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Alginates in Metabolic Syndrome

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Alginates extracted from seaweeds are widely used for nutrition, but they are underutilised for the prevention or reversal of human disease. Alginates are long chains of α-L-guluronic acid and β-D-mannuronic acid from brown seaweeds that act as readily available, low cost, non-toxic and biodegradable biopolymers. Sodium alginates are primarily used for the management of gastrointestinal tract disorders, but they are of potential use to attenuate the components of the metabolic syndrome including obesity, type 2 diabetes, hypertension, non-alcoholic fatty liver disease and dyslipidaemia. As prebiotics, alginates changed the gut microbiome to increase production of short-chain fatty acids as substrates for Bifidobacteria. Alginates inhibited pancreatic lipases and so decreased triacylglycerol breakdown and uptake. Treatment with alginates decreased food intake by inducing satiety and increased weight loss in patients on a calorie-restricted diet. Both glucose and fatty acid uptake were reduced. In rat models of hypertension, alginates decreased blood pressure. An alginate-antacid combination is an effective treatment of gastric reflux disease by forming a raft on the gastric contents. Alginates are important as drug carriers in microparticles and nanoparticles to increase drug bioavailability, for example, in drugs used for treatment of metabolic syndrome. Alginates are also used to protect cells during transplantation from immune responses of the host, allowing potential long-term control of some endocrine disorders such as type 1 diabetes and increased thermogenesis by brown adipocytes in obesity. There are many potential uses for these versatile biopolymers in the treatment of human disease.
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223© Springer Nature Singapore Pte Ltd. 2018
B.H.A. Rehm, M.F. Moradali (eds.), Alginates and Their Biomedical Applications,
Springer Series in Biomaterials Science and Engineering 11,
https://doi.org/10.1007/978-981-10-6910-9_9
Chapter 9
Alginates inMetabolic Syndrome
SenthilArun Kumar andLindsayBrown
Abstract Alginates extracted from seaweeds are widely used for nutrition, but they
are underutilised for the prevention or reversal of human disease. Alginates are long
chains of α-L-guluronic acid and β-D-mannuronic acid from brown seaweeds that
act as readily available, low cost, non-toxic and biodegradable biopolymers. Sodium
alginates are primarily used for the management of gastrointestinal tract disorders,
but they are of potential use to attenuate the components of the metabolic syndrome
including obesity, type 2 diabetes, hypertension, non-alcoholic fatty liver disease
and dyslipidaemia. As prebiotics, alginates changed the gut microbiome to increase
production of short-chain fatty acids as substrates for Bidobacteria. Alginates
inhibited pancreatic lipases and so decreased triacylglycerol breakdown and uptake.
Treatment with alginates decreased food intake by inducing satiety and increased
weight loss in patients on a calorie-restricted diet. Both glucose and fatty acid
uptake were reduced. In rat models of hypertension, alginates decreased blood pres-
sure. An alginate-antacid combination is an effective treatment of gastric reux dis-
ease by forming a raft on the gastric contents. Alginates are important as drug
carriers in microparticles and nanoparticles to increase drug bioavailability, for
example, in drugs used for treatment of metabolic syndrome. Alginates are also
used to protect cells during transplantation from immune responses of the host,
allowing potential long-term control of some endocrine disorders such as type 1
diabetes and increased thermogenesis by brown adipocytes in obesity. There are
many potential uses for these versatile biopolymers in the treatment of human
disease.
Keywords Alginates • Metabolic syndrome • Gastrointestinal tract • Hypertension
• Inammation • Nanoparticle delivery • Cell transplantation
S.A. Kumar
Advanced Centre for Treatment, Research and Education in Cancer (ACTREC),
Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, 410210, India
L. Brown (*)
School of Health and Wellbeing, University of Southern Queensland, Toowoomba, Australia
e-mail: Lindsay.Brown@usq.edu.au
224
9.1 Introduction
The human diet in Japan, Korea, China, Vietnam and the Philippines has included
seaweeds for hundreds of years. As potential functional foods, seaweeds may pre-
vent or treat disease in addition to their nutritional advantages [1, 2], but their use-
fulness is underestimated. Seaweeds are aquatic photosynthetic plants separated
into macroalgae and microalgae, with macroalgae classied into three types: brown
algae (Phaeophyta), red algae (Rhodophyta) and green algae (Chlorophyta) [3].
Brown seaweeds contain alginates as viscous water-soluble polysaccharides that
consist of (1,4)-linked chains of α-L-guluronic acid and β-D-mannuronic acid as the
major sugar residues [4, 5]. The concentration of alginates can be high in seaweeds,
for example, 15–30% in Ascophyllum nodosum (rockweed or Norwegian kelp),
20–45% in Laminaria digitata (oarweed) and 21–42% in Alaria esculenta (dabber-
locks or winged kelp) [6]. Brown seaweeds such as Sargassum sp. are widely used
in food and have been used in Traditional Chinese Medicine for nearly 2000years
as potential anticancer, anti-inammatory, antibacterial and anti-viral medicines
[7]. Laminaria japonica, a source of alginate and fucoidan, as well as fat-soluble
components, such as fucoxanthin and fucosterol, is widely used in Japan as a healthy
food (kombu) that may prevent obesity and diabetes [8]. The physiological responses
to consumption of seaweeds containing alginates mainly involve the gastrointestinal
tract, including increased gastric distension, delayed gastric emptying and enhance-
ment of satiety together with delayed postprandial glycaemia and insulin responses
[9]. Sodium alginates have found applications in the management of gastrointestinal
and metabolic complications, primarily of the components of the metabolic syn-
drome including obesity, type 2 diabetes, hypertension, non-alcoholic fatty liver
disease and dyslipidaemia [1012]. This chapter will discuss the role of alginates to
improve health, primarily based on their changes in gastrointestinal function.
9.2 Alginates intheGastrointestinal Tract
Alginates have multiple effects on gastrointestinal function including reduction of
intestinal absorption rates and systemic effects, decreased uptake of fats and reduced
plasma cholesterol, increased faecal bile and cholesterol excretion, reduction in
blood peak glucose and plasma insulin rise, stool bulking, adsorption of toxins
found within the colon, alteration of colonic microora, direct effects on colonic
mucosa and increased sensation of satiety and reduced caloric intake [10]. Some of
these will now be further examined. Polysaccharides from seaweeds and microalgae
such as alginates, fucoidans and carrageenans may act as prebiotics [10, 13].
Prebiotics are long-chain carbohydrates that are not broken down in the stomach but
metabolised by bacteria in the colon to short-chain fatty acids such as acetate, butyr-
ate and propionate which serve as metabolic substrates for some gut bacteria [14
16]. Treatment with alginates (10g/day) in healthy male volunteers enhanced the
S.A. Kumar and L. Brown
225
growth of benecial gut microbes, particularly Bidobacterium species, with a con-
comitant decrease in Gram-negative Enterobacterium and Clostridium species, with
increased acetate and propionate production and decreased release of toxic metabo-
lites such as sulphide, p-cresol and indole in the faecal samples [14].
Pancreatic lipase is an important enzyme in triacylglycerol breakdown in the gas-
trointestinal tract. Therefore, inhibition of this enzyme is a potential mechanism for
the reduction of obesity as shown by orlistat, a commonly prescribed antiobesity
medication. Alginates also inhibit pancreatic lipase [10]. Alginates high in guluronic
acid from Laminaria hyperborea inhibited lipase activity more than alginates high in
mannuronic acid from Lessonia nigrescens suggesting that guluronic acid- rich algi-
nates could help in treating obesity by reducing dietary triacylglycerol uptake [17].
Interactions between the negatively charged alginates and positively charged proteins
are more likely at low pH, as in the stomach [10]. Testing alginates in a bread vehicle
using a model gut showed that alginates retained their lipase inhibitory properties
despite cooking at 150°C, showing the potential for this product in obesity [18].
Altered satiety signalling plays an important role in type 2 diabetes and obesity,
both key components of metabolic syndrome [19]. Treatment of healthy humans
with sodium alginate treatment at 9.9–15g/day reduced energy intake by inducing
a feeling of satiety, probably caused by increased viscosity causing swelling in the
gastrointestinal tract [20]. This gelling effect plays a central role in delaying the
gastric emptying by increasing stomach extension in the antrum and in slowing
down nutrient absorption in the small intestine. An increased guluronic to mannu-
ronic acid ratio increases viscosity and gel strength of the sodium alginate and so
could increase satiety [21]. A short-term trial using guluronic acid-enriched algi-
nates together with calcium or pectin for 7 days increased satiety in overweight
individuals [22, 23]. This protocol reduced daily energy intake by 134.8 kcal (7%)
associated with reductions in mean daily intake of sugar, saturated fats and proteins
[23]. In contrast, 10-day treatment with CM3 alginate, a compressed, lyophilised
sodium-alginate active complex, based on the brown seaweed Laminaria digitata,
had no effect on satiety, appetite, gastric function or gut hormone secretion [24].
There are only limited studies on weight-reducing effects of alginates, despite
newspaper articles with anecdotes that alginates in seaweeds can help control obesity
(e.g. http://www.telegraph.co.uk/foodanddrink/foodanddrinknews/11853491/Can-
seaweed-really-help-you-lose-weight.html). The paucity of studies is surprising,
given the evidence showing weight loss with administration of prebiotics [25]. There
is solid evidence that alginates moderate many mechanisms that should assist in
weight management [10, 26], but there are few studies demonstrating an anti-obesity
effect. In a single study, patients on a calorie-restricted diet of 300kcal/day showed
a further increase in weight loss from 5.0 to 6.7kg when given 15g bre as alginates
three times a day for 12weeks, mainly as a reduction of body fat, while plasma mark-
ers of glucose and lipid metabolism and inammation were unchanged [27]. Long-
term studies remain necessary to dene the anti-obesity effects of alginates [26].
9 Alginates inMetabolic Syndrome
226
9.3 Alginates inMetabolic Changes
Insulin resistance or diabetes together with dyslipidaemia are used as clinical signs
to dene metabolic syndrome. High-viscosity dietary bres, including guar gum
and alginates, when incorporated in edible crispy bars containing 50 g carbohy-
drate, attenuated postprandial glycaemia without any change in gastrointestinal tol-
erance in healthy adults [28]. Supplementation with alginates and calcium in rats
attenuated postprandial glycaemic responses in streptozotocin (STZ)-induced dia-
betes in rats, probably due to increased viscosity as well as calcium-induced gel
formation [29]. This increased gelling is likely to delay gastric emptying and
decrease nutrient absorption in the small intestine, and both changes will decrease
postprandial glycaemic responses and attenuate peak insulinaemic responses [26].
In male patients, cholesterol uptake from a xed diet increased with increasing
body fat; a single administration of 1.5g sodium alginate with calcium carbonate
decreased uptake of glucose, cholesterol and triacylglycerols to the levels in healthy
subjects [30]. In rats fed a high cholesterol diet, addition of 2% calcium alginate to
the diet decreased plasma cholesterol concentrations, possibly due to an increased
bile acid excretion due to reduced intestinal reabsorption [31]. The gelling of both
high and low molecular weight alginates from Laminaria angustata in the stomach
was proposed as the mechanism for the reduced glucose uptake and insulin response
and increased cholesterol excretion from the gastrointestinal tract [32]. These stud-
ies suggest that the gastrointestinal changes induced by alginates can reduce dys-
lipidaemia in overweight/obese patients.
9.4 Alginates inHypertension
Hypertension is one of the diagnostic criteria for metabolic syndrome, and, further,
metabolic syndrome increases the risk of cardiovascular disease. Oral administra-
tion of low molecular weight potassium alginates (250 or 500mg/kg body weight)
extracted from brown seaweeds normalised the cardiovascular changes in DOCA-
salt hypertensive rats to a greater extent than the same dose of potassium chloride
[33]. Sodium alginate oligosaccharides (60 mg/kg given subcutaneously) almost
completely abolished the increased blood pressure in Dahl salt-sensitive rats fed 4%
sodium chloride; this response may be due to improved kidney function with
decreased sclerosis and vascular injury in the kidney, together with direct effects on
vascular function, rather than by reducing salt absorption [34]. Dietary sodium algi-
nate oligosaccharides given as a 4% intervention in the diet induced small changes
in systolic blood pressure in male SHR, but renal glomerular damage was markedly
decreased [35]. In obese patients, sodium alginates had no effect on borderline
hypertensive patients with a baseline systolic blood pressure of 132.7±2.2mmHg
[27]. No studies were found that reported changes in blood pressures in hyperten-
sive patients following alginate interventions.
Alginates derived from Sargassum vulgare have shown antitumour activity in
mice. However, these mice developed acute tubular necrosis, suggesting intrinsic
S.A. Kumar and L. Brown
227
nephrotoxicity, producing increased perfusion pressure, renal vascular resistance,
glomerular ltration rate, urinary ow and sodium, potassium and chloride excre-
tion and reduction of chloride tubular transport, possibly due to direct vascular
effects [36]. These actions could be due to direct actions on the renal vasculature, as
shown for mesenteric blood vessels [36]. No studies were found showing toxicity of
alginates in heart or liver or in humans.
9.5 Alginates inGastric Reux Disease
Alginates have been given to relieve gastric reux for many years. They precipitate upon
contact with gastric acid to produce low-viscosity gels of near-neutral pH, triggering the
sodium bicarbonate in the formulation to release carbon dioxide in the gel, which then
oats on the stomach contents as a raft close to the oesophageal- gastric junction [37].
Combination of calcium carbonate and sodium bicarbonate with sodium alginate reduced
gastric reux episodes and increased time to reux symptoms compared to patients
given antacid only [38]. This study showed that the alginate-antacid raft was localised to
below the diaphragm in these gastric reux patients [38]. Despite a substantial placebo
response, an alginate-antacid combination reduced heartburn, regurgitation and dyspep-
sia in a randomised trial of 1107 patients with mild-to-moderate symptoms [38].
9.6 Alginates inLiver Disease
Obesity increases the risk of developing non-alcoholic fatty liver disease (NAFLD),
which may develop into non-alcoholic steatohepatitis (NASH) and then progress to
hepatocellular carcinoma [39]. In monosodium glutamate-treated mice with NASH
symptoms, oral sodium alginate treatment improved liver steatosis, insulin resis-
tance and chronic inammation, and prevented the progression to carcinoma [11].
Translation to humans with NAFLD or NASH has not been reported.
9.7 Alginates inInammation
Obesity is dened as a chronic inammation [40], yet no studies have reported anti-
inammatory effects of alginates in obese rats or humans. Adjuvant-induced
arthritic rats as a model of rheumatoid arthritis when treated with alginate from
Sargassum wightii showed decreased paw oedema, reduced activities of inamma-
tory enzymes and reduced plasma inammatory biomarkers [41]. However, anti-
inammatory compounds such as indomethacin will induce gastric and small
intestinal ulcers. Sodium alginate has been proposed as a treatment to prevent
indomethacin- induced small intestinal injury as mice showed reduced intestinal
injury and reduced expression of mucin following alginate treatment [42] (Fig.9.1).
9 Alginates inMetabolic Syndrome
228
Fig. 9.1 Possible therapeutic effects of alginates in the attenuation of metabolic complications. NAFLD non-alcoholic fatty liver disease; () increased
response; () diminished response
S.A. Kumar and L. Brown
229
9.8 Alginates asDrug Carriers forTreatment ofMetabolic
Syndrome
Alginates are readily available, low cost, non-toxic, biodegradable and versatile bio-
polymers and are therefore useful as drug carriers for therapy, for example, as
hydrocolloids in sustained-release products [43]. Further development to produce
nanoparticles with improved drug delivery is one of the success stories in pharma-
ceutical technology in the last 20years, with a wide range of techniques being avail-
able for their preparation [44]. The effectiveness of nanoparticles depends on their
size and surface area, with a wide range of possible shapes giving a range of poten-
tial applications [45]. As an example, the oral bioavailability of insulin has been
improved by formulation as polymer-based nanoparticles, including alginate, but
these products have not reached the market [46]. The preparation of alginate mic-
roparticles and nanoparticles has been summarised, and future challenges have been
outlined [47].
There is now clear evidence that alginate-containing microparticles of oral hypo-
glycaemic drugs could be effective in type 2 diabetic patients. Metformin encapsu-
lated in alginate oating beads produced greater decreases in blood glucose
concentrations in Sprague-Dawley rats made diabetic following injection of strep-
tozotocin (60 mg/kg ip for 3days) than with metformin alone [48]. Microcapsules
of gliclazide prepared using taurocholic acid and sodium alginate decreased hyper-
glycaemic responses in alloxan-induced type 1 diabetic rats [49]. Exenatide deliv-
ered orally in microcapsules with alginates and hyaluronate to db/db mice normalised
the blood glucose concentrations for 2 h; this response could be prolonged until 4 h
with increased exenatide doses for effective control of type 2 diabetes [50]. These
studies show the potential of micro- and nanoparticles to increase treatment options
for type 2 diabetes. These techniques may also apply to insulin treatment of type 1
diabetes, now exclusively given subcutaneously. Oral administration of chitosan-
alginate insulin nanoparticles reduced blood glucose concentrations in alloxan-
diabetic mice more slowly than subcutaneous insulin, with bioavailability of
approximately 8% [51]. Liver damage is common in diabetes. One possible alterna-
tive for treatment of liver tumours is the use of alginate microspheres with the anti-
neoplastic drug, amonade, that causes serious adverse effects with oral delivery, to
achieve targeted delivery with reduced systemic toxicity [52]. Another option for
intracellular targeting of liver tumour cells is the use of microspheres with meso-
porous silica nanoparticles together with alginate providing high biocompatibility
and sustained release [53].
Alginate-containing nanoparticles may also be useful to administer lipid-
lowering drugs such as probucol [54]. The physical characteristics of these probucol
nanoparticles were appropriate for treatment [54]; similar nanoparticles of probucol
improved insulin release and decreased TNF-alpha production by pancreatic beta
cells cultured in 25.5 mM glucose [55].
Hypertension is an important component of the metabolic syndrome. Many anti-
hypertensive drugs have been formulated in alginate-containing nanoparticles for
9 Alginates inMetabolic Syndrome
230
oral administration to produce sustained-release characteristics, including nifedipine
[56], diltiazem [57], carvedilol [58] and propranolol [59]. Possible alternative routes
of administration include transdermal delivery of an alginate hydrogel containing
prazosin [60] and buccal absorption of nimodipine [61]. There are no reports of
studies specically targeting hypertension in patients with metabolic syndrome
using micro- or nanoparticles, but these formulations may offer advantages for spe-
cic drugs and patients. Intramyocardial injections of alginate hydrogel implants in
dogs with cardiac failure following intracoronary micro-embolisations improved
left ventricular structure and function with reduced left ventricular end-diastolic and
end-systolic volumes, improved left ventricle sphericity and an improved systolic
function with increased ejection fraction [62]. Local application of amiodarone in
an alginate-based glue to the right atrial wall of goats markedly decreased the rapid
atrial response to burst pacing, suggesting a potential use in postoperative atrial
brillation in humans [63] .
9.9 Alginates inCell Transplantation
Transplantation has a long history in endocrinology with recent studies using iso-
lated β-islet cells or stem cells showing the potential of this procedure to restore the
endocrine activity of the pancreas [64]. Procedures to improve success include treat-
ment of the cells with alginates. In immune-competent STZ-induced type 1 diabetic
C57BL/6J mice, transplantation of in vitro-derived glucose-responsive mature
β-cells from human embryonic stem cells encapsulated using chemically modied
alginates via the intraperitoneal route normalised blood glucose concentrations up
to 174days after transplantation with minimal graft rejection [65]. The develop-
ment of an oxygenated chamber system with immune-isolating alginate and poly-
membrane covers allowed the survival and function of human pancreatic islets
without immunosuppression [66]. Transplantation of these cells into a 63-year-old
man with a history of type 1 diabetes for 54years was followed by persistent graft
function and regulated insulin secretion for at least 10months, without immunosup-
pression [66].
As myocytes cannot replicate, cell transplantation is an attractive alternative to
improve cardiac function after injury. Foetal cardiomyocytes grown on porous algi-
nate scaffolds were transplanted into rats 7days after myocardial infarction [67].
After 9weeks, the transplanted cells had stimulated intense neovascularisation and
attenuated left ventricular dilatation and cardiac failure [67].
Unlike the heart, the liver can regenerate, but hepatocyte transplantation may be
needed in acute liver failure to provide short-term support. Further, these patients
may require liver transplantation, a major challenge for the health system [68].
Transplantation of rat hepatocytes microencapsulated with alginate markedly
improved liver parameters in a rat model of D-galactosamine-induced acute liver
failure; further, recovery of microbeads on day 8 after transplantation showed no
signs of adhesion or inammation [69]. Alginate-polyethylene glycol microspheres
S.A. Kumar and L. Brown
231
of human mesenchymal stem cells transplanted into mice delayed the development
of brosis in bile duct-ligated or carbon tetrachloride-treated mice [70]. After partial
hepatectomy in mice, the use of implanted alginate scaffolds supported the growth
of the remaining kidney, decreasing liver injury and improving survival [71].
Alginate microspheres with adipose tissue-derived stem cells could be transplanted
into recipient mice where the stem cells underwent hepatogenic differentiation to
cells that secreted albumin in the liver [72].
In contrast to white adipocytes, brown adipocytes may help control obesity [73].
The encapsulation of mouse embryonic stem cells in alginate hydrogel microstrands
allowed differentiation into brown adipocytes conrmed by the expression of
uncoupling protein 1 which is characteristic of these cells, as well as increased
expression with β3-adrenoceptor agonists [74]. Cell entrapment within alginate
microcapsules allows the cells to avoid the immune responses of the host; the use of
this technique with catabolic cells that use lipids for thermogenesis may be appli-
cable for the treatment of obesity [75]. Alginate-poly-L-lysine microencapsulated
Chinese hamster ovary (CHO)-E3 cells secreted apolipoprotein E3 when given
intraperitoneally to mice, leading to decreased cholesterol and increased HDL con-
centrations in the plasma [76]. This technology may be feasible to minimise athero-
sclerosis in obese and diabetic patients.
In conclusion, alginates are low cost, mostly non-toxic and versatile biopolymers
that can be used for treatment of many gastrointestinal problems. In addition, they
are useful in microparticles and nanoparticles as drug carriers and to protect cells
during transplantation. However, the full potential of these natural products as func-
tional foods needs to be further researched.
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9 Alginates inMetabolic Syndrome
... They could also protect cells during transplantation from immune responses of the host, and, in combination with antacid alginates, be applied in the treatment of gastric reflux disease. Moreover, alginates decrease food intake by inducing satiety, increase weight loss in patients on a calorie-restricted diet, and reduce both glucose and fatty acid uptake, and a decrease in blood pressure by alginates in rat models of hypertension was reported as well [194]. ...
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