Exotic Fruits as Therapeutic Complements for Diabetes, Obesity and Metabolic Syndrome

Abstract

The prevalence and severity of obesity, type 2-diabetes, and the resultant metabolic syndrome are rapidly increasing. As successful preventive and therapeutic strategies for these life-threatening health ailments often come with adverse side effects, nutritional elements are widely used in many countries as preventive therapies to prevent or manage metabolic syndrome. Fruits are important dietary components, and contain various bioactive constituents. Many of these constituents have been proven to be useful to manage and treat various chronic diseases such as diabetes, obesity, cancer and cardiovascular diseases. Although exotic fruits are understudied throughout the world due to their limited regional presence, many studies reveal their potent ability to ameliorate metabolic derangements and the resultant conditions i.e. diabetes and obesity. The aim of this article is to review the role of exotic fruits and their constituents in the regulation of metabolic functions, which can beneficially alter diabetes and obesity pathophysiology.

1. Introduction

The prevalence of obesity and type 2 diabetes is rapidly increasing around the world, and its growth has become a major challenge for health care professionals to combat (Hossain et al, 2007; Young, 2010). Obesity is characterized by the accumulation of excess fat in adipose tissues, and results in various life threatening complications such as cardiovascular diseases, type 2 diabetes, and cancer (Lois and Kumar, 2009). At heart, the obesity epidemic arises from the sedentary modern lifestyle, in which unhealthy dietary practices place a heavy strain on the delicate balance between energy intake and energy expenditure (Lois and Kumar, 2009). It is well established that a correction of lifestyle, such as the intake of a healthy and low energy diet along with increased physical activity is the most effective preventive therapy to ameliorate the prevalence of obesity and diabetes in society. Therefore, research exploring nutritional composition is robustly expanding in the field of obesity and diabetes (Foltran et al, 2010). Recently, the bioactive components in foods and functional foods have become popular and have been considered as complementary or alternative therapeutic agents to manage and/or treat chronic diseases. Moreover, it is illustrated that in addition to standard prescribed therapies, a host of complementary and alternative herbs and dietary supplements are widely used to manage obesity and diabetes (Connell, 2001). Currently, approximately one-third of patients with diabetes mellitus employ some form of complementary and alternative medicine (Metcalfe et al, 2010).

Fruits are important components of our daily diet that contain various bioactive nutraceuticals, which enhance our body’s strength to fight various illnesses. Various ethnically and geographically specific fruits are used in traditional therapies for treatment of various health problems including diabetes and obesity (Babio et al, 2009). Ancient Chinese medicine heavily incorporates local fruits to treat diabetic patients (Ceylan-Isik et al, 2008). Some of these ancient Chinese natural therapeutics have been shown to have high content of antioxidants, which is well known to directly improve metabolic syndrome (Liu et al, 2008). In India and Bangladesh, Ayurvedic medicines employ a wide range of locally harvested fruits (Krishnaveni and Mirunalini, 2010). Recent research has also indicated that fruits local to India, such as Garcina indica, possess potent medicinal uses (Baliga et al, 2011). However, many of these fruits are “exotic” to the rest of the world, thus the global community at large does not benefit from their potentially bio-defensive effects. The vast majority of basic research is conducted in countries in which these fruits are grown – mainly in developing countries. Due to various resource limitations, the anti-diabetic and anti-obese potential of exotic fruits is under-studied. Hence, we believe it is immensely important that the global scientific community should further evaluate the potential of these exotic fruits and their constituents to prevent the pathogenesis of diabetes, obesity and metabolic syndrome.

2. Pathophysiology of Diabetes and Obesity

Before discussing the anti-diabetic or anti-obese effects of exotic fruits and their bioactive nutraceuticals, it is important to discuss the pathophysiological mechanism of diabetes and obesity. Obesity itself is defined by the World Health Organization (WHO) as a body mass index (BMI) of 30 kg/m² or higher, and is significantly associated with increased predisposition to all-cause and cause-specific morbidity and mortality (Prospective Studies Collaboration, 2009). Overweight and obesity are conditions well established to increase the likelihood of hyperlipidemia, hyperglycemia, insulin resistance (type 2-diabetes) and cardiovascular diseases (Lois and Kumar, 2009). Among others, obesity and diabetes lead to the pathogenesis of metabolic syndrome, characterized by a state of chronic low grade inflammation, oxidative stress, hyperlipidemia and insulin resistance (Martínez, 2006; Neligan, 2010). Obesity, diabetes and the resultant metabolic syndrome thus serve as a trigger for a host of multi-organ complications, from cardiovascular disease to cancer. Curtailing hyperglycemia, hyperlipidemia, insulin resistance, inflammation and oxidative stress are critical factors that could be used for therapeutic/ preventive targets to combat the pathogenesis of metabolic syndrome (Figure 1).

Figure 1.

Pathophysiology of obesity and diabetes, and their associated factors

In in-vitro systems, animal models, and clinical trials, various exotic fruits have been demonstrated to decrease the abovementioned parameters (Table 1). The current article explores the immense potential of exotic fruits to ameliorate the pathogenesis of metabolic syndrome by acting on various targets.

Table 1.

Nutrient composition of exotic fruits.

Nutrient (Units)	Litchi	Durian	Jackfruit	Mangosteen	Acai	Pomegranate	Avocado	Persimmon	Guava	Blueberry
	Value per 100g
Proximates
Water (g)	81.76	64.99	73.23	80.94	88.4	77.93	73.23	80.32	80.8	84.21
Energy (kcal or kJ)	66	147	94	73	45	83	160	70	68	57
Protein (g)	0.83	1.47	1.47	0.41	0	1.67	2	0.58	2.55	0.74
Total lipid (g)	0.44	5.33	0.3	0.58	0	1.17	14.66	0.19	0.95	0.33
Ash (g)	0.44	1.12	1	0.16	0.62	0.53	1.58	0.33	1.39	0.24
Carbohydrate (g)	16.53	27.09	24.01	17.91	10.98	18.7	8.53	18.59	14.32	14.49
Fiber, total dietary (g)	1.3	3.8	1.6	1.8	0	4	6.7	3.6	5.4	2.4
Sugars, total (g)	15.23	ND	ND	ND	10.57	13.67	0.66	12.53	8.92	9.96
Minerals
Calcium, Ca (mg)	5	6	34	12	1	10	12	8	18	6
Iron, Fe (mg)	0.31	0.43	0.6	0.3	0.81	0.3	0.55	0.15	0.26	0.28
Magnesium, Mg (mg)	10	30	37	13	ND	12	29	9	22	6
Phosphorus, P (mg)	31	39	36	8	98	36	52	17	40	12
Potassium, K (mg)	171	436	303	48	ND	236	485	161	417	77
Sodium, Na (mg)	1	2	3	7	28	3	7	1	2	1
Zinc, Zn (mg)	0.07	0.28	0.42	0.21	ND	0.35	0.64	0.11	0.23	0.16
Copper, Cu (mg)	0.148	0.207	0.187	0.069	ND	0.158	0.19	0.113	0.23	0.057
Manganese, Mn (mg)	0.055	0.325	0.197	0.102	ND	0.119	0.142	0.355	0.15	0.336
Selenium, Se (mcg)	0.6	???	0.6	ND	ND	0.5	0.4	0.6	0.6	0.1
Vitamins
Vitamin C (mg)	71.5	19.7	6.7	2.9	40.7	10.2	10	7.5	228.3	ND
Thiamin (mg)	0.011	0.374	0.03	0.054	ND	0.067	0.067	0.03	0.067	ND
Riboflavin (mg)	0.065	0.2	0.11	0.054	ND	0.053	0.13	0.02	0.4	ND
Niacin (mg)	0.603	1.074	0.4	0.286	ND	0.293	1.738	0.1	1.084	ND
Pantothenic acid (mg)	???	0.23	ND	0.032	ND	0.377	1.389	???	0.451	ND
Vitamin B-6 (mg)	0.1	0.316	0.108	0.018	ND	0.075	0.257	0.1	0.11	ND
Folate, total (mcg)	14	36	14	31	ND	38	81	8	49	ND
Folic Acid (mcg)	0	???	0	0	ND	0	0	0	0	ND
Folate, food (mcg)	14	36	14	31	ND	38	81	8	49	ND
Folate, DFE (mcg)	14	???	14	31	ND	38	81	8	49	ND
Choline, total (mg)	7.1	???	ND	ND	ND	7.6	14.2	7.6	7.6	ND
Vitamin B-12 (mcg)	0	0	0	0	ND	0	0	0	0	ND
Vitamin A, RAE (mcg_RAE)	0	2	15	2	ND	0	7	81	31	ND
Retinol (mcg)	0	0	0	ND	ND	0	0	0	0	ND
Carotene, beta (mcg)	0	23	ND	16	ND	0	62	253	374	ND
Carotene, alpha (mcg)	0	6	ND	1	ND	0	24	0	0	ND
Cryptoxanthin, beta (mcg)	0	0	ND	9	ND	0	28	1447	0	ND
Vitamin A, IU (IU)	0	44	297	35	6	0	146	1627	624	ND
Vitamin D (D2 + D3) (mcg)	0	ND	ND	0	ND	0	0	0	0	ND
Vitamin D (IU)	0	ND	ND	0	ND	0	0	0	0	ND
Vitamin E (mg)	0.07	ND	ND	ND	1.83	0.6	2.07	0.73	0.73	ND
Vitamin K (mcg)	0.4	ND	ND	ND	ND	16.4	21	2.6	2.6	ND

ND: Not Detected

This data was adopted from: USDA National Nutrient Database, 2010, 2011

3. Exotic Fruits and their Biodefensive Potential in Metabolic Syndrome

3.1. Litchi

The botanical name of Litchi is Litchi chinensis. Litchi is originally from Southeast Asia, and is a tropical/ subtropical crop that has experienced a gradual increase in production in both the Southern and Northern hemispheres (Huang and Xu, 1983). The fruit’s stunning red skin and savory taste has resulted in increased exports to other parts of the world, including Europe and North America (Huang and Xu, 1983). The 100g edible portion of litchi contains water (81.76 g), protein (0.83 g), lipids (0.44 g), ash (0.44 g), carbohydrates (16.53 g), fiber (1.3g) and sugars (15.23 g) (Table 1). Both in-vitro and in-vivo studies have been conducted exploring the beneficial effects of Litchi, most of which suggest a solid potential for the use of Litchi extract as a supplemental therapeutic to ameliorate diabetes, obesity and its complications (Huang & Wu, 2002; Guo et al, 2004; Obrosova et al, 2010).

It has been found that feeding of Litchi water extract improved the metabolic profile of rats, characterized by decreased body weight, fasting blood glucose, total cholesterol, triglycerides, free fatty acid (FFA), leptin, and fasting insulin levels (Guo et al, 2004). Furthermore, Guo et al (2004) also found that the water extract of Litchi diminished insulin resistance in these rats. Later on, it has been found that the anti-diabetic potential of the water extract of Litchi was through the anti-inflammatory effects in these rat models (Guo et al, 2004). Guo and colleauges illustrated that tumor necrosis factor (TNF-α), a cytokine involved in system inflammation, was significantly decreased after feeding litchi water extract in type 2 diabetic rats. These findings suggest that the Litchi fruit possesses bioactive components that enhance body’s immune system, which can protect from diabetes or obesity induced chronic inflammation. It was further explored that Litchi extract enhances basal prostaglandin E2 (PGE2) production in a macrophage cell line (RAW264.7), which is considered a key inhibitor of the inflammatory immune response (Huang & Wu, 2002).

Glucose induced cataract (blindness/ retinopathy) is a major complication that arises from the long term existence of uncontrolled diabetes (Cheung et al, 2010). Aldose reductase is the critical initiator of cataractogenesis (Obrosova et al, 2010). This enzyme exists around the cornea, and catalyzes the first reaction of polyol pathway and induces sorbitol formation. In diabetic or hyperglycemic conditions, the enhanced activity of aldose reductase renders excess formation of sorbitol. Higher sorbitol formation leads to accumulation around the cornea, and subsequent development of cataract. Methanol and ethylacetate extracts of Litchi fruit preicarp (LFP) were found to be potent inhibitors of rat lens aldose reductase in-vitro. Interestingly, Delphinidin 3- O-β galactopyranoside-3′-O-β– glucopyranoside was isolated from the ethylacetae extract of LFP and demonstrated potent inhibitory activity for rat lens aldose reductase. This suggests that LFP and its constituents contain potent inhibitors of aldose reductase, and can be used to prevent diabetes-induced blindness and retinopathy (Lee et al, 2009).

Oxidative stress is the hallmark of various chronic diseases (Spiteller, 1993). In diabetes and obesity (metabolic syndrome) the levels of oxidative stress i.e. production of reactive oxygen species (ROS) get significantly increased and led to damage in micro and macro-vascular tissues (Spiteller, 1993). Litchi polysaccharides from pulp tissue demonstrated potential antioxidant capacities (Kong et al, 2010). Four polysaccharide-enriched fractions extracted from pulp tissue of Litchi have been shown to exhibit a dose-dependent free radical scavenging activity (Kong et al, 2010). The LFP-III demonstrated highest scavenging activity against the DPPH radical, superoxide, and hydroxyl radicals and chelating ability (Kong et al, 2010). A new litchi derived polyphenol mixture, coined Oligonol (Amino Up Chemical Co., Ltd., Sapporo, Japan), significantly decreased the levels of ROS and the gene expression level of Superoxide Dismutase (SOD) in white and brown mouse adipocytes. The Litchi polyphenol mixture also attenuated the gene expression of the adipokines TNF-α, MCP-1, PAI-1, adiponectin and leptin in white adipocytes, all of which strongly contribute to the pathogenesis of obesity-associated metabolic syndrome. (Sakurai et al, 2008). Thus, the Litchi polyphenol mixture has marked promise in preventing and alleviating obesity-induced metabolic syndrome.

3.2. Durian

Durian is widely distributed in Southeast Asia and is considered as “the king of fruits.” Durian (Durio zibethinus) commonly grows up to 30 centimeters long and 15 centimeters in diameter. Hundred grams of edible portion of durian contains water (64.99 g), protein (1.47 g), lipids (5.33 g), ash (1.12 g) and carbohydrate (27.09 g), fiber (3.08 g) (Table 1). Although only a small number of studies have been conducted to explore the anti-diabetic and anti-obesity potential of durian, these studies show that durian can be further explored to detail its anti-diabetic and anti-obese potential. Durian exhibits potential effects on metabolic parameters in human and animal models (Roongpisuthipong, 1991; Leontowicz et al, 2007; Toledo et al, 2008). When rats were fed durian in addition to a cholesterol enriched diet (1% cholesterol), it positively influenced the plasma lipid profile, plasma glucose and antioxidant activity. These metabolically beneficial effects of durian might be due to the higher contents of bioactive compounds with various biological activities, such as metabolic enhancer and antioxidant. This suggests that durian consists of few critical bioactive components that can be further evaluated for hypoglycemic and anti-hyperlipidemic effects (Leontowicz et al, 2007). Interestingly, in a small clinical trial, durian has been shown to improve glucose homeostasis by altering insulin secretion and its action (Roongpisuthipong, 1991). After ingestion of durian, the insulin response curve of 10 diabetic patients was significantly improved compared to the ingestion of other fruits (mango, pineapple, banana, rambutan) and control (no fruit) (Roongpisuthipong, 1991). Various durian cultivars have also been shown to possess anti-oxidant capacities due to the relatively high level of total polyphenols (Toledo et al, 2008). This anti-oxidant property of durian and its components can be useful for prevention of oxidative stress mediated induction of diabetic and obesity complications. Studies delineating the anti-inflammatory properties of durian are yet to be reported. Although preliminary research of the durian fruit demonstrate fairly promising anti-diabetic and anti-obesity effects, in-depth studies are essential to solidify durian and identify specific components that can be used as therapeutic complements to combat diabetes, obesity and their associated metabolic derangements.

3.3. Jackfruit

The jackfruit, (Artocarpus heterophyllus), is native to Western Ghats in India and is widely prevalent throughout the Southeast Asian region. It is rich in phenolic compounds such as flavonoids, stilbenoids and arylbenzofurons (Hakim et al, 2006). The 100 g of edible portion of jackfruit contains water (73.23 g), protein (1.47 g), lipids (0.3 g), ash (1 g), carbohydrates (24.01 g), fiber (1.6 g) and Vitamin A (297 IU). A considerable number of studies have explored various health benefits of jackfruit, as reviewed elsewhere (Jagtap & Bapat, 2010). Although research exploring the detailed anti-obesity and anti-diabetic effects of jackfruit is fairly naïve, but there are strong preliminary results that suggest important effects of jackfruit and its components to ameliorate diabetes and obesity. In one study, the extracts of jackfruit (at an oral dosage of 20 g/kg of starting material) significantly improved glucose tolerance in both normal and diabetic patients (Fernando, 1991). Studies have also explored the anti-inflammatory role of jackfruit, which can be important for the prevention of the progression of obesity-associated low grade inflammation and its complications. Phytochemical investigations of ethyl acetate extracts of jackfruit led to the isolation of the phenolic compound artocarpesin [5,7,2′,4′-tetrahydroxy-6-(3-methylbut-3-enyl) flavone], which was further shown to possess potent anti-inflammatory effects in RAW264.7 murine macrophage cells by suppressing lipopolysaccharide (LPS) induced production of nitric oxide (NO) and prostaglandin E 2 (PGE2) (Vuolteenaho et al, 2009). NO and PGE2 are potential inflammatory molecules and play important roles in the pathogenesis of the low-grade state of inflammation associated with obesity and diabetic complications (Vuolteenaho et al, 2009). Further, artocarpesin significantly suppressed LPS-induced inflammation by reducing NO synthesizing enzyme [inducible nitric oxide synthase (iNOS)] and PGE2 producing enzyme [cyclooxygenase 2 (COX2)] protein expressions (Fang et al, 2008). Moreover, the antioxidant capacity of jackfruit is fairly well established (Feng et al, 1998; Soong & Barlow, 2004; Jagtap & Bapat, 2010). The ethanolic extracts of jackfruit were shown to have DPPH scavenging activity (IC50 410ug/ml). The antioxidant characteristics of prenylflavones from jackfruit inhibited ferric-induced lipid peroxidation in rat brain homogenate. Cycloheterophyllin scavenged 1,1-diphenyl-2-picrylhydrazyl (DPPH), and artonins A and B scavenged hydroxyl and peroxyl radicals that were generated by 2,2′-azobis (2-amidinopropane) dihydrochloride and the Fe³⁺–ascorbate–EDTA–H₂O₂ system (Feng et al, 1998). Interestingly, the seeds of jackfruit demonstrate much higher antioxidant capacities than the edible portion (Soong & Barlow, 2004; Jagtap & Bapat, 2010).

3.4. Mangosteen

The mangosteen fruit, (Garcina mangostana), grows on tropical tress in India, Myanmar, Malaysia, Philippines, Sri Lanka, and Thailand. The 100 g of edible portion of mangosteen contains water (80.94 g), protein (0.41 g), lipids (0.58 g), Ash (0.16 g), carbohydrates (17.91 g) and fibers (1.8 g) (Table 1). Mangosteen fruit has long been used throughout Southeast Asia as a medical plant for a wide variety of treatments, including specific diabetic complications. Low grade inflammation in white adipose tissue (WAT) plays an important role in pathophysiology of obesity and its associated complications. A vast number of studies have demonstrated the anti-inflammatory properties of mangosteen. In a clinical study, mangosteen juice exhibited potential anti-inflammatory potential. Udani et al (2009) conducted an 8 week randomized, double blind, placebo-controlled trial with 40 subjects and a proprietary mangosteen juice blend (XanGo Juice, 18oz per day) was fed. Interestingly, they found that, XanGo juice significantly reduced c-reactive protein (CRP) levels in humans compared to those taking placebo (Udani et al, 2009). Also, a trend towards a decrease in BMI was noticed, which is the indicator of the anti-obese potential of mangosteen juice. Although mangosteen juice has shown preliminary anti-inflammatory and anti-obese (decreased BMI) potential, larger and more defined studies are required to establish mangosteen’s benefits in prevention/ treatment of combat obesity and diabetes, and their associated life threatening complications. Further research exploring the role of mangosteen in-vitro demonstrates that mangosteen inhibits key features that are critical for inflammatory cytokine production in WAT. Primary human adipocytes treated with xanthones, the major bioactive compounds found in mangosteen, demonstrated reduced LPS-induced expression of pro-inflammatory genes (i.e. TNF-α, IL-6, IFN-γ and IL-10) (Bumrungpert et al, 2009; Bumrungpert et al, 2010). In RAW264.7 macrophage cells, mangosteen extract, α-mangostin and γ-mangostin demonstrated a clear ability to inhibit NO and PGE2 release, along with the gene encoding iNOS and COX-2 (Tewtrakul et al, 2009).

In addition, the antioxidant compounds of mangosteen are well documented in the literature. Various extracts from the fruit hull of mangosteen demonstrated antioxidative capacities that might be due to the presence of phenolic compounds (Ngawhirunpat et al, 2010). A host of xanthones isolated from mangosteen demonstrated antioxidant capacities (Jung et al, 2006). Mangostin (Figure 2), one of the most potent xanthones isolated from mangosteen, exhibited potential free radical scavenging property and protected oxidation of low density lipoprotein (Williams et al, 1995). α-Mangostin also demonstrated a protective effect by reducing oxidative stress in tissues during isoproterenol-induced myocardial infarction in rats (Devi Sampath & Vijayaraghavan, 2007). α-Mangostin, mangostanin, xanthones (1,2-dihydro-1,8,10-trihydroxy-2-(2-hydroxypropan-2-yl)-9-(3-methylbut-2-enyl)furo[3,2-a]xanthen-11-one and 6-deoxy-7-demethylmangostanin and 1,3,7-trihydroxy-2,8-di-(3-methylbut-2-enyl) xanthone isolated from the fruit mangosteen all exhibited quinone reductase-inducing activity, and γ-mangostin exhibited hydroxyl radical-scavenging activity (Devi Sampath & Vijayaraghavan, 2007).

Figure 2.

Chemical structures of few bioactive components isolated from exotic fruits

3.5. Açaí

The açaí fruit (Euterpe oleracea), grows on a large palm tree indigenous to South America, and serves as a major source of food to the native people of Brazil, Columbia and Suriname. It is a dark, purple, berry like fruit, and has been widely used as a medicinal agent by the indigenous people of various South American countries. The 100 g portion of açaí fruit contains water (3.4g), protein (8.1g), fat (32.5g), ash (0.62g), carbohydrates (10.98g), and sugars (10.57g) (Table 1). Açaí palm fruit pulp has been shown to improve the survival of Drosophila melanogaster fed with high-fat diet, possibly by activation of stress response pathways and suppression of the gene expression i.e. PEPCK, a key WAT marker and hepatic-gluconeogenic enzyme (Sun et al, 2010). Administration of açaí pulp in female Fischer rats fed a hypercholesterolemic diet, dramatically improved the food efficiency and reduced total and non-high-density lipoprotein cholesterol, suggesting a clear hypocholesterolemic effect (deSouza et al, 2010).

In addition, açaí possesses antioxidant and anti-inflammatory properties. Supplementation of açaí to a hypercholesterolemic diet also demonstrated decreased serum levels of end products of oxidative stress i.e. carbonyl proteins, protein sulfhydryl groups, PON-arylesterase and PON-paraoxonase activities, and increased SOD activity. These findings demonstrate that açaí pulp improves the biomarkers of physiological oxidative stress (deSouza et al, 2010). Current research strives to explore the general antioxidant capacity of specific compounds of the açaí fruit in in-vitro, animal, and human models. Açaí fruit possesses high contents of anthocyanins and polyphenols, both of which were shown to synergistically contribute to the majority of the fruit’s antioxidant capacity in MCF-7 cells stressed with H₂O₂ (Chin et al, 2008). Pretreatment of frozen açaí fruit pulp on cerebral cortex, hippocampus, and cerebellum of rats treated with the oxidizing agent H₂O₂ significantly decreased H₂O₂ induced damage of both lipids and proteins in all tissues. In addition, açaí was able to reduce SOD and catalase (CAT) to basal levels. Overall, there was a negative correlation between total polyphenol content of açaí and levels of lipid and protein damage, clearly indicating the involvement of polyphenols in the demonstrated antioxidant activity (Spada et al, 2009). In an acute (24 hour) human trial of 11 subjects, administration of açaí juice (7mL/ kg) significantly increased plasma antioxidant capacity, and suppressed generation of reactive oxygen species (Mertens-Talcott et al, 2008).

However, although several anthocyanins and various flavonoids have been reported and well studied in the açaí berry, the major phytoconstituents contributing to the antioxidant capacity are yet to be identified. Of the anthocyanin and polyphenolic compounds present in açaí, cyanidin 3-glucoside (1040 mg/L) was the predominant anthocyanin that contributed to the fruit’s antioxidant capacity (Del-Pozo-Insfran et al, 2004). However, a later published study found that cyanidin 3-glucoside contributed to less than 10% of the açaí’s antioxidant activity, suggesting that unidentified compounds are responsible for the majority of its antioxidant capacity (Lichtenthäler et al 2005; Schauss et al, 2006). Açaí was also found to be a potential COX-1 and COX-2 inhibitor and exhibited potential inflammatory potential (Schauss et al, 2006). A recent public analysis that examined consumer knowledge of the benefits of flavonoids calls for increased public awareness of their potent benefits (Lampila et al, 2009).

3.6. Goji

The goji fruit (Lycium barbarum) is a native to East Asia, and is heavily used in Traditional Chinese medicine to alleviate a spectrum of health ailments including diabetes and obesity. For the past 10 years, goji, or wolfberry, has become tremendously popular throughout the world due to its medicinal potential and as a result experienced a tremendous spike in its consumption (Potterat, 2010). There are in fact two closely related species of goji – Lycium barbarium and Lycium chinense (Potterat, 2010). Based on existing literature and purpose of this review, both species are considered as one goji fruit (Potterat, 2010). Goji fruit appears to have promising therapeutic applications for obesity, diabetes and the resultant complications. Goji fruit’s water decoction, crude polysaccharide extracts, and purified polysaccharide fractions markedly reduced blood glucose levels, serum total cholesterol and triglyceride content and increased HDL levels in alloxan-induced diabetic or hyperlipidemic rabbits. These results clearly suggest a hypoglycemic and hypolipidemic effect of the goji fruit and its constituents (Luo et al, 2004). In addition, it has been found that goji fruit administration decreased body weight, plasma insulin levels, and increased the insulin sensitive index in diabetic rats (Zhao et al, 2005). Subsequent, studies demonstrated that this effect is possibly mediated by increasing the cell-surface level of GLUT-4 and improving GLUT-4 trafficking and insulin signaling (Zhao et al, 2005).

Goji fruit also possesses potent antioxidant and cardio-protective effects. A plethora of literature is available documenting the antioxidant effects of goji in diverse models (Jia et al 1998; Huang et al, 1999; Li et al, 2002). In rat liver homogenate, goji fruit extract showed an inhibitory effect on iron-chloride induced lipid peroxidation and a superoxide scavenging activity (Wu et al, 2004). Further, goji polysaccharide treatment (10mg/ kg) for 4 weeks resulted in decreased levels of blood glucose, malondialdehyde (MDA) and NO, while increased levels of SOD in the serum of fasting rats. The study thus suggests that goji is able to regulate glucose metabolism and homeostasis, and render significant protection from diabetes-induced oxidative stress-mediated complications (Wu et al, 2006). In healthy adults, goji may have an antioxidative effects by enhancing endogenous antioxidant markers such as SOD, glutathione peroxidase (GSH-Px) and lipid peroxidation (Amagase et al, 2009). Recent research establishes the antioxidant capacity of goji in multiple organs and stress models, and revolves around exploring the role that specific polysaccharides play in ameliorating obesity and diabetes induced oxidative stress (Yu et al, 2006; Li, 2007; Li et al, 2007; Zhao et al, 2009)

3.7. Pomegranate

The pomegranate (Punica garanatum L.) is an ancient fruit native to regions from the Himalayas in northern India to Iran. In recent years, however, cultivation of pomegranate has disseminated throughout many dry regions of the world, including parts of the United States. The fruit itself has a distinctive rich red, leathery skin and can grow up to 13 centimeters. Inside the fruit are many seeds covered by little amounts of red juice, each separated by a membranous white pericarp. The 100 g edible portion of pomegranate contains water (77.93 g), protein (1.67 g), lipids (1.17 g), ash (0.53 g), carbohydrates (18.7 g), fiber (4 g) and sugars (13.67 g). Pomegranate has been heavily used in various ancient medicines, such as Ayurveda, for treatment of diabetes. As a result of its rapidly increasing production and consumption throughout the world, a considerable amount of recent research has explored the potential of pomegranate to fight for obesity and diabetes. A study in CD-1 male mice showed that consumption of pomegranate seed oil reduced weight gain, improved key markers that lead to the development of type-2 diabetes, and improved insulin sensitivity – all suggesting a diminished develpoment to type-2 diabetes (McFarlin et al, 2009). Experiments in 3T3-L1 pre-adipocytes demonstrated that punicic acid, a conjugated linolenic acid found in pomegranate, activates peroxisome proliferator-activated receptor-gamma (PPAR-γ, an important target of insulin action and energy metabolism. Pucinic acid also augmented PPARγ downstream gene expression, and demonstrates an impaired ability to alleviate the pathogenesis of diabetes in PPARγ knockdown immune cells (Hontecillas et al, 2009). This suggests that pomegranate may be a natural complement to the synthetic thiazolidinediones (anti-diabetic drugs and PPAR-γ agonists), and alleviate pathogenesis of obesity and diabetes through a PPAR-γ mediated mechanism. In the Otsuka Long-Evans Tokushima Fatty (OLETF) rat model, pomegranate seed oil rich in punicic acid significantly decreased hepatic triacylglycerol contents and levels of monounsaturated fatty acid (MUFA) , which can be preventive for development of hepatic steatosis (Arao et al, 2004). In obese Zucker rats, a model of metabolic syndrome, supplementation with pomegranate fruit extract and juice markedly decreased expression of vascular inflammatory markers such as thrombospondin and TGF-β (de Nigris et al, 2007). Also, a 4 week clinical trial administering 400 mg of pomegranate seed oil twice a day in hyperlipidemic subjects significantly improved the lipid profile as shown by a decreased triglyceride:HDL cholesterol ratio (Mirmiran et al, 2010). Furthermore, pomegranate has shown dramatic antioxidant potential. It has been shown that pomegranate fruit extract, which is rich in polyphenolic antioxidants, represses the expression of oxidation-sensitive genes at the site of stress. More recently, studies show that pomegranate juice extract may prevent high blood pressure induced by Angiotensin II in diabetic rats by ameliorating oxidative stress and inhibiting Angiotensin-converting enzyme (ACE) activity (Mohan et al, 2010). Research is also heading towards development of a synergistic combination of various extracts. Recently, Fenercioglu et al (2010) demonstrated antagonizing effects on oxidative stress and lipid peroxidation of a supplement containing pomegranate extract, green tea extract, and absorbic acid in type 2 diabetic patients. All the above mentioned results clearly suggest that pomegranate can play an important role in the prevention of diabetes, obesity and their associated complication. Basis on these findings it can be suggested that pomegranate can considered as a rational complementary therapeutic agent to ameliorate obesity, diabetes and the resultant metabolic syndrome. A thorough review of biological properties of pomegranate has been recently published elsewhere (Basu & Penugonda, 2009).

3.8. Avocado

Avocado (Persea americana) is a fruit native to the Caribbean, Mexico, South America and Central America. The 100 g of edible portion contains water (73.23 g), protein (2 g), lipids (14.66 g), Ash (1.58 g), carbohydrates (8.53 g), fibers (6.7 g) and sugars (0.66 g) (Table 1). Although many claims have been made about the unhealthy effects of avocados, key research debunks the myth that avocados are fattening and must be avoided in any sort of energy-restricted diet. Surprising data from a clinical trial came out that, the of feeding 55 subjects 200 g/day of avocado for 6 weeks with an energy restricted diet dramatically decreased demonstrated body weight, body mass index and percentage body fat, suggesting that consumption of avocado plays a role in regulating energy homeostasis and maintains body weight balance (Pieterse et al, 2005). Indeed, the MUFAs highly present in avocado which might be responsible agents to show the improved the lipid profile and adequately maintained glycemic control in patients with type 2 diabetes (Lerman-Garber et al, 1994). In another study, MUFAs decreased serum total cholesterol levels by 17%, LDL-cholesterol by 22%, triglycerides by 11%, and increased HDL-cholesterol by 11% in mild hypercholesterolemic patients (López Ledesma et al, 1996). Furthermore, the antioxidant and anti-inflammatory capacities of avocado are well established, suggesting that incorporation of avocado into the diet might ameliorate the pathogenesis of metabolic syndrome (Kim et al, 2000a). Persenone A, a compound isolated from the avocado fruit, nearly wholly suppressed protein expression of iNOS and COX-2 in RAW 264.6 mouse macrophage cells (Kim et al, 2000b). Overall, the results from studies exploring the role of avocado in various models can be well correlated with preventive effects of avocado to obesity and diabetes. However, it is critical to note that an optimal quantity of avocado must be consumed for the observed anti-diabetic and anti-obese effects, which is true to any natural components or food function.

3.9. Persimmon

The persimmon fruit (Diospyros digyna), is native to Japan and China. The published literature demonstrates a potent anti-diabetic and anti-obesity capacity of the persimmon fruit (Lee et al, 2007a; Dewanjee et al, 2009a; Matsumoto et al, 2006). Proanthocyanidin is the major component isolated from persimmon peel and has been demonstrated to play a role in obesity and diabetes. Administration of proanthocyanidin from the peel of persimmon in streptozotocin (STZ)-induced diabetic rats decreased the elevation of lipid peroxidation, suppressed generation of reactive oxygen species, decreased serum glucose, glycosylated hemoglobin (HbA1C), serum urea nitrogen, urinary protein, and renal advanced glycation endproducts under diabetic conditions. This clearly suggest an overall protective effect against oxidative stress-related inflammatory processes and diabetes (Lee et al, 2007a). In addition, administration of persimmon exhibited dose dependent hypoglycemic and hypolipidemic activity in STZ-induced diabetic rats. In addition, the activity of SOD, catalase, and glutathione content was increased in the liver and kidney, which is highly correlated with preventing oxidative stress mediated diabetic complications in this severe diabetic model (Dewanjee et al, 2009a). In the diet-induced obesity mouse model, feeding of persimmon significantly attenuated the elevation in plasma lipids (total cholesterol, triglyceride, LDL cholesterol) (Matsumoto et al, 2006). In male db/db mice (leptin receptor deficient mice), administration of proanthocyanidins reduced hyperglycemia through reduction of serum glucose and glycosylated protein levels, and hyperlipidemia (reduction of triglyceride, total cholesterol and non-esterified fatty acids) (Lee et al, 2008). Polymers from proanthocyanidins of persimmon exhibited a strong inhibitory effect on α-amylase, while oligomers exerted a stronger protective activity against α-glucosidase activity and AGE formation, suggesting that oligomers may have more potential as anti-diabetic agents (Lee et al, 2007b). Proanthocyanidins from persimmon also attenuated the increased oxidative stress in db/db mice by suppressing lipid peroxidation, ROS, protein expression of iNOS and COX-2, and increasing the reduced glutathione/oxidized ratio (Lee et al, 2008). Another study in Wistar albino diabetic rats also suggests persimmon is rendered a hypoglycemic effect from its antioxidant defense mechanisms (Dewanjee et al, 2009b). Tanin, also isolated from persimmon pulp, was demonstrated to have hydroxyl radical scavenging antioxidant capacities (Gu et al, 2008). Overall, the studies suggest that polymerization of proanthocyanidin has an important effect on its ability to combat the obese and diabetic phenotype, and that its oligomers are the more potent and promising compounds.

3.10. Guava

According to ancient Chinese Medicine, guava (Psidium guajava) is highly useful in the treatment of diabetes and other chronic diseases. However, the results regarding the anti-diabetic potential of guava fruit are ambiguous, clearly suggesting the need for further characterization for its hypoglycemic effects (Cheng & Yang, 1983; Roman-Ramos et al, 1995).

In alloxan-treated diabetic mice, intraperitoneal administration of 1g/ kg of guava juice dramatically reduced the blood glucose levels (Cheng & Yang, 1983). However, other studies have over counted with a non-significant effect of guava treatment on glucose homeostasis in rabbits (Roman-Ramos et al, 1995). But here this might be because of the difference in doses and duration of treatment. In STZ-induced diabetic rats, oral administration of guava fruit peel extract actually induced a hyperglycemic effect, suggesting that guava fruit peel should be peeled before eating in diabetic patients (Rai et al, 2007). In contrast, another study found that that oral administration of guava fruit peel extract demonstrated significant hypoglycemic and hypolipidemic effects in same model (Rai et al, 2010). Hence, it is highly evident that the literature is inconclusive regarding the hypoglycemic and hypolipidemic effects of guava; larger studies in diverse diabetic and obesity models are critical to solidly characterize the role of guava in glucose and energy homeostasis. Moreover chemical composition analysis of guava constituents will give further opportunity to develop a unique anti-diabetic and anti-obese component.

3.11. Other Exotic Fruits (Recent Findings)

In an effort to include the most up-to-date research on the role of exotic fruits in obesity and diabetes, a brief summary of ongoing research (articles in press) is presented. A recent study demonstrated a potential antioxidant capacity for raw Spondias pinnata K., an exotic fruit of India. The authors suggest Spondias pinnata K. may contain neutraceutical and therapeutic potential for chronic diseases like diabetes (Satpathy et al, 2011). Yang et al. review the potent therapeutic effects of Longan fruit, emphasizing its potent antioxidant and anti-glycated activity, hinting a role in prevention of diabetic complications (Yang et al, 2011). A review of the Kokum fruit, which is widely used in many Ayurvedic therapies, displays its evident anti-diabetic and anti-obese effects (Baliga et al, 2011). In addition to lowering circulating glucose levels in streptozotocin-induced type 2 diabetic rats, Kokum has been shown to possess free radical scavenging properties anti lipid peroxidation (Baliga et al, 2011). Further, hydroxycitric acid and cyaniding 3-glucoside were isolated and found to have potent anti-obesity effects through mechanistic pathways described in the review (Baliga et al, 2011). Copaifera langsdorffii Desf., the fruit of which is widely distributed in Brazil, demonstrate potential cholesterol and glucose-lowering effects (lower LDL, HDL, triglycerides, blood glucose, liver and fecal lipids) in male rats fed a 10% fruit supplemented diet (Esteves et al, 2010). The Bakul fruit, native to India, has been shown to have many anti-diabetic effects; oral administration of the extract resulted in a significant decrease in blood glucose and glycosylated hemoglobin levels, and an increase in serum insulin levels, along with other positive effects (reviewed by Baliga et al) (Baliga et al, 2011). Recently Hervert-Hernandez and colleagues (2011) reported that less consumption of fruits and vegetables is strongly related to obesity in women in rural Mexico. They suggested that this might be because of insufficient supply of dietary bioactive polyphenols and and their anti-oxidant potential. Another study conducted by Arancibia-Avila et al (2011) screened-out various bioactive compounds with anti-oxidant properties, which suggest that these compunds can be further studied for their role in obesity and diabetes pathophysiology. Ongoing research in the field is robust, and the potential of exotic fruits to aid as therapeutics for metabolic conditions is promising.

4. Effects of exotic fruit consumption in fatty liver disease

Fatty liver disease is characterized by extra accumulation of fat droplets in the liver, and this condition is independent of alcohol consumption and termed Non-Alcoholic Fatty Liver Disease (NAFLD) (Krawczyk et al, 2010). Fatty liver disease is common in obesity and type 2 diabetes and is considered a major cause of hepatic insulin resistance. Hepatic insulin resistance plays an important role to induce hyperglycemia in type 2 diabetic patients through increased hepatic endogenous glucose production (Lockman & Nyirenda, 2010). The major cause of fatty liver disease is consumption of high fat/ calorie diet. Hence the low calorie and high fiber diet is highly recommended for healthy liver function (Yki-Järvinen, 2010). Exotic fruits contain higher amount of fibers and various other bio-constituents that can enhance liver function and protect this precious organ from obesity/ diabetes induced metabolic derangements. For example, Oh et al (2005) described the beneficial effects of Psidium guajava (guava) in the type 2 diabetic and fatty liver disease phenotype in Lep^db/db mice. Interestingly, they found that extract of Psidium guajava (10 mg/ kg body weight) significantly decreased blood glucose levels and accumulation of fat droplets in liver tissues of Lep^db/db mice. This effect was mediated through the inhibition of protein tyrosine phosphatase 1B (a negative regulator of insulin signaling). Recently, Abodov et al (2010) found that the combination of pomegranate seed oil (PSO) and brown marine algae fucoxanthin (Xanthigen) significantly reduced occurrence of fatty liver disease in human subjects. The findings were characterized by significantly decreased body weight, waist circumference, hepatic fat content, triglyceride and improved liver function tests. The mechanism of Xanthigen for these beneficial effects were through increased whole body energy expenditure that was characterized by increased resting energy expenditure in Xanthigen fed subjects (Abidov et al, 2010).

5. Conclusions

Exotic fruits have various bioactive components with potential health benefits, including anti-diabetic, anti-obese, anti-oxidant and anti-inflammatory. Alone or together, a combination of these health beneficial effects rendered by the reported exotic fruits is very important to prevent the development of complex pathophysiology of obesity and diabetes. The whole fruit(s) and their bio-constituents can act on various pathophysiological targets of obesity and diabetes. However, the anti-diabetic and anti-obese effects of here reviewed exotic fruits and their bioactive constituents are clearly understudied. Further large scale and defined basic and clinical studies are critical to determine optimal dietary regimens to achieve the desired beneficial health effects. In addition, components of exotic fruits are clearly attractive targets for the scientific community to develop novel anti-diabetic and anti-obese compounds for future treatment/prevention of these life-threatening diseases.

Table 2.

Biological activities of exotic fruits and their bio-constituents

	Anti-adipocity	Anti- Hyperlipidemia/ Dyslipidemia	Anti- Hyperglycemia	Anti-Inflammation	Anti-Oxidant	Other(s)
Litchi	Decreased body weight gain, which correlates with adipocity (Guo et al, 2004).	Decreased total cholesterol, triaglycerol, free fatty acid, leptin in type II diabetic rats (Guo et al, 2004).	Decreased blood glucose in type II diabetic rats (Guo et al, 2004).	Decreased TNF-a, increased PGE2 production in type II diabetic rats (Huang & Wu, 2002; Guo et al, 2004).	Dose dependent free radical scavenging activity, decreased SOD and ROS levels in mouse adipocytes (Sakurai et al, 2008; Kong et al, 2010;	Reduced glucose induced cataract shown through aldose reductase in- vitro ( Lee et al, 2009; Cheung et al, 2010; Obrosova et al, 2010)
Durian		Improved plasma lipid profile in rats fed cholesterol enriched diet	Decreased hyperglycemia and improved insulin response curve in NIDDM patients (Roongpisuthipong, 1991; Leontowicz et al, 2007)		High levels of total polyphenols results in antioxidant capacity (Toledo et al, 2008)
Jackfruit			Improved glucose tolerance in normal and diabetic patients (Fernando, 1991;	Suppressed LPS induced production of nitric oxide and PGE-2 in RAW264.7 murine macrophage cells ( Fang et al, 2008; Vuolteenaho et al, 2009)	Ethanolic extracts possess DPPH scavenging activity, inhibited ferric induced lipid peroxidation in rat brain ( Feng et al, 1998)
Mangosteen	Mangosteen Significantly decreased BMI, which is an indirect measure of adipocity in human subjects (Udani et al, 2009; )	Reduced CRP levels in human subjects (Udani et al, 2009; )		Reduced LPS induced expression of proinflammatory genes (TNF-a, IL-6, etc.) in primary human adipocytes, inhibited nitric oxide and PGE-2 release in RAW264.7 macrophage cells (Bumrungpert et al, 2009; Bumrungpert et al, 2010)	Xanthones such as mangostin demonstrated tremendous antioxidant capacities ( Williams et al, 1995; Jung et al, 2006; Ngawhirunpat et al, 2010)
	Adipocity	Hyperlipidemia	Hyperglycemia	Inflammation	Oxidative Stress	Other
Acai	Reduced adipocity specific markers i.e. PEPCK (Sun et al, 2010)	Improved survival of drosophila fed with a high-fat diet, improved food efficiency in female Fischer fed a hypercholesterolemic diet (Sun et al, 2010; deSouza et al, 2010)	Supresses gluconeogenic genes in high-fat diet drosophila (Sun et al, 2010)		High contents of anthocyanins and polyphenols contribute to immense antioxidant capacity (Schauss et al, 2006; Chin et al, 2008; Spada et al, 2009; deSouza et al, 2010)
Goji	Decreased body weight in NIDDM rats (Luo et al, 2004; Zhao et al, 2005)	Improved plasma lipid profile in alloxan induced hyperlipidemic and NIDDM rats (Luo et al, 2004; Zhao et al, 2005;	Reduced blood glucose in alloxan induced diabetic rats (Luo et al, 2004)		Superoxide scavenging activity in rat liver, enhanced antioxidant markers such as SOD in healthy adults (Wu et al, 2004; Yu et al, 2006; Li, 2007; Li et al, 2007; Zhao et al, 2009)
Pomegranate	Reduced weight gain in CD-1 male mice and ameliorate adipogenesis (McFarlin et al, 2009; Hontecillas et al, 2009)	Decreased hepatic triaglycerol and MUFA levels in OLETF rats, 4wk clinical trial improved lipid profile in hyperlipidemic subjects (Arao et al, 2004; Mirmiran et al, 2010)	Activates PPARg and PPARg downstream expression in 3T3- L1 pre-adipocytes (Hontecillas et al, 2009)	Markedly decreased expression of vascular inflammatory markers such as thrombospondin and TGF-β (de Nigris et al, 2007)	Rich in polyphenolic antioxidants, which repress oxidation- sensitive genes at the site of stress (Basu & Penugonda, 2009)	Prevented high blood pressure in Ang II diabetic rats (Mohan et al, 2010)
Avocado	Decreased body fat mass in energy restricted diet in humans (Pieterse et al, 2005)	Decreased serum total cholesterol levels in humans (Lerman-Garber et al, 1994; Pieterse et al, 2005)	Maintained glycemic control in NIDDM patients (Lerman-Garber et al, 1994)	Suppressed iNOS and COX-2 in mouse macrophage cell line (Kim et al, 2000a, b)	Tremendous antioxidant capacity demonstrated in various models (Kim et al, 2000a, b)
Persimmon		Demonstrated hypolipidemic activity in STZ - induced diabetic rats (Lee et al, 2007a; Lee et al, 2008)	Demonstrated hypoglyemic activity in STZ- induced diabetic rats (Matsumoto et al, 2006; Lee et al, 2007a; Dewanjee et al, 2009b).	Overall protective effect against oxidative stress related inflammatory processes and diabetes (Lee et al, 2007a; Lee et al, 2008)	Potent antioxidant effects in diabetic conditions (Lee et al, 2007a; Lee et al, 2008; Dewanjee et al, 2009a; b)

Abbreviations

BMI

Body Mass Index

FFA

Free Fatty Acid

TNF-a

Tumor Necrosis Factor-a

PGE2

Prostaglandin E2

ROS

Reactive Oxygen Species

SOD

Super Oxide Dismutase

DPPH

2-2 Diphenyl-1-Picrylhydrazyl

NO

Nitric Oxide

iNOS

Inducibel Nitric Oxide Synthase

COX2

Cyclo-oxygenase 2

WAT

White Adipose Tissue

CRP

C-Reactive Protein

IFN-γ

Interferon-gamma

PEPCK

Phospho-Enol-Carboxy Kinase

HDL

High Density Lipoprotein

LDL

Low Density Lipoprotein

MDA

Malondialdehyde

GSH

Glutathione

GSH-Px

Glutathione-Peroxidase

PPAR-γ

Peroxisome Proliferator-Activated Receptor-gamma

MUFA

Mono-Unsaturated Fatty Acid

TGF-β

Transforming Growth Factor-beta

ACE

Angiotensin-Converting Enzyme

STZ

Streptozotocin

HbA1c

Glycosylated Hemoglobin