fat diet (HFD) and streptozotocin (STZ). Oral administration of DJ significantly reduced non-fasting blood glucose (NFBG) and insulin levels, as well as glycated hemoglobin (HbA1c) level, a representative marker for diabetes, in HFD/STZ treated rats whereas the administration of green hot pepper (GHP) and green sweet pepper (GSP) did not show the significant effect. Quercitrin was quantified (40.97 mg/100 g of DJ) by HPLC, and administration of the same amount of quercitrin with DJ exerted the significant reduction of blood glucose level, strongly supporting that quercitrin is the key component in ameliorating the hyperglycemia of DJ in HFD/STZ treated rats. These results suggest that DJ can be considered as a potent functional food in preventing hyperglycemia in type 2 diabetes mellitus.

Keywords: DANGJO, Glycated hemoglobin, Hyperglycemia, Quercitrin, Type 2 diabetes mellitus

Introduction

Diabetes mellitus is one of the major causes of death and the prevalence of diabetes was estimated to increase to 7.7% among adults in 2030 in the world, which indicates a 69% increase between 2010 and 2030 (Zheng et al., 2018) (Shaw et al., 2010). Approximately 90% of diabetes mellitus is type 2 diabetes mellitus (T2DM); the number of patients with T2DM in Asia is rapidly growing (Zheng et al., 2018). Diabetes mellitus is characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both (American Diabetes Association, 2009). In particular, the accumulating evidence has demonstrated that insulin resistance and the early loss of function in pancreatic β-cell play crucial roles in the pathogenesis of T2DM (Unnikrishnan et al., 2017). To prevent or delay the development of T2DM and the related complication, the inhibitors targeting alpha‐glucosidase have been investigated (Moelands et al., 2018). Due to the associated side effect in gastrointestinal tract by synthetic alpha‐glucosidase inhibitors, the phytochemicals such as alkaloids, flavonoids, and terpenoids as well as the plant extracts have been evaluated for suppressing the alpha‐glucosidase activity (Assefa et al., 2020; Gong et al., 2020).

Peppers belonging to Capsicum species are attractive natural materials that contain different natural inhibitors of α-amylase and α-glucosidase, the key enzymes that hydrolyze polysaccharides into glucose (Kwon et al., 2007), and their extracts have been also demonstrated to possess activity of α-glucosidase and α-amylase inhibition (Watcharachaisoponsiri et al., 2016). Capsicum annuum L.cv. DANGJO (DJ), a new cultivar developed in Korea, was reported to contain approximately 5 times higher amount of α-glucosidase inhibitors than other Capsicum species (Zhu, 2015), and its ethanol extract showed the significant effect on inhibiting the activity of starch degrading enzymes (Lee, 2017), suggesting the possible roles of DJ in regulating the blood glucose. In addition, Park et al. demonstrated that water extract of DJ leaves possesses the inhibitory activity of α-glucosidase and α-amylase in vitro and in vivo, and luteolin-7-O-glucoside was suggested as the key component (Park, 2016). However, the effect of the whole powder of DJ pepper on glycemic regulation in type 2 diabetes mellitus (T2DM) animal model and the underlying mechanism has not been investigated.

The T2DM animal model has been developed to mimic the pathogenesis of disease in human, including alloxan/streptozotocin (STZ), high-fat diet (HFD), fructose, or monosodium glutamate indued model (Islam and Loots du, 2009). However, STZ injection was not enough to induce insulin resistance and HFD feeding failed to cause pancreatic β-cell dysfunction (Islam and Loots du, 2009). Therefore, it was developed the combination treatment model of high-fat diet (HFD) feeding which reduced glucose disappearance rate and low dose of streptozotocin (STZ) injection which induced hyperglycemia by partial pancreatic β-cell dysfunction (Srinivasan et al., 2005). In addition, HFD/STZ model was found to be responsive to the anti-diabetic drugs (Islam and Loots du, 2009), suggesting the model as an appropriate choice for evaluating the efficacy of natural and dietary agents in T2DM prevention.

In this study, we evaluated the effect of the whole fruit powder of DJ on ameliorating the hyperglycemia in HFD-fed/STZ-injected T2DM animal model and compared with commonly consumed peppers in Korea, green hot pepper (GHP) and green sweet pepper (GSP). In addition, the potent candidate which is responsible for the functionality of DJ, quercitrin, was investigated in the same animal model.

Material and methods

Materials and diet preparation

Capsicum annuum L. cultivar DANGJO (DJ), green hot pepper (GHP), and green sweet pepper (GSP) were purchased from the local market in Wanju-Gun (Jeollabuk-do, Korea). STZ was purchased from Sigma-Aldrich (ST. Louis, USA), and quercitrin was from Chemfaces (Hubei, China). DJ, GHP, and GSP were freeze-dried (IlShin Lab Co., Ltd, Kyunggi-do, Korea). After pulverization, the powders were mixed with 60% high fat diet (HFD) containing crude protein (23.5%), fat (34.3%) and carbohydrate (27.3%) (Envigo, USA). The diets of DJ-L (0.4%), DJ-H (2.0%), GHP (2.0%), and GSP (2.0%) were prepared (DooYeol Biotech, Seoul, Korea).

Animal study

In the first animal study, adult male Sprague–Dawley (SD) rats (150-200 g) were purchased from DooYeol Biotech, and randomly divided into six groups: Control (Con, n = 5), HFD + STZ (T2DM, n = 8), T2DM + DJ-L (n = 8), T2DM + DJ-H (n = 8), T2DM + GHP (n = 8), and T2DM + GSP (n = 8). All animals were housed at under controlled conditions of relative humidity (50 ± 10%), and room temperature (25 ± 5 °C) with 12 h light and dark cycles. The animals except Con group were fed with HFD for 2 weeks, and STZ (40 mg/kg BW) was injected intraperitoneally. Then, the formulated diets were provided for 4 weeks. One week after STZ injection, the non-fasting blood glucose (NFBG) in the blood from the tail was measured every week with a portable gluco-meter (Accu chek Active, Roche Diagnostics Ltd, Germany). Body weight, food intake and water intake were measured every week. In the second animal study, the rats were randomly divided into four groups: Control (Con, n = 5), HFD + STZ (T2DM, n = 8), T2DM + DJ-H (n = 8), T2DM + Quercitrin (3 mg/Kg BW, n = 8). The experimental scheme is same with the first experiment. Quercitrin was provided by oral administration after dissolving in medium chain triglycerides oil (MCT). All animal experiments were performed according to the guidelines and approved from the Animal Care and Use Committee at Chung-Ang University (Approval number: A2021035).

Blood collection and analysis of blood markers for toxicity and diabetes mellitus

Fourteen hours before the sacrifice, the rats were starved, and then blood was collected by cardiac puncture. The blood was saved in K2 EDTA (K2E) blood collection tube (Becton, Dickinson and Company, Franklin, NJ, USA) to obtain blood plasma for the analysis of hemoglobin A1C (HbA1C). The serum was also collected after centrifugation at 3,000 rpm for 15 min at 25 °C. The liver toxicity markers including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum and HbA1c level in blood plasma were analyzed using a biochemical blood analyzer (BS220, Mindray, China) and Hematology Analyzer (Procyte-Dx, ME, USA), respectively. The level of insulin in the serum was measured by ELISA kits (Shibayagi, Shibukawa, Japan), following the manufacturer’s guidance. In brief, the serum was incubated in the well where the antibody is pre-coated. Then, the primary antibody and horseradish peroxidase (HRP)-conjugated secondary antibody were treated. After the substrate solution added, the developed color was measured at 450 nm (Molecular devices, San Jose, CA, USA).

Quantification of quercitrin

Quercitrin was analyzed using a method described by Kwak et al. (2017) with slight modifications. Agilent 1200 series HPLC (Agilent, Palo Alto, CA, USA) with a diode array detector (DAD) was used for the quercitrin analysis. The freeze-dried DJ (1.0 g) was dissolved in methanol (50 mL, J.T. Baker, Phillipsburg, NJ, USA). The mixture was ultrasonically extracted at 65 °C for 60 min, cooled at room temperature, and filtered through a 0.45 μm syringe filter (Sartorius Minisart®, Sartorius RC, Göttingen, Germany). A Capcell Pak C18 UG120 column (4.6 mm i.d. × 250 mm; 5 μm; Osaka Soda Co., Ltd., Osaka, Japan) was applied for chromatographic separation at 40 °C. HPLC analysis was performed using mobile phase A (0.1% formic acid in distilled water) and B (methanol) in a gradient program at a flow rate of 1.0 mL/min. The gradient program was 0–40 min, 30–50% B; 41–43 min, 100% B; and 44–50 min, 30% B. The DAD was positioned at a wavelength of 360 nm (Kwak et al., 2017). The determination was performed five times and the results were shown as average ± SD (mg/100 g) with the relative standard deviation [RSD (%) = (standard deviation/mean measured amount) × 100].

Statistical analysis

The data was shown as means ± SD, and the statistical differences were analyzed by Student’s t-tests. When p value is lower than 0.05, it was considered statistically significant.

Results and discussion

DJ protected body weight loss and reduced daily water intake in HFD/STZ treated rats

After STZ injection, it was reported to be developed the phenotypic symptoms of diabetes mellitus such as increase of water intake and urine volume and loss of body weight, compared to the control (Akbarzadeh et al., 2007). In addition, the animals after HFD feeding and STZ injection exerted hyperglycemia and body weight loss (Magalhaes et al., 2019). In our study, we also confirmed that STZ injection to HFD-fed rats significantly induced the reduction of body weight from 429.04 ± 24.17 g in Con to 384.9 ± 28.08 g in T2DM, which was recovered to 420.57 ± 22.25 g and 420.49 ± 24.20 in DJ-L and DJ-H, respectively (Fig. 1(A)) whereas GHP and GSP did not exerted the effect (Fig. 1(A)). Daily water intake was also increased from 33.3 ± 3.0 mL in Con to 76.7 ± 16.1 mL in T2DM, which was decreased by DJ-H administration, but not by GHP and GSP administration (Fig. 1(B)). Daily food intake was not significantly affected by diets among the animals with STZ injection and HFD administration (Fig. 1(C)). These results indicate that DJ administration significantly ameliorated the diabetic symptoms in HFD/STZ treated animals.

Fig. 1.

Fig. 1

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Body weight changes, daily water intake and daily food intake. (A) Average of body weight changes during the animal experiment. (B) Average of daily water intake changes during the animal experiment. (C) Average of daily food intake changes during animal experiment. CON: control group; T2DM, HFD/STZ treated group; T2DM + DJ-L, HFD/STZ + 0.4% DJ treated group; T2DM + DJ-H, HFD/STZ + 2% DJ treated group; T2DM + GHP, HFD/STZ + 2% GHP treated group; T2DM + GSP, HFD/STZ + 2% GSP treated group. The results are expressed as mean ± SD. *Significant at p < 0.05, **Significant at p < 0.01, compared to T2D group

DJ significantly reduced the non-fasting blood glucose level in HFD/STZ treated rats without liver toxicity.

In the blood analysis, we first determined the possibility whether the diet administration may cause the liver toxicity. As shown in Table 1, the level of alanine transaminase (ALT) and aspartate transaminase (AST), the well-known markers of liver toxicity, was not significantly affected by different diet treatments. As reported previously (Oza and Kulkarni, 2018; Srinivasan et al., 2005), we confirmed that STZ injection to HFD-fed rats dramatically increased the non-fasting blood glucose level (> 300 mg/dL) which was maintained until the end of experiment, compared to Con (Fig. 2). The administration of DJ-H significantly reduced the level of non-fasting blood glucose from 410.14 ± 35.97 mg/dL to 287.38 ± 95.22 mg/dL at 4 weeks after STZ injection (Fig. 2). Interestingly, however, GHP and GSP administration exerted the significant effect at the first week and the second week after STZ injection, respectively, but the effect was not maintained until the end of animal experiment (Fig. 2). In HFD/STZ animal model, HFD and STZ are involved in inducing insulin resistance and hyperglycemia, respectively, leading to high blood glucose level (Lee et al., 2003). Therefore, the results indicate that DJ possess a potent activity ameliorating the hyperglycemia in HFD/STZ treated T2DM animals.

Table 1.

The effect of Capsicum annuum L. cv DANGJO on liver toxicity & lipid parameter in serum following type 2 diabetes model

CON T2DM T2DM + DJ-L T2DM + DJ-H T2DM + GHP T2DM + GSP
ALT (U/L) 48.96 ± 9.67 63.77 ± 26.32 45.66 ± 13.50 43.81 ± 10.92 68.01 ± 28.71 41.26 ± 10.20
AST (U/L) 184.02 ± 43.19 194.27 ± 89.29 204.25 ± 70.92 164.94 ± 35.86 271.14 ± 115.14 234.09 ± 55.24
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The results are expressed as mean ± SD in each group

ALT alanine transaminase, AST aspartate transaminase, DJ DANGJO pepper, GHP green hot pepper, GSP green sweet pepper

Fig. 2.

Fig. 2

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The level of non-fasting blood glucose (NFBG) by DJ, GHP, and GSP administration. The blood was collected from the tail every week, and NFBG level was measured as described in Materials and Methods. The results are expressed as mean ± SD. *Significant at p < 0.05, **Significant at p < 0.01, ***Significant at p < 0.001, compared to T2DM group

DJ reduced the blood level of glycated hemoglobin and insulin in HFD/STZ treated rats

Hemoglobin A1c (HbA1c) is a variant of hemoglobin (Hb) formed by glycation via nonenzymatic post-translational modification, and possesses glycated N-terminal β-chains (Peterson et al., 1998). The contents of HbA1c in the blood is positively associated with T2DM, HbA1c has been used as the key marker for monitoring glycemic control as well as diagnosing T2DM (English and Lenters-Westra, 2018). HFD/STZ treatment significantly increased the levels of HbA1c from 3.32 ± 0.64% to 8.94 ± 1.72%, compared to Con (Table 2). The oral administration of DJ-H significantly reduced the level of HbA1c to 6.30 ± 1.66% and exerted a dose-dependent responses. In addition, insulin level was also increased from 0.34 ± 0.19 to 1.14 ± 0.64 ng/mL by STZ injection, which was down-regulated to 0.57 ± 0.13 ng/mL by DJ-H administration (Table 2). We also confirmed that GHP and GSP administration did not exerted the significant reduction of HbA1c and insulin level although the average value is lower than that in HFD/STZ group. The increase of insulin sensitivity improves the carbohydrate metabolism regulating the blood glucose level (Andre et al., 2017), and the decrease of HbA1c level reduces the risk of T2DM development (English and Lenters-Westra, 2018). In addition, ethanol extract of DJ and the pasta prepared with DJ exerted the significant inhibition of in vitro activity of starch degrading enzymes, α-amylase and α-glucosidase (Lee, 2017; Lee and Joo, 2019). Taken together, DJ may improve hyperglycemia by suppressing the starch degrading enzymes in HFD/STZ treated rats.

Table 2.

The effect of Capsicum annuum L. cv DANGJO on diabetes parameter in type 2 diabetes model

CON T2DM T2DM + DJ-L T2DM + DJ-H T2DM + GHP T2DM + GSP
HbA1c (%) 3.32 ± 0.64*** 8.94 ± 1.72 7.69 ± 1.00 6.30 ± 1.66* 8.00 ± 0.40 8.39 ± 0.54
Insulin (ng/mL) 0.34 ± 0.19* 1.14 ± 0.64 0.68 ± 0.16 0.57 ± 0.13* 0.65 ± 0.14 0.73 ± 0.24
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DJ: DANGJO pepper, GHP: green hot pepper, GSP: green sweet pepper. The results are expressed as mean ± SD in each group. *Significant at p < 0.05, **Significant at p < 0.01 and *** significant at p < 0.001, compared to T2D treated group

Quercitrin, a major phenolic component in DJ, was quantified by HPLC

Recently, it was reported that quercitrin was identified as the major phenolic compound in both raw and griddled green pepper extract (Huarte et al., 2021). From the chromatographic profiling of Ashanti pepper seed extract, quercitrin was found to be the most abundant phenolic component, and the administration of Ashanti pepper seed in the diet improved the lipid profile and oxidative stress in acarbose-induced T2DM animal model (Adefegha et al., 2017). Therefore, we hypothesized that quercitrin may be a potent candidate responsible for the activity of DJ, and determined its concentration. The peak of quercitrin compound was verified by comparing the retention time in the HPLC chromatogram and the UV spectrum (Fig. 3(A)). Moreover, quercitrin quantification was calculated by comparing peak area with the external calibration curve from standard solution. The linear regression equation was Y = 17.92x + 4.591, r2 = 0.999. It was obtained from the calibration curve as Y = Ax + B, where A is the slope of the calibration curve, B is the intercept of the calibration curve, x is the concentration of quercitrin, and Y is the peak area. The average amount of quercitrin in DJ was determined to 40.97 ± 0.78 mg/100 g with 1.91% RSD. RSD results were within the acceptable range based on the AOAC guideline (AOAC, 2016).

Fig. 3.

Fig. 3

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Chromatogram of quercitrin and the level of non-fasting blood glucose (NFBG) by DJ and quercitrin administration. (A) Quercitrin chemical structure, HPLC–DAD Chromatogram and UV spectrum of DJ. The peak at retention time, 21.66 min, is quercitrin. (B) The blood was collected from the tail every week, and NFBG level was measured as described in Materials and Methods. The results are expressed as mean ± SD. *significant at p < 0.05, ** significant at p < 0.01, *** significant at p < 0.001, compared to T2DM group

Quercitrin significantly suppressed the increase of non-fasting blood glucose level in HFD/STZ treated rats

We conducted the second animal experiment to evaluate whether quercitrin may exert the significant activity in HFD/STZ-induced T2DM rat model. The amount of quercitrin in DJ-H diet was calculated, normalized with daily diet intake, and finally determined the concentration of quercitrin (3 mg/kg BW) in T2DM + Quercitrin group. Here, we confirmed that administration of DJ-H significantly reduced the level of NFBG from 381.38 ± 37.70 to 308.11 ± 72.39 mg/dL at the last week of experiment, corresponding to approximately 20% decrease, compared to the T2DM group (Fig. 3(B)). Quercitrin administration was also shown to the significant reduction of NFBG level from 381.38 ± 37.70 mg/dL to 339.89 ± 37.49 mg/dL, about 11% decrease compared to the T2DM group (Fig. 3(B)), indicating that quercitrin is the key component responsible for ameliorating hyperglycemia induced by HFD/STZ in rats.

In the study of antidiabetic properties of natural compounds and/or extract, the mechanism of action has been suggested as regulation of glucose transport from the intestinal lumen to the blood, inhibition of α-glucosidase activity in the brush border, and protection of pancreatic β-cell from reactive oxygen species (AL-Ishaq et al., 2019; Eid and Haddad, 2017). Quercetin glycosides was reported to inhibit sodium dependent and independent glucose uptake in the jejunum of pigs (Cermak et al., 2004). In addition, Babujanarthanam et al. (2010; 2011) showed that quercitrin administration (30 mg/kg BW) regulated the activity of glycolytic enzymes leading to the glucose homeostasis improvement as well as enhanced antioxidant status by increasing the activity of endogenous antioxidant enzymes and non-enzymatic antioxidants in STZ-treated diabetic rat model. In line with the previous studies, it is speculated that the effect of quercitrin administration on lowering the NFBG level in the current study may be derived from the combined activity in regulating glucose transport, inhibiting the glycolytic enzymes, and improving the antioxidant activity in HFD/STZ induced diabetic animal model.

In conclusion, we investigated the effect of DJ on improving the carbohydrate metabolism and found that DJ protected body weight loss and blood glucose level in HFD/STZ treated rats whereas the powder of other peppers, GHP and GSP was not effective. Furthermore, DJ administration significantly downregulated the level of HbAlc and insulin in the blood. After the quantification of quercitrin in DJ, administration of the same amount of quercitrin in HFD/STZ treated rats exerted the significant reduction of blood glucose level, strongly supporting that quercitrin is the main component in ameliorating the hyperglycemia of DJ. Taken together, DJ and a major component quercitrin can be considered as a potent functional food in preventing hyperglycemia in type 2 diabetes mellitus.

Acknowledgements

This research was supported by '2021 Discovering Functional Crops Project' of The Food Industry Promotional Agency of Korea.

Declarations

Conflict of interest

The authors declare no conflict of interest.

Footnotes

Publisher's Note

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

Change history

4/11/2022

A Correction to this paper has been published: 10.1007/s10068-022-01081-4

Contributor Information

Jin Tae Kim, Email: jiny-1001@nate.com.

Yimeng Zhou, Email: zym95@cau.edu.cn.

Shuai Qiu, Email: qsly2018@naver.com.

Seung Beom Lee, Email: lsbeee99@naver.com.

Ho Jin Park, Email: 1108ghwls@naver.com.

Min Jeong Kim, Email: minjung8128@gmail.com.

Sung Keun Jung, Email: skjung04@knu.ac.kr.

Eunbin Seo, Email: tjdmsqls95@naver.com.

Young-Jun Kim, Email: kimyj@seoultech.ac.kr.

Hong Jin Lee, Email: hongjin@cau.ac.kr.

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