**1. Introduction**

The growing prevalence of type 2 diabetes worldwide is particularly alarming. Based on recent world statistics [1], 352 million adults aged from 20 to 79 years old were glucose intolerant (7.3%), and 425 million (8.8%) had type 2 diabetes in 2017 [1]. The association between the dramatic increase of the disease and the rising prevalence of obesity is often highlighted [2]. Obesity and overweight initiate several metabolic disorders [3] that include insulin resistance, which is considered to be the central feature leading to type 2 diabetes [4].

**Citation:** Vodouhè, M.; Marois, J.; Guay, V.; Leblanc, N.; Weisnagel, S.J.; Bilodeau, J.-F.; Jacques, H. Marginal Impact of Brown Seaweed *Ascophyllum nodosum* and *Fucus vesiculosus* Extract on Metabolic and Inflammatory Response in Overweight and Obese Prediabetic Subjects. *Mar. Drugs* **2022**, *20*, 174. https://doi.org/10.3390/md20030174

Academic Editors: Donatella Degl'Innocenti and Marzia Vasarri

Received: 14 January 2022 Accepted: 24 February 2022 Published: 26 February 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Prediabetes is an intermediate stage in the development of type 2 diabetes and is characterized by abnormal high fasting glucose, impaired glucose tolerance, and/or high-fasting insulin [5]. A number of other metabolic dysfunctions are linked to prediabetes and type 2 diabetes, such as chronic systemic low-grade inflammation [6,7], oxidative stress, endothelial dysfunction [8], and impaired gut integrity [9]. The extent to which these phenomena are observed differs with respect to diet composition, among other environmental factors. These disorders may be reversible at the prediabetes stage when nutritional interventions are implemented.

In a clinical setting, the implementation of a weight-loss approach is generally the first-line intervention in the prevention and management of type 2 diabetes among overweight or obese people. The main recommended nutritional treatment to lose weight and prevent type 2 diabetes is the reduction of energy intake [10]. Caloric restriction and weight loss have been shown to improve insulin sensitivity and reduce hyperglycemia [11,12]. A moderate caloric intake restriction of approximately 2093 KJ (500 kcal) per day is recommended [10,13] for a weight loss of 2 to 4 kg/month as suggested by the 2006 Canadian Obesity Guidelines [14].

Marine organisms are rich sources of compounds with diverse biological activities [15]. Among the most promising bioactive molecules in preventing type 2 diabetes are the phlorotannins, a class of polyphenols exclusively produced by brown seaweeds [16]. In vitro and in vivo studies [17,18] show that phlorotannin-rich extracts of brown seaweed *Ascophyllum nodosum* and *Fucus vesiculosus* reduce the α-amylase and α-glucosidase activities involved in the digestion of carbohydrates, resulting in a 90% reduction of glucose 30 min after a meal and a 40% decrease in peak insulin secretion in mice, as reported by Roy et al. [17]. In humans, it has been demonstrated that a single acute dose of 500 mg of a polyphenol-rich extract of *Ascophyllum nodosum* and *Fucus vesiculosus* had no significant effect on glycemia but induced a 12% reduction in the insulin incremental area under the curve (IAUC) following consumption of 50 g of bread compared with a placebo in healthy adults [19]. Fucoidan, a polysaccharide found in brown seaweeds, has also been recognized as a promising bioactive molecule with glucose-lowering potential [20,21], via a reduction of α-amylase and α-glucosidase activities, and therefore a diminution of intestinal absorption of glucose, and an enhancement of cellular glucose uptake via insulin through modulation of cellular glucose transporter GLUT-4 and AMP-activated protein kinase (AMPK). However, there are few studies addressing the chronic physiological effects of brown seaweed extract on metabolic and inflammatory markers in humans and particularly in people at high risk of type 2 diabetes.

Achieving normal blood glucose levels is one of the major goals in diabetes prevention, and it can be reached by different means, such as weight loss or an improvement of glucose homeostasis through a nutritional supplement [22]. From a biological perspective, the response to an energy-restricted diet varies between individuals [23], and this strategy alone is somewhat less effective in the long term [24]. Therefore, a nutritional supplement is often necessary in adjunction to energy restriction [25]. In this context, a brown seaweed extract, which has been shown to reduce waist circumference [26], could be administered in addition to a reduced-calorie diet to obtain additional effects.

The present study was thus undertaken to evaluate the effect of daily consumption of 500 mg of brown seaweed (*Ascophyllum nodosum* and *Fucus vesiculosus*) capsules rich in polyphenols associated with a reduced-energy diet on body weight and blood glucose homeostasis (glucose, insulin, and C-peptide in the fasting state and duringa2h oral glucose tolerance test) for 12 weeks in overweight prediabetic subjects. Lipid profile, heart rate, markers of inflammation, oxidative stress, and integrity of the intestinal barrier were measured as secondary outcomes. We expect that brown seaweed extract lowers body weight and improves glucose homeostasis and metabolic and inflammatory markers in the context of moderate weight loss in this 12-week clinical trial.
