Dietary red chilli (Capsicum frutescens L.) is insulinotropic rather than hypoglycemic in type 2 diabetes model of rats

RED CHILLI AND TYPE 2 DIABETES 1025

Copyright © 2008 John Wiley & Sons, Ltd. Phytother. Res. 22, 1025–1029 (2008)DOI: 10.1002/ptr

Copyright © 2008 John Wiley & Sons, Ltd.

PHYTOTHERAPY RESEARCHPhytother. Res. 22, 1025–1029 (2008)Published online in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/ptr.2417

Dietary Red Chilli (Capsicum frutescens L.)is Insulinotropic rather than Hypoglycemic inType 2 Diabetes Model of Rats

Md. Shahidul Islam* and Haymie ChoiDepartment of Food and Nutrition, Seoul National University, Seoul 151-742, South Korea

The present study was conducted to clarify whether a low or a high, but tolerable, dietary dose of red chilli(RC) can ameliorate the diabetes related complications in a high-fat (HF) diet-fed streptozotocin (STZ)-induced type 2 diabetes model of rats. Five-week-old male Sprague Dawley rats were fed a HF diet for2 weeks then randomly divided into four groups namely: normal control (NC), diabetic control (DBC), redchilli low (RCL, 0.5%) and red chilli high (RCH, 2.0%) groups. Diabetes was induced by an intraperitoneal(i.p.) injection of STZ (40 mg/kg BW) in all groups except the NC group. After 4 weeks feeding of experimen-tal diets, the fasting blood glucose concentrations in both RC fed groups were not significantly different. Theserum insulin concentration was significantly (p <<<<< 0.05) increased in the RCH group compared with the DBCand RCL groups. Blood HbA1c, liver weight, liver glycogen and serum lipids were not influenced by thefeeding of RC-containing diets. The data of this study suggest that 2% dietary RC is insulinotropic rather thanhypoglycemic at least in this experimental condition. Copyright © 2008 John Wiley & Sons, Ltd.

Keywords: red chilli; Capsicum frutescens L.; type 2 diabetes; high-fat diet; rats.

Received 1 January 2007Revosed 19 September 2007

Accepted 27 September 2007

* Correspondence to: M. S. Islam, Department of Nutrition, Faculty ofHealth Sciences, North-West University (Potchefstroom Campus),Potchefstroom 2520, South Africa.E-mail: [email protected]/grant sponsor: Korean Health 21 R&D Project, Ministry ofHealth and Welfare, South Korea; contract/grant number: 03-PJ1-PG1-CH12-0002.

INTRODUCTION

Diabetes is a major threat to global public health andrapidly worsening, the biggest impact being on adultsof working age in developing countries. At least 177million people worldwide have diabetes and this figureis likely to be more than double by 2030 (WHO Report,2000). The prevalence of type 2 diabetes (T2D), whichaccounts for 90–95% of total diabetics worldwide, iscontinuing to grow annually by 6%, and is expectedto reach a total of 200–300 million cases by 2010 (Amoset al., 1997). T2D is a heterogeneous disorder char-acterized by a progressive decline in insulin action(insulin resistance), followed by the inability of β-cellsto compensate for insulin resistance (β-cell dysfunction)(Srinivasan et al., 2005). If not controlled, these mayresult in other microvascular and macrovascular com-plications such as cardiovascular disease, blindness,renal failure and limb amputations due to neuropathyand poor wound healing (Ross, 1986).

Red chilli (RC) (Capsicum frutescens L.) is widelyused as a spice for flavoring foods, particularly in South-East Asian and Latin-American countries. The majoractive ingredients of RC are pungent capsaicinoids(capsaicin, dihydrocapsaincin), antioxidant vitamins(ascorbic acid, vitamin E), carotenoids (β-carotene, β-cryptoxanthine) and several organic acids and minerals(Antonious et al., 2006; Conforti et al., 2007), which are

found to be significantly higher in RC compared withthe green chilli of same species (Martinez et al., 2007;Conforti et al., 2007). Capsaicin, the primary pungentprinciple present in chillies, has been found to be effec-tive in relieving diabetic and common neuropathic pains(Head, 2006; Ogata et al., 1996; Rashid et al., 2003),prevents adipocyte differentiation (Hwang et al., 2005),improves glucose tolerance and glucose stimulated in-sulin response (Gram et al., 2000a, 2000b) and reducesdiabetic hyperglycemia (Tolan et al., 2004). Thera-peutic effects of RC have been also reported in theprevention of microbial growth (Leuschner and Ielsch,2003), hyperglycemia and diabetic nephropathy (Babuand Srinivasan, 1999). Although several of the abovestudies have shown the antidiabetic effects of capsaicin,the effect of whole RC, that is usually consumed in thediet as a flavoring spice, has not been adequately inves-tigated in this regard.

It has been reported that excessive intake of wholeRC has some adverse effects in stomach and intestines;however, capsaicin has not been found to be responsi-ble for these gastrointestinal problems (Satyanarayana,2006). Furthermore, capsaicin does not stimulate, butinhibits gastric acid secretion, stimulates alkali and mucussecretions, and promotes gastric mucosal blood flow,which helps in preventing and healing gastric ulcers(Satyanarayana, 2006). Epidemiological surveys inSingapore have shown that gastric ulcers are three timesmore prevalent in the ‘Chinese’ than among Malaysiansand Indians, who are in the habit of consuming morechillies (Satyanarayana, 2006).

In the literature, data on the tolerable dosages of RCis conflicting. Jang et al. (1992) reported that up to a10% dietary dose of RC was easily tolerated by maleB6C3F1 mice during a 4 week experimental period,however, the tolerance abilities of mice and rats may


1026 M. S. ISLAM AND H. CHOI

not be similar. Feeding rats with the same dose for 4 or8 weeks, has been shown to cause exfoliation of theintestinal epithelium into the lumen and cytoplasmicfatty vacuolation and necrosis of the centrilobularhepatocytes including a reduction of food intake andgrowth rate when a lower dietary dose (2%) was welltolerated (Al-Qarawi and Adam, 1999). So, the doseof RC may be an important factor for achieving safermaximum beneficial effects, but according to our know-ledge no dose response study of RC has been doneuntil now regarding the prevention of diabetes.

The aim of the present study was to investigatewhether a low (0.5%) or a tolerable-high (2%) dietarydose of freeze-dried RC powder is effective in amelio-rating diabetes related complications in a high-fat (HF)diet-fed streptozotocin (STZ)-induced diabetes modelof rats, which recently was found to be a better modelfor T2D (Islam and Choi, 2007).

MATERIALS AND METHODS

Preparation of red chilli powder. Fresh RC (Capsicumfrutescens L.) was purchased from the local market,made calyx- and stalk-free, washed and cut into smallpieces before freeze-drying. The freeze-dried RC wasfinely ground by using a kitchen blender to makepowder and preserved in an air-tight container atroom temperature until the preparation of experimen-tal diets (discussed below).

Animals. Five-week-old male Sprague-Dawley (SD) ratsweighing 120–140 g were procured from Orient CharlesRiver Technology, Seoul, South Korea. The animals werehoused two per big polycarbonated cage in an auto-matic ambient humidity, temperature and light-dark(12:12) controlled room. After free access to HF-containing diet (Table 1) and drinking water for 2 weeks,the animals were randomly divided into four groups ofeight animals namely: normal control (NC), diabeticcontrol (DBC), red chilli low (RCL) and red chillihigh (RCH) groups, where ‘low’ and ‘high’ indicate theaddition of 0.5% and 2.0% freeze-dried RC powder totheir respective diets. Animals were maintained accord-ing to the rules and regulations of the Animal CareEthical Committee of the Institute of Laboratory AnimalResources (ILAR) of Seoul National University.

Induction of diabetes. After 2 weeks feeding of HFdiet, diabetes was induced in overnight fasted animalsby a single intraperitoneal injection of STZ (40 mg/kgBW) dissolved in citrate buffer (pH 4.5). Only bufferwas injected into the NC group. One week after STZinjection, the non-fasting blood glucose (NFBG) of allanimals was checked by a portable gluco-meter (Accu-Check Active, Roche Diagnostics Ltd, Germany) inthe blood collected from the tail vein. Animals wereconsidered diabetic with NFBG values of ≥300 mg/dL.Animals with a blood glucose <300 mg/dL were excludedfrom the study.

Diets and feeding. All diets (control and experimental)were prepared in our laboratory by uniformly mixingthe necessary ingredients. The detail compositions ofdiets are presented in Table 1. Control diet was simplya HF-containing diet without RC powder. The prepa-ration of the RC-containing experimental diets was doneby replacing an equal amounts of corn starch in thecontrol diet with freeze-dried RC powder. The animalswere allowed to feed ad libitum on the allocated dietsfor a 4-week period after the confirmation of diabetes(1 week after the STZ injection). During this period,diet intake was measured daily and body weight changewas monitored weekly.

Intraperitoneal glucose tolerance test (IPGTT). In thelast week of the experiment, IPGTT was performedin each animal. The animals were fasted overnight priorto receiving an intraperitoneal injection of glucose (2 g/kg BW). The glucose concentrations were subsequentlymeasured in blood collected from the tail vein at 0(just before injection), 30, 60, 90, and 120 min after theglucose injection.

Sampling. At the end of the experiment, the fastedanimals were killed by decapitation, and blood andliver were sampled for further analysis. Approximately0.5 mL of whole blood was taken in heparinizedmicrotubes from the total blood of each animal, col-lected in 14 mL falcon tubes, and immediately preservedin the refrigerator for subsequent analysis of glycatedhemoglobin (HbA1c). Remaining blood was centrifugedat 3000 rpm for 15 min and separated serum collectedand preserved at −80 °C until further analysis. Collectedliver was trimmed, washed with cold saline, wiped withfilter paper, weighed and snap frozen in liquid nitrogenand preserved at −80 °C until further analysis.

Analytical methods. Blood glucose concentration wasmeasured by glucose oxido-peroxidase method byusing a portable gluco-meter (Accucheck Active, RocheDiagnostics Ltd, Germany). Serum insulin concentra-tion was analysed by using an ultra-sensitive rat insulinELISA kit (Mercodia AB, Uppsala, Sweden, Lot no.14154) in a multi-plate ELISA reader (Biorad-680,Biorad Ltd, Japan). Blood HbA1c was extracted fromheparinized blood by using a chromatographic cationexchange disposable column after hemolysis and con-centration was measured spectrophotometrically accord-ing to the description available with purchased HbA1ckit (Lot no. 488AA, Biosystems, Costa Brava, Barcelona,Spain). Serum total cholesterol, HDL-cholesterol andtriglycerides (TG) were determined photometrically byusing commercial kits purchased from ACE Chemicals

Table 1. Composition of control and experimental diets

Red chilli Red chilliIngredient Control low (RCL) high (RCH)

Corn starch 37.7 37.2 35.7Sucrose 10.0 10.0 10.0Casein 20.0 20.0 20.0Lard 20.0 20.0 20.0Soybean oil 2.0 2.0 2.0Cellulose 5.0 5.0 5.0Vitamin-mix 1.0 1.0 1.0Mineral-mix 4.0 4.0 4.0L-Methionine 0.3 0.3 0.3Red chilli powder 0.0 0.5 2.0Total 100.0 100.0 100.0



Table 3. Liver weight, relative liver weight, and liver glycogen levels in normal control (NC), diabetic control (DBC), red chilli low(RCL) and red chilli high (RCH) groups at the end of the experimental period

NC DBC RCL RCH

Liver weight (g) 13.34 ± 2.13 12.81 ± 1.74 12.97 ± 1.39 13.01 ± 2.04Relative liver weight (%) 2.85 ± 0.21a 3.91 ± 0.40b 3.63 ± 0.48b 3.55 ± 0.52b

Liver glycogen (mg/g tissue) 3.15 ± 1.58a 20.0 ± 6.65b 18.25 ± 5.39b 20.01 ± 4.85b

Values are shown as mean ± SD of 6–8 animals.a,b Values with different superscript letters within a row are significantly different from each other (Tukey-Kramer’s multiple rangepost-hoc test, p < 0.05).Relative liver weight (%) = (Liver weight/Body weight) × 100.

Table 2. Food intake, body weight, fasting blood glucose, serum insulin and blood glycated hemoglobin (HbA1c) levels in normalcontrol (NC), diabetic control (DBC), red chilli low (RCL), and red chilli high (RCH) groups at the end of the experimental period

NC DBC RCL RCH

Food intake/rat/day (g) 19.41 ± 1.15a 22.46 ± 2.94b 20.61 ± 3.98ab 22.17 ± 3.00ab

Body weight (g) 466.74 ± 48.80a 330.76 ± 57.08b 361.19 ± 48.20b 371.86 ± 74.07b

Fasting blood glucose (mg/dL) 113.13 ± 24.42a 181.71 ± 60.13ab 172.00 ± 63.09ab 209.57 ± 83.48b

Serum insulin (pmol/L) 295.69 ± 85.69a 61.83 ± 27.31c 88.02 ± 55.59c 203.11 ± 89.62b

Blood HbA1c (%) 5.18 ± 0.46a 7.78 ± 1.51b 6.90 ± 1.53b 6.78 ± 1.17b

Values are shown as mean ± SD of 6 –8 animals.a,b,c Values with different superscript letters within a row are significantly different from each other (Tukey-Kramer’s multiple rangepost-hoc test, p < 0.05).

The results of IPGTT are shown in Fig. 1. The bloodglucose concentration at 0 min after glucose injectionwas significantly higher in the RCH group than in theNC group when no significant difference was foundbetween the DBC and RCL groups. Although no sig-nificant difference of blood glucose concentration wasobserved among the DBC, RCL and RCH groups inthe following time intervals of IPGTT, better glucosetolerance was observed in both the RC fed groups com-pared with the DBC group.

Figure 2 shows the concentrations of serum lipidsat the end of the experimental period. Serum totalcholesterol, HDL-cholesterol, LDL-cholesterol and TG

Figure 1. Intraperitoneal glucose tolerance test (IPGTT) in nor-mal control (NC), diabetic control (DBC), red chilli low (RCL)and red chilli high (RCH) groups in the last week of experimen-tal period. Values are shown as mean ± SD of 6–8 animals.a,bValues with different letters for a given period of time aresignificantly different from each other group of rats (Tukey-Kramer’s multiple range post-hoc test, p < 0.05).

Ltd, Seoul, Korea. The concentration of serum LDL-cholesterol was calculated according to the formuladrawn by Friedewald et al. (1972):

LDL-cholesterol = [Total cholesterol –(HDL-cholesterol + TG/5)]

where, TG/5 is an estimate of VLDL cholesterol.Liver glycogen levels were measured by a phenol-

sulfuric acid method as described by Lo et al. (1970).

Statistical analysis. All data are presented as the mean± SD of 6–8 animals. Data were analysed by a statisti-cal software (Statview, Version 5.0, St Louis, MO, USA)using Tukey-Kramer multiple range post-hoc test. Valueswere considered significantly different at p < 0.05.

RESULTS

Food intake was significantly (p < 0.05) higher in theDBC group and body weight gain was significantly lowerin the DBC, RCL and RCH groups compared with theNC group (Table 2). Fasting blood glucose (FBG) wasinsignificantly decreased in the RCL group and rela-tively increased in the RCH group compared with theDBC group when no significant difference was observedbetween the NC and DBC groups (Table 2). Theserum insulin concentration was significantly increasedin the RCH group compared with the DBC and RCLgroups when no significant difference was observedbetween the DBC and RCL groups. The concentrationof blood HbA1c, relative liver weight and liver glyco-gen of DBC, RCL and RCH groups were significantlyincreased compared with the NC group when the in-crement was relatively lower in the RCL and RCHgroups compared with the DBC group except for theliver glycogen (Tables 2 and 3).


1028 M. S. ISLAM AND H. CHOI

Moreover, although not significant, better glucose toler-ance abilities were observed in both the RC fed groupscompared with the DBC group during IPGTT. Theseresults may have been due to a combined effect ofcapsaicin and other antioxidant vitamins such asvitamin C, vitamin E and carotenoids (β-carotene, β-cryptoxanthine) present in RC (Conforti et al., 2007).Capsaicin-sensitive nerves might be also involved in theinduction of insulin secretion, which is associated withthe improvement of glucose tolerance ability, but notwith the reduction of diabetic hyperglycemia foundin this and some previous studies (van de Wall et al.,2005; Guillot et al., 1996).

Moreover, the major difference between our andthe above capsaicin-based studies is that they used anormal fat-containing diet while in the present study,a moderately HF-containing diet was used in STZinduced diabetic rats to induce a T2D model. There-fore, glucose sensitization to pancreatic beta-cells andsensitivity of secreted insulin might be modulated bythis HF diet, used in our study (Cerf, 2006). As a result,the blood glucose concentration was not decreased evenwith a 2% dietary dose of RC powder.

Srinivasan and Satyanarayana (1989) reported that11 weeks feeding of a synthetic analogue of capsaicin(0.2 mg%) with a HF diet lowered serum and liverTG and adipose tissue weight in female Wistar rats.However, the effect of RC-based natural capsaicinand its synthetic analogues may not be similar either inhumans or in experimental animals. In another study,it has been reported that 8 weeks feeding of 0.015%dietary capsaicin significantly reduced serum and liverTG, but not total cholesterol, in HF diet-fed femaleWistar rats, when they used a 30% plant-originatedfat-containing diet (25% hydrogenated vegetable fatand 5% peanut oil), which contains much lower satu-rated fat compared with animal fats (Kempaiah andSrinivasan, 2006). Our study used neither plant origi-nated fat nor pure capsaicin and did not find any sig-nificant effect on serum lipids concentrations. The HFdiet used in our study contained mainly animal origi-nated saturated fat (20% lard and 2% soybean oil)that facilitates the induction of blood lipids in rats sincesaturated or animal-originated fats are more effectivethan unsaturated or vegetable-originated fats to increaseserum lipid concentrations (Imaki et al., 1989; Elshafei,1992). Moreover, the RC powder used in our studycontained smaller amounts of capsaicin (0.0007% or0.0028%), which was not enough to reduce saturatedfat-induced serum lipids in diabetic rats. In a previousstudy, Kawada et al. (1986) also did not find any sig-nificant effect of 0.014% dietary capsaicin on serumcholesterol and pre-beta-lipoprotein in male Wistar ratswhen fed with an animal-originated HF (30% lard)containing diet. The 0.015% dietary capsaicin was alsoshown not to reduce blood cholesterol, phospholipidsand TG concentrations in STZ-induced diabetic rats(Babu and Srinivasan, 1997). In a human-based study,regular consumption of freshly chopped chilli (30 g/day)for a 4 week period did not have any effect on serumlipid profiles (Ahuja and Ball, 2006). Our results sup-port the results of these studies. Therefore, the com-positions of diet and the type and dose of dietary fatare crucial factors in ameliorating the serum lipidlevels together with RC or capsaicin in experimentalanimals. Although capsaicin is effective in reducing

Figure 2. Serum lipid profiles in normal control (NC), diabeticcontrol (DBC), red chilli low (RCL) and red chilli high (RCH)groups at the end of the experimental period. Values are shownas mean ± SD of 6–8 animals.

concentrations were not influenced by the feeding ofeither low or high dose of dietary RC in this experiment.

DISCUSSION

The dietary dose of RC is an important factor in achiev-ing its maximum beneficial effects as well as to avoid itspossible toxicological side effects. The present studyinvestigated the antidiabetic effects of a low (0.5%)and a high (2%), but equivalent to human dietary con-sumption, dose of RC in a HF diet-fed STZ-inducedT2D model of rats. The high dose of RC (2%) used inthis study, was also confirmed as a non-toxic and welltolerated dose in experimental animal (Al-Qarawi andAdam, 1999).

Babu and Srinivasan (1997) fed 15 mg% (0.015%)dietary capsaicin to STZ-induced diabetic albino ratsfor an 8-week experimental period and found no sig-nificant effect on the reduction of blood glucose level.In another Caribbean study, ingestion of a single oraldose of capsaicin (500 mg capsaicin dissolved in 50 mLwater), 1 h prior to the ingestion of glucose (1.75 g/kgBW), significantly reduced plasma glucose and increasedplasma insulin levels in the following 2.5 h time inter-val of the oral glucose tolerance test (OGTT) performedin a model of dogs (Tolan et al., 2001). Recently, vande Wall et al. (2005) reported that a subcutaneousinjection of capsaicin (50 mg/kg BW) to neonatal ratssignificantly increased glucose stimulated insulin secre-tion in their growing age, however, that is not directlyinvolved in the regulation of blood glucose levels. Theresults from these previous studies are supported bythe results of our study. In the present study, the amountof capsaicin equivalent to 0.5% and 2% dietary dosesof RC were 0.0007% and 0.0028%, respectively (10 gRC powder is equivalent to 14 mg capsaicin). Capsaicinconcentrations in both doses of the present study werelower than all the above studies. Consequently bloodglucose concentrations were not significantly decreasedwith either dose of RC, however, the serum insulinconcentration was significantly increased in the RCHgroup compared with the DBC group (Table 2).



at least in this experimental condition. The effects ofdietary RC may be more pronounced in amelioratingdiabetes related complications when supplied with anormal, rather than HF-containing, diet. Further studywill be needed to ascertain this hypothesis.

Acknowledgements

This study was supported by a grant of Korean Health 21 R&D Project,Ministry of Health and Welfare, South Korea (03-PJ1-PG1-CH12-0002).

the blood cholesterol level when fed with a standardand plant originated HF-containing diet, it may not beeffective when fed with an animal-originated HF diet.

In summary, the results of this study suggest that arelatively high, but tolerable, and equivalent to humandietary dose (2%) of RC is insulinotropic, which maybe associated with the induction of glucose toleranceability rather than the reduction of diabetic hyper-glycemia in a HF diet-fed STZ-induced T2D model ofrats. The concentrations of serum lipids are not influ-enced by either the dose of dietary RC (0.5% or 2.0%)

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Dietary red chilli (Capsicum frutescens L.) is insulinotropic rather than hypoglycemic in type 2 diabetes model of rats