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Potential Bioactive Compounds from Seaweed for Diabetes Management

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Mar. Drugs 2015, 13, ; doi: /md Review OPEN ACCESS marine drugs ISSN Potential Bioactive Compounds from Seaweed for Diabetes Management
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Mar. Drugs 2015, 13, ; doi: /md Review OPEN ACCESS marine drugs ISSN Potential Bioactive Compounds from Seaweed for Diabetes Management Yusrizam Sharifuddin 1,2, *, Yao-Xian Chin 1,2, Phaik-Eem Lim 1,2 and Siew-Moi Phang 1,2 1 Institute of Ocean and Earth Sciences, University of Malaya, Kuala Lumpur, Malaysia; s: (Y.-X.C.); (P.-E.L.); (S.-M.P.) 2 Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia * Author to whom correspondence should be addressed; Tel.: ; Fax: Academic Editor: Orazio Taglialatela-Scafati Received: 8 April 2015 / Accepted: 11 June 2015 / Published: 21 August 2015 Abstract: Diabetes mellitus is a group of metabolic disorders of the endocrine system characterised by hyperglycaemia. Type II diabetes mellitus (T2DM) constitutes the majority of diabetes cases around the world and are due to unhealthy diet, sedentary lifestyle, as well as rise of obesity in the population, which warrants the search for new preventive and treatment strategies. Improved comprehension of T2DM pathophysiology provided various new agents and approaches against T2DM including via nutritional and lifestyle interventions. Seaweeds are rich in dietary fibres, unsaturated fatty acids, and polyphenolic compounds. Many of these seaweed compositions have been reported to be beneficial to human health including in managing diabetes. In this review, we discussed the diversity of seaweed composition and bioactive compounds which are potentially useful in preventing or managing T2DM by targeting various pharmacologically relevant routes including inhibition of enzymes such as α-glucosidase, α-amylase, lipase, aldose reductase, protein tyrosine phosphatase 1B (PTP1B) and dipeptidyl-peptidase-4 (DPP-4). Other mechanisms of action identified, such as anti-inflammatory, induction of hepatic antioxidant enzymes activities, stimulation of glucose transport and incretin hormones release, as well as β-cell cytoprotection, were also discussed by taking into consideration numerous in vitro, in vivo, and human studies involving seaweed and seaweed-derived agents. Mar. Drugs 2015, Keywords: α-glucosidase; aldose reductase; algae; antioxidant; biotechnology; diabetes; DPP-4; GIP; PTP1B; seaweed 1. Introduction 1.1. Definition and Current Incidence of Diabetes Diabetes mellitus is a group of chronic diseases, which can be attributed to hyperglycaemia, a condition characterised by an excessive concentration of glucose circulating in the blood. Diabetes mellitus can be categorised into two main forms namely Type I diabetes mellitus (T1DM), caused by the absolute absence of insulin production due to auto-immune mediated disintegration of pancreatic β-cells, and Type II diabetes mellitus (T2DM), which is due to the relative deficiency of the same hormone involving insulin resistance, aberrant synthesis of hepatic glucose and progressive deterioration of pancreatic β-cell functions [1]. T2DM sufferers are not dependent on insulin injection, unlike those with T1DM, if diet and hypoglycaemic agents were sufficient for effective glycaemic control. The World Health Organisation (WHO) had projected the total number of people with diabetes mellitus (DM) worldwide to increase from 171 million in 2000 to nearly 370 million in 2030, with the prevalence of the disease for all age groups to be 4.4% in 2030, compared with 2.8% in 2000 [2]. Diabetes is frequently correlated with increased risk in hypertension, macrovascular and microvascular complications, blindness and kidney failure [3]. Macrovascular complications have been observed to be higher in T2DM patients with the risk of developing diseases involving the human vascular tree such as stroke, coronary artery disease and peripheral arterial disease to be fourfold higher, which developed relatively earlier in diabetic than non-diabetic patients [4,5]. Sufferers of T2DM normally have reduced life expectancy due to these various co-morbidities [6,7] Pathophysiology and Prevalence of Type II Diabetes Mellitus (T2DM) T2DM accounts for approximately 90% of diabetes cases worldwide, verging on epidemic proportions affecting both developed and developing countries [8]. This increase is attributed to greater prevalence of sedentary lifestyle, unhealthy diet and rise of obesity within modern society as well as an increasing number of elderly populations [2]. Furthermore, the pathophysiological processes leading to T2DM including deterioration of β-cells functions, chronic hyperglycaemia, and insulin resistance in musculoskeletal and adipose tissues [9,10] may be latently present for a considerably long period, prior to any diagnosis or manifestations of medical complications. Often, β-cell functions are reduced to approximately 50% by the time diabetes is diagnosed [11]. In normal individuals, a fairly constant level of insulin is released into the bloodstream by pancreatic β-cells, which will increase the blood level of the hormone upon food ingestion. Post-prandial insulin release, as well as increased blood glucose level, inhibit renal and hepatic secretion of glucagon into circulation, effecting glucose uptake into various tissues. Individuals with post-prandial hyperglycaemia exhibit decreased insulin secretion after food consumption and less inhibition on the release of glucagon, leading to aberrant hepatic and renal glucose production, reduced glucose uptake by cells and consequently elevated blood glucose levels [12,13]. Mar. Drugs 2015, Progressive entry of ingested and endogenous glucose into the circulation that outpace the removal rate causes prolonged high concentrations of blood glucose, leading to loss of homeostatic post-prandial glycaemic control followed by hyperglycaemia [12 14]. Preventing this costly lifestyle disease is more desirable than treating its various associated complications and in light of the rapid escalation of T2DM cases globally, urgent action in identifying new prevention strategies are needed. Prevention is crucial due to the premature morbidity and mortality associated with the disease that could potentially burden personal, as well as annual national, healthcare expenditures. Previous major studies have demonstrated the beneficial values of glycaemia control in preventing and/or reducing the risk of microvascular complications related to diabetes such as neuropathy, nephropathy and retinopathy as well as various macrovascular complications [15,16]. Other subsequent large-scale studies also showed the positive effect of lifestyle intervention approaches [17,18]. Indeed, the primary objective in T2DM management is to ensure sufficient delivery of glucose to various tissues of the body and also to delay, and/or prevent associated complications of T2DM due to hyperglycaemia by achieving good glycaemic control. Current medical care employs a wide array of pharmacological and lifestyle intervention approaches aimed at managing hyperglycaemia. Lifestyle interventions consisting of suitable diet and physical exercise decreased the incidence of diabetes by up to 58% [19,20] and long-term glycaemic control was found to be beneficial in reducing the risk of both micro- and macrovascular complications in T2DM patients [21]. Understanding the complexity of glucose homeostasis, diabetes pathophysiology and other associated risk factors such as obesity is important considering the multi-factorial nature of the disease. Nutrition has been regarded to play a pivotal role within this complex pathophysiology of T2DM and in the last several years, increasing amount of evidence has emerged linking several nutrients and food sources in positively managing T2DM. Previous studies have suggested that high dietary intake of fruit, whole-grain, and vegetables may confer protection against or reduced the risk of T2DM development [22,23] Seaweed Consumption and Diabetes Seaweed have been traditionally consumed as a readily available wholefood especially among coastal communities particularly in Asia [24,25], for example the Japanese were reported to consume seaweed in their daily diet approximately 5.3 g per day [26]. Additionally, seaweed has also been prescribed for numerous ailments in different Asian traditional medical systems. Although consumer awareness and dietary seaweed intake are generally low in other regions [27], popularisation of East-Asian diet worldwide has gradually increased public interest and acceptance of seaweed as a food source, partly due to their suggested health benefits. As adoption of good nutritional habits as part of a healthy lifestyle are currently in vogue and concomitant increase of consumers market influence on the food industry, consumption of seaweed and seaweed-based products are rising similar to the trend observed with fresh fruits and vegetables. In other parts of the world, seaweed use is generally limited to extracts and food additives [28], as well as isolates, such as carrageenan and alginate, which are normally used in various applications [29]. Currently, there is a growing awareness on the role of food beyond the basic nutritional value by providing health benefits and reducing the risk of various illnesses including diabetes [30,31]. High consumption of seaweed in daily diet has been associated with lower risk of diseases, such as cardiovascular disease and hyperlipidaemia [32], as well as breast cancer [33]. Furthermore dietary Mar. Drugs 2015, changes involving reduction of daily seaweed consumption due to a more Westernised diet in Asian societies that traditionally consumed seaweed, indicated increased incidence of chronic lifestyle diseases, hence highlighting seaweed s health benefits [34 36]. Indeed, seaweed have often been overlooked as a good source of functional food and are under-utilised dietary source of novel as well as structurally diverse bioactive compounds with high biomedical potential that are not commonly present in terrestrial plants. In this review paper, we aim to narrate the diversity of beneficial contents and bioactive compounds from seaweed, which are potentially useful in preventing or managing T2DM via various pharmacologically relevant targets. Seaweeds are rich in bioactive compounds in the form of polyphenols, carotenoids, vitamins, phycobilins, phycocyanins, and polysaccharides, among others, and many of these are known to possess beneficial applications in human health [27]. There is also an incomparably rich amount of minerals and trace elements content in seaweed due to their ability in retaining inorganic marine substances attributed to the features of their cell surface polysaccharides where several of these essential minerals can be found at relatively higher levels than in terrestrial food sources [37 39]. Some seaweed species may contain minerals in more than 30% of their dry weight [40] and all of the essential minerals and trace elements required for healthy human diet can be found in seaweed [37]. Edible seaweed are also low in calories and rich in dietary fibre, unsaturated fatty acids and vitamins [41,42], making them suitable for managing diabetes. Indeed, dietary consumption of Porphyra yezoensis and Undaria pinnatifida was associated with low incidence of diabetes in Korean men [43]. A nationally representative survey conducted on health and nutrition, suggests that the risk of developing T2DM in Korean men may be reduced by dietary consumption of seaweed [44]. The consumption of commercial blend of Ascophyllum nodosum and Fucus vesiculosus was associated with improved insulin regulation and sensitivity, measured in human subjects using the Cederholm index upon carbohydrate ingestion, compared with placebo [45]. Consumption of mekabu (sporophylls of Undaria pinnatifida) with a white rice-based breakfast by healthy volunteers demonstrated a reduction of post-prandial glucose concentration and this was attributed to the content and viscosity of fucoxanthin in mekabu [46]. Recently, a study involving more than 4000 participants in Korea revealed that insulin level and insulin resistance were inversely associated with dietary intake of flavonols and flavones, thereby reducing the risk of T2DM [47]. However, not all of these studies fully elucidate the factors involved in beneficial properties of seaweed dietary intake in managing diabetes. Therefore, the potential of various beneficial components in seaweed and their possible modes of action against the development of T2DM deserve a closer investigation. 2. Seaweed Composition and Effects on Diabetic Targets 2.1. Unsaturated Fatty Acids from Seaweed Seaweeds are rich in unsaturated fatty acids. Fatty acids containing two or more methylene-interrupted double bonds are important for normal cellular functions and have gained worldwide interest in their utilisation as nutraceuticals including against T2DM. Mar. Drugs 2015, Monounsaturated Fatty Acids (MUFA) from Seaweed The substitution of saturated fatty acids with monounsaturated fatty acids (MUFA) was found to improve insulin sensitivity in healthy and glucose-intolerant subjects [48] with no excessive total fat intake [49]. Even though the suggested positive effects of MUFA were not found by other earlier studies [50,51], they are generally considered as a useful source of fat for sufferers with varying degrees of insulin resistance [52]. The exact mechanisms of MUFA in diabetes management are still not fully elucidated but several possible modes of action have been suggested including promoting glucose uptake by up-regulating glucose transporter type 1 (GLUT1) and type 4 (GLUT4) in the cell membrane [53], as well as possessing cytoprotective effects on pancreatic β-cells. Furthermore, the beneficial effect of dietary MUFA in improving insulin sensitivity in rats was attributed to the preservation of IRS/PI3K insulin pathway and increased GLUT4 translocation to the cell membrane [54]. MUFA has also been linked to changes in incretin responses and gastric emptying, where dietary MUFA elevated the glucagon-like peptide (GLP-1) in both healthy and diabetic subjects [55]. In addition, the intake of dietary MUFA increased the levels of adiponectin [56], which is associated with reduced risk of T2DM [57]. Wang and colleagues reported that the extracts and MUFA derivatives isolated from the green seaweed Ulva lactuca induced many antioxidant-response element (ARE)-driven antioxidant genes in various mouse tissues [58]. Antioxidant, anti-inflammatory properties and stimulation of hepatic antioxidant enzymes have been reported as one of the anti-diabetic potential of seaweed as discussed in the later section of this review Polyunsaturated Fatty Acids (PUFA) from Seaweed Comparable to MUFA, polyunsaturated fatty acids (PUFA) also play various important biological functions both structural and physiological in nature [59]. They are also involved in cellular and tissue metabolism including thermal adaptation and membrane fluidity regulation [60]. Furthermore, increased public interest in healthy lifestyle and diet had propelled PUFA into popular market demands [61]. The potential of seaweed as a good source of PUFA has been well documented [62 65]. Seaweed may contain lipids, which represent up to 2% in algal dry weight and primarily PUFA [62,66]. Majority of the PUFA present in seaweed are in the form of omega-3 and omega-6 fatty acids, both are essential in human diet and generally present in an almost frequent ratio [62]. Various edible seaweeds, such as Undaria pinnatifida, Himanthalia elongata, and Laminaria ochroleuca, contain higher percentage of unsaturated fatty acids (MUFA and PUFA) compared with saturated fatty acids, with U. pinnatifida containing almost 70% of fatty acids as PUFA [62]. A balanced diet should consists of omega-3 and omega-6 fatty acids in a suitable ratio and ideal ratio should range from 1:3 to 1:5 of omega-3 to omega-6 fatty acids, as it affects the ratio of resultant eicosanoids [38,67]. Many seaweed species from the Phaeophyta and Rhodophyta phyla contain higher concentrations of unsaturated fatty acids compared with those from Chlorophyta, with the exception of Ulva sp., which possesses high concentrations of omega-3 fatty acids [65,68]. Furthermore according to Pereira and colleagues, almost all seaweed species they had studied encompassing the three phyla can be regarded as a good source of dietary PUFA as their omega-6 and omega-3 fatty acids ratio ranged from 0.29 to 6.73, which is within the recommended value [65]. Omega-6 PUFA from plant sources exhibit positive effects on insulin sensitivity [69] and are linked to lower risk of developing T2DM [70 72]. Mar. Drugs 2015, Diet rich in omega-6 PUFA was shown to improve insulin sensitivity in human subjects during a five-week study [69]. Just as observed with MUFA, PUFA also affects insulin action by changing physical properties of cellular membranes such as elevating binding affinity of the insulin receptor and increasing glucose uptake by cells via glucose transporters [73 75]. Omega-3 PUFA may also reduce insulin resistance via other mechanisms including decreasing circulating triglycerides and low-density lipoprotein particles [76] as well as being anti-inflammatory via toll-like receptors (TLR) inhibition. TLR-2 and TLR-4 can be inhibited by omega-3 PUFA [77] and long-chain omega-3 PUFA have been associated with increased levels of anti-inflammatory cytokines including interleukin-6r and interleukin-10 (IL-10), as well as lower concentration of pro-inflammatory interleukin-1ra and tumour necrosis factor-α (TNF-α) [78]. Omega-3 PUFA supplementation reduced triglycerides concentration, blood pressure and inflammatory markers in T2DM patients [79]. Khan and colleagues screened 37 species of seaweed representative of three different phyla collected from Korean coast for their anti-inflammatory activities measured by potential inhibition of mouse ear erythema and edema [80]. The methanolic extracts of an edible species of brown seaweed popular in Korean traditional medicine, Undaria pinnatifida and a species of green seaweed, Ulva linza exhibited the best inhibitory activities against inflammatory response attributable to their PUFA content [80]. Furthermore, omega-3 PUFA also influenced expression of several genes that are involved in lipid and carbohydrate metabolism by affecting their expression or the activity of several transcription factors including hepatic nuclear factors, sterol-regulatory element-binding protein-1c and liver X receptor [81] Dietary Fibres from Seaweed Consumption of dietary fibre has been associated with weight loss due to prolonged gastric clearance rate leading to increased satiety and concomitant reduction of food intake. Previous large-scale prospective observation studies have demonstrated that high intakes of dietary fibre are consistently correlated to a markedly reduced incidence of T2DM [82,83] and many international organisations issued guidelines recommending high daily intakes of dietary fibres, ranging from at least 30 g/day for healthy individuals to 50 g/day for diabetic patients [84,85]. Many seaweed species contain similar or higher total fibre content compared with their terrestrial counterparts [38]. For example, Himanthalia elongata, Ascophyllum nodosum, Laminaria digitata and Palmaria palmata contain higher percentage of total dietary fibre and lower soluble carbohydrate (g/100 g weight) compared with brown rice and bananas [38]. Furthermore, 8 g seaweed per serving can potentially provide close to 12.5% of an individual s daily fibre requirement suggesting high-fibre intake with low glycaemic load is achievable with small quantity of seaweed consumption, hence its suitability for T2DM management [38]. The total dietary fibre intake by diabetic patients given seaweed supplements containing Undaria pinnatifida and Saccharina japonica for four weeks was observed to be 2.5 times higher compared with control, accompanied by concomitant
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