Exploring the Potential of Brown Seaweed in Managing Type 2 Diabetes Mellitus

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Over the last decades, diabetes mellitus has become a worldwide pandemic. Of approximately 537 million diabetes cases worldwide, 90% represent type 2 diabetes mellitus (T2DM). The development of T2DM is often caused by chronic positive energy balance, and its increased prevalence is accompanied by the increasing prevalence of obesity. Nutritional interventions may prevent or even reverse T2DM.

Specific species of brown seaweed might be an important part of such a nutritional intervention. Examples of brown seaweed species are Sargassum fusiforme (S. fusiforme, also called ‘Hijiki’), which grows along the coastlines of East Asia, and Fucus vesiculosus (F. vesiculosus), which is a seaweed found on the coasts of the North Sea, the western Baltic Sea, and the Atlantic and Pacific Oceans. Brown seaweeds contain a high amount of health-promoting compounds, including soluble and insoluble dietary fibers, polysaccharides, ω3-polyunsaturated fatty acids, carotenoids, polyphenols, fat-soluble vitamins and minerals, and phytosterols, like fucosterol, saringosterol, and the carotenoid fucoxanthin. The bioactive constituents of brown seaweeds were found to improve glucose tolerance, regulate blood lipids, and enhance feelings of satiety, thereby contributing to the prevention of weight gain, which are all important in the treatment of people with T2DM.

In animal models, positive effects were observed for S. fusiforme and for a combination of Ascophyllum nodosum and F. vesiculosus. S. fusiforme administration (100 mg/kg, 4 weeks) alleviated hyperglycemia in diabetic mice. The administration of an extract of Ascophyllum nodosum and F. vesiculosus reduced both overall and postprandial blood glucose levels in a mouse model of non-alcoholic steatohepatitis. The mechanisms of action underlying these effects of seaweed components on glucose regulation may be multiple.

It may decrease the absorption of glucose as a result of inhibitory effects on the major intestinal carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase. Seaweed extracts were reported to inhibit α-glucosidase and α-amylase activity but did not affect fasting blood glucose in obese individuals. Increased fiber intake from seaweed may also improve glucose regulation via beneficially modulating the gut microbiome, resulting in an increased production of short-chain fatty acids. In addition, evidence was obtained for the regulation of lipid metabolism and satiety hormones in animal models. Seaweed-derived fucoidan reduces plasma triglycerides, total cholesterol, and LDL levels in high-fat-fed mice. Also, fucoidan inhibits adipogenesis and reduces leptin levels in obese mice with hyperleptinemia. Moreover, evidence was obtained that fucoxanthin supplementation can reduce body weight and white adipose tissue weight in mice.

Up to now, clinical studies addressing the beneficial effects of daily consumption of seaweed in T2DM patients are limited. A recently published meta-analysis on the effect of brown seaweed consumption for blood glucose management showed that postprandial blood glucose, glycated hemoglobin (HbA1c), and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) levels significantly improved in the seaweed group compared to the control group. Although promising, the majority of studies used supplements with high dosages of seaweed extracts. To find out whether the use of seaweed in its natural form as part of a healthy diet can also contribute to improving glucose regulation, pragmatic dietary trials are needed. Therefore, the aim of the present study was to determine the effect of daily consumption of feasible amounts of the brown seaweed S. fusiforme or F. vesiculosus on top of the habitual diet and medication on average blood glucose levels in overweight adults with T2DM. In addition, we examined the effect of the administration of S. fusiforme or F. vesiculosus on body weight, self-reported energy intake, and risk factors for cardiovascular disease (CVD).

In this randomized, double-blind, placebo-controlled pilot study, we found that 5-week intake of 5 g of S. fusiforme or F. vesiculosus in overweight T2DM patients in addition to their habitual diet and medication did not affect their weekly average blood glucose levels when measured continuously, although eHbA1c was significantly different between the control and S. fusiforme groups in favor of the control group. When looking at anthropometrics, only waist circumference was different between the control and the S. fusiforme groups in favor of the control group. There were no between-group differences in plasma lipid levels. Plasma triglycerides and ApoA-I as well as 27-hydroxycholesterol changed significantly within the groups upon administration of S. fusiforme and F. vesiculosus but also in the control group. The usage of antidiabetic drugs decreased in 42% of the participants in the control group and in 50% of the S. fusiforme group following 5 weeks of intake, which may have affected the plasma glucose and lipid levels.

The lack of effect of brown seaweed administration on glucose metabolism is unexpected and not in line with the recently published meta-analysis that showed that supplementation with different brown seaweed species led to significant improvements of postprandial blood glucose, HbA1c, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). In this meta-analysis, most studies included were using seaweed extracts, and only three included studies used fresh seaweed. None of those three studies included S. fusiforme or F. vesiculosus but utilized the brown seaweed Undaria pinnatifida. In subgroup analyses, the use of fresh seaweed was related to improved postprandial blood glucose levels, contrary to our findings. The study population consisted of healthy or overweight people without T2DM, which is different from our T2DM population. Hypothetically, the advanced state of disease might call for a more intensive, higher-dose intervention to be effective.

Apart from the use of a different brown seaweed species, the dosage was similar (5 g/day), while the duration of those interventions was even shorter (acute effects or 17-day intervention) than ours. This suggests that the specific brown seaweed used (Undaria pinnatifida) was more potent than the seaweeds we used in our study. On the other hand, the use of F. vesiculosus in the form of extracts was found to be more effective at improving blood glucose levels than the control treatments. Our participants may not have ingested the recommended 5 g/day because there was evidence of non-compliance in this very group. Three people in the F. vesiculosus group stopped the intervention because of gastrointestinal complaints, while in the S. fusiforme and control groups, there were no withdrawals related to gastrointestinal complaints. Therefore, it could be that F. vesiculosus is not as well-tolerated in its natural form, so that the actual dose taken was much lower and did not result in health effects.

We did observe some positive effects in the control group, which was unexpected and could potentially explain the lack of between-group differences. The modest lower weekly average glucose levels in combination with a reduction in the usage of antidiabetic drugs, as observed in the control group, favors a possible positive effect of the intervention approach itself, such as continuous monitoring of glucose and weekly visits to the hospital, independent of the treatment. However, the S. fusiforme group did not show such effects. It cannot be excluded that daily intake of small amounts as low as 0.5 g/day of the red macro algae Porphyra yezoensis that we used as a control may have induced the observed beneficial effects.

Though beneficial effects of Porphyra on blood glucose parameters have been reported, positive effects of only 0.5 g/daily were not anticipated. Several reports indicate that Porphyra might be positively related to lower blood glucose levels. The daily intake of at least 8.6 g per day of edible algae, such as the red algae Porphyra yezoensis and brown algae Undaria pinnatifida, has been associated with a lower incidence of T2DM in Korean men. The red algae contain classes of polysaccharides that can exert strong inhibitory effects on α-amylase in rats and were found to suppress postprandial blood glucose levels in healthy and diabetic rats. Therefore, it cannot be excluded that Porphyra exerted a positive effect on blood glucose homeostasis in our study participants; however, it is unlikely due to the low dosage. The intake of the red algae Porphyra was possibly better tolerated than the intervention seaweeds in this trial, as the dosage was lower and had less smell.

In line with our finding of reduced circulating cholesterol concentrations upon intake of Porphyra and S. fusiforme, various human and animal studies have shown the cholesterol-lowering effects of brown algae. Overall, brown seaweeds decrease levels of TC, TG, and LDLc, while those of HDLc increase when used in amounts of 2 g/day dried seaweed. Accordingly, we observed an increase in HDLc upon S. fusiforme intake. The phytosterols in brown algae may reduce plasma cholesterol by competing with cholesterol uptake in the intestine in addition to activating the liver X receptor (LXR), resulting in an increased excretion of cholesterol in the feces. Moreover, supplementation of rats fed a high-fat diet with fucoxanthin, prevalent in brown seaweeds such as S. fusiforme and F. vesiculosus, at 0.2% of dietary intake decreased TG and TC while enhancing their fecal excretion. In line with these findings, our data showed a slight reduction in total cholesterol and 27-hydroxycholesterol and a slight increase in HDLc following S. fusiforme intake. However, a decrease in total cholesterol and 27-hydroxycholesterol was also observed in the control group.

The relatively small effects on plasma lipids may be due to the low daily amount of seaweed consumed or to the fact that the consumption of seaweed was on top of the habitual diet and medication of the participants. The absence of effects on plasma lipids in the F. vesiculosus group may be due to the lack of compliance. The amount of seaweed (extract) used in the literature to induce the hypocholesterolemic effects is relatively high compared to the amount that was used in this study. Our results are in line with those of a recent placebo-controlled, double-blind intervention study showing no effects of consumption of 4.8 g of spirulina and wakame for 17 days on lipid parameters in non-hypercholesteremic adult men and women. A previous clinical trial already showed that the administration of higher daily dosages of seaweed, a total of 48 g per day for 4 weeks, did reduce fasting blood glucose, 2-hour postprandial blood glucose, and TG, and increase HDLc.

A recently performed randomized-controlled trial, where patients with metabolic dysfunction-associated fatty liver disease (MAFLD) were supplemented twice daily for 6 months with a combination of isolated sulfated polysaccharide fucoidan (875 mg) and xanthophyll (875 mg), resulted in a lower TC and TG ratio and an increased amount of anti-diabetic adipokines, adiponectin, and leptin as compared to the control group. Intake of fucoidan and fucoxanthin further led to an attenuation in MAFLD-mediated insulin resistance. Approximately 131 kg of S. fusiforme would be required to consume 1750 mg fucoxanthin, which is not a realistic amount. However, the fact that 48 g of seaweed per day was found to affect glucose metabolism is supportive of a strong synergistic effect of various nutraceuticals present in seaweed and seems feasible in clinical practice. It is, therefore, likely that higher dosages of the brown seaweeds F. vesiculosus or S. fusiforme can affect glucose metabolism and blood lipids and help in T2DM disease management.

We tried to verify adherence to the interventions by measuring seaweed-derived plant sterols in the blood. However, the seaweed-derived fucosterol and saringosterol in serum remained below the detection limit, but brassicasterol increased in the S. fusiforme group during the intervention but not in the F. vesiculosus group, in line with the potential non-adherence in the latter group. Brassicasterol is often detectable in Phaeophyta, brown seaweeds such as Sargassum asperifolium, but also in terrestrial plants, so it is not a perfect measure of adherence to seaweed interventions since it can also reflect vegetable intake.

This pilot study has several limitations. First, this study had a relatively low sample size. Due to several study withdrawals, less than 36 participants were included in the final analyses. This has a potential effect on the study power and external validation, although this study was of an explorative nature. Moreover, due to the low sample size, the randomization could not prevent a slightly unequal distribution of sex and medication use over the three groups. However, no significant difference between both sexes was found for blood lipids and glucose levels at baseline. Third, there may have been recall bias in checking the nutritional intake of the participants. All the nutritional data were derived from questionnaires. In the nutritional diaries, under-reporting was noticed; however, this was the same for all study groups. Fourth, it was not possible to check for compliance in an objective way during the intervention because the values of seaweed-derived plant sterols were below the detection limit. Fifth, in this study, the blood glucose levels of the majority of the participants were already well-regulated due to polypharmacy. It is possible that the effects of seaweed on top of several antidiabetic and lipid-lowering drugs are less evident. Finally, the included group was quite heterogeneous in diabetes medication, which in turn increased the generalizability.

A strength of the current study is that we determined for the first time, in a randomized, controlled manner, that a small consumable amount of crude S. fusiforme and F. vesiculosus could affect glucose regulation or risk factors for CVD. Our study was pragmatic in design, allowing us to examine the effects of ingesting fresh seaweed as part of a healthy diet in a real-life setting. Moreover, to our knowledge, we were the first to use a blinded CGM in a human seaweed intervention study to determine glucose parameters, giving a sophisticated view on trends and effects. Also, there is little research to date on the effects of fresh S. fusiforme and F. vesiculosus intake in overweight individuals with T2DM.

In conclusion, our data show that small consumable amounts of the seaweed species S. fusiforme or F. vesiculosus on top of regular treatment did not affect average blood glucose levels as determined by CGM. Possible explanations for this lack of effect could be the compliance with the intervention or a too-low dosage of seaweed. This pilot trial teaches us that it is difficult to persuade people to ingest enough of these brown seaweed species (especially of F. vesiculosus) when offered in their natural form as part of a healthy diet. Moreover, in people with T2DM and polypharmacy, a more potent intervention, such as an extract with higher amounts of the effective compounds, may be needed to yield effects. Future randomized, controlled studies are needed on parameters of metabolic health using other seaweed species in higher doses and focusing on compliance with the interventions to take a step toward implementing this sustainable nutritional strategy in the treatment of people with T2DM.


reference link: https://www.mdpi.com/2072-6643/16/12/1837

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