Journal of Diabetes & Metabolic Disorders
https://doi.org/10.1007/s40200-020-00664-4

COMMENTARY

Biological response modifier glucan through balancing of blood
glucose may have a prophylactic potential in COVID-19 patients
Nobunao Ikewaki 1,2 & Masaru Iwasaki 3 & Samuel J. K. Abraham 3,4,5,6Received: 25 August 2020 / Revised: 1 October 2020 / Accepted: 12 October 2020
# The Author(s) 2020

Abstract
With the COVID-19 pandemic causing huge threat to public health and definite treatment modalities and preventive vaccines yet
to be arrived at, some of the key indicators of relevance to its prognosis have started emerging. One such independent predictor ofoutcome has been fasting plasma glucose (FPG) at the time of admission. Earlier, co-morbidities such as diabetes also have beenreported to have a risk of relatively increased mortality due to COVID-19. In this background, we herein report on the beneficial
effects of Biological response modifier glucan (BRMG) secreted by the black yeast Aureobasidium pullulans AFO-202 which
has been proven to bring under control blood sugar levels in human subjects and also has potential in enhancing & regulating theimmune parameters in relevance to COVID-19. We further recommend that this BRMG be tried in clinical studies of COVID-19
to provide a prophylactic effect for validation.
Keywords COVID-19 . Biological response modifier glucan (BRMG) . Fasting plasma glucose (FPG) . Diabetes . Prophylaxis

Introduction
Fasting plasma glucose (FPG) level at admission has been indicated as a strong independent predictor of mortality in COVID19 affected patients [1.2]. Wang et al. published their report of
605 COVID-19 patients in whom fasting plasma glucose (FPG)* Samuel J. K. Abraham
drsam@nichimail.jp; drspp@nichimail.jp

level ≥ 7.00 mmol/L at admission was a strong independent predictor of 28-day mortality [1] and recommended glycaemic testing & control in all COVID-19 patients even where they have no
pre-existing diabetes. Zhang et al. also reported about 461
COVID-19 patients in whom fasting plasma glucose (FPG) level ≥ 6.23 mmol/L at admission was a strong independent predictor of poor outcomes. They further suggested that acute
hyperglycaemia may cause organ damage by inducing endothelial dysfunction and thrombosis, which may be one of the key
underlying mechanisms connecting the higher FPG with pooroutcome of COVID-19 [2].

Nobunao Ikewaki
nikewaki@phoenix.ac.jp
Masaru Iwasaki
miwasaki@yamanashi.ac.jp
1

Department of Medical Life Science, Kyushu University of Healthand Welfare, Nobeoka, Japan

2

Institute of Immunology, Junsei Educational Institute,
Nobeoka, Miyazaki, Japan

3

Yamanashi University- School of Medicine, Yamanashi Chuo, Japan

4

Edogawa Evolutionary Laboratory of Science (EELS), Edogawa
Hospital, Tokyo, Japan

5

The Mary-Yoshio Translational Hexagon (MYTH), Nichi-In Centre
for Regenerative Medicine (NCRM), Chennai, India

6

GN Corporation Co. Ltd, 3-8, Wakamatsu, 400-0866 Kofu, Japan

Biological response modifier glucans (BRMG)
Beta-D-glucans are highly conserved structural componentsof cell walls in yeast, fungi, or seaweed which are naturally
occurring physiologically active compounds termed as biological response modifier glucans (BRMGs) [3]. BRMGs
from barley, oats, or wheat consist of linear β-(1,3;1,4)-Dglucans while those from the cell walls of yeast, fungi, andsome bacteria consist of β -(1,3)- or β -(1,4)-glucan backbone
with either (1,2)- or (1,6)-linked β -glucopyranosyl side
branches. The structure of a beta glucan shapes its associatedbiological activities [3]. Both oat and fungal BRMGs havebeen shown to have biological response modifying effects

J Diabetes Metab Disord

but the BRMG content is more in yeast than in sources such asoats and hence yeast BRMGs are believed to be having morefunctional activity [4]. The effects of BRMGs on metabolic
syndrome has been well documented in animal experiments
and clinical trials [5]. BRMGs form highly viscous solutionsin the human gut thereby leading to delayed gastric emptying,
which leads to dietary glucose to be absorbed more gradually.
The shape of the plasma glucose response curve is much flatter after BRMG intake. This in in turn contributes to the effects of lowering postprandial glucose and insulin responses,
potentiating the feelings of satiety [5]. BRMGs also improve
insulin sensitivity [6]. BRMGs have been shown to downregulate blood glucose by suppressing sodium-glucose transporter-1 expression in intestinal mucosa and by promoting glycogen synthesis along with inhibiting fat accumulation in theliver [7]. BRMGs help in maintaining glucose levels byforming a barrier in the small intestine, which prevents absorption of glucose and other nutrients, thereby reducing
glycaemia, insulinaemia and cholesterol serum levels [8].
Decreased PI3K/Akt activity plays a key role in the pathogenesis of diabetes. BRMGs increase PI3K/Akt through several
receptors, including Dectin-1, complement receptor 3,
lactosylceramide and scavenger and toll-like receptors [5].
The effects on dyslipidaemia is attributed to the action of
BRMG in altering bile acid excretion and the composition ofbile acid pool. Increased bile acid excretion and increased
activity of cholesterol 7 α -hydrolase, a major enzyme leads
to cholesterol elimination in the body. BRMG can decrease
the reabsorption of bile acids and increase their transport towards the large intestine [6] thus contributing to lessen theeffects of metabolic diseases.

AFO-202 derived BRMG & effect on FPG levels
Given this background on BRMGs, we wish to refer to a
BRMG derived from the AFO-202 strain of Aureobasidium
pullulans. This BRMG is secreted as an exo-polysacchride by
the AFO-202 black yeast and hence does not involve additional purification or extraction processes, thus giving a highly
pure BRMG [9]. The purity of a BRMG determines its functionality [10]. Dectin-1 having been identified as a receptor to
regulate the PI3K/Akt activity leading to anti-diabetogenic
effects of BRMG [11], it is noteworthy that, Dectin-1 is the
key receptor for the AFO-202 BRMG to exert its biologicalactions [9].
We wish to highlight three clinical studies of this AFO-202
BRMG in relevance to its action of bringing down high FPG
levels to normal values in patients with diabetes while maintaining the levels at a normal standard in healthy volunteers. The firststudy involved 22 healthy volunteers for whom regular consumption of this AFO-202 BRMG for three months helped tomaintain FPG levels in subjects whose levels were within thenormal standard while decreasing the high levels to normal
values in 95% of the subjects who had high FPG at the start ofthe study [12]. In another study, when this AFO-202 BRMG wasadded to rice and consumed by 10 healthy male and female
volunteers, significant inhibition of blood sugar elevation wasobserved at 60 minutes and 120 minutes after glucose load[12]. In a case study, three patients who consumed this AFO202 BRMG for two months had baseline FPG levels of 171 mg/
dl (9.4905 mmol/l), 114 mg/dl (6.327 mmol/l) and 129 mg/dl(7.1595 mmol/l), which decreased to 106 mg/dl (5.883 mmol/l),
103 mg/dl (5.7165 mmol/l) and 85 mg/dl (4.7175 mmol/l) at theend of the study. In the same three subjects, post-prandial blood
glucose level decreased from 244 mg/dl (13.542 mmol/l) at baseline to 203 mg/dl (11.2665 mmol/l), 192 mg/dl (10.656 mmol/l)to 111 mg/dl (6.1605 mmol/l) and 252 mg/dl (13.986 mmol/l) to
118 mg/dl (6.549 mmol/l), respectively, at the end of the study[13]. The National Institute for Clinical Excellence (NICE)
guidelines of the UK recommend FPG values of 4.0 to
5.9 mmol/L and 90 minutes after meal (post-prandial) values ofunder 7.8 mmol/L in non-diabetic individuals as normal [14].

Mechanisms of AFO-202 BRMG’santi-glycation effects in COVID-19
The possible role of AFO-202 BRMG’s anti-glycation effectresults from its anti-inflammatory effect in diabetes. Patientswith diabetes generally have a weakened immune system [15,16], and BRMG can enhance the immune system [9]. The
immunity-enhancing effect of BRMG is interconnected with
its possible anti-glycation effect (normalization of HbA1c) inpatients with diabetes. Beyond acting on blood glucose levels,
this AFO-202 BRMG has been indicated as worthwhile to beconsidered for clinical trials in COVID-19 patients due to its
balanced immune enhancement by decreasing hyperinflammation factors such as IL-6 that lead to cytokine storms;
increasing IFN-γ, sFAS, and factors like IL-7; and enhancing
anti-viral cytotoxic immunity, as mediated by T cells, NK
cells, macrophages, and antibody production by B cells [17].
Now, with Zhang et al. [2] having reported that high FPG
level is a precipitating factor leading to poor COVID-19 outcomes, this BRMG has gained further significance as a prophylactic agent whose continuous supplementation has also
been proven to balance FPG levels. In addition, they also playa vital role by both enhancing individuals’ immune capabilities to tackle COVID-19 infection and downregulating thefactors responsible for hyperinflammation leading to cytokine
storms, thereby preventing morbidity and mortality.
Advanced glycation end-products (AGEs) that accumulate indiabetic and ageing tissues elicit a wide range of cell-mediatedresponses, leading to vascular dysfunction and atherosclerosis[15, 18]. With the renin-angiotensin (RAS) signalling pathway, oxidative stress and cell death, cytokine storm andJ Diabetes Metab Disord

endothelial dysfunction being implicated as the four major
pathways involved in the pathogenesis of COVID-19,
BRMGs have also been shown to help alleviate oxidative
stress [19]. Diabetes is associated with persistent chronic inflammation of beta cells (β cells) in the pancreas caused byglycation [20] and with increased haemoglobin A1C(HbA1C), i.e., glycated haemoglobin levels with clinical significance as an indicator of diabetes diagnosis and glycaemic
control. Three processes are presumed to underlie the pathogenesis of diabetes and glycation: persistent chronic inflammation, decreased function of vascular endothelial cells anddecreased immune function [21]. Proper control of these factors can lead to the normalization of HbA1C levels and even
improvement of diabetes. Further, increased blood sugar
levels increased levels of clotting factors and relative inhibition of the fibrinolytic system, endothelial dysfunction, andenhanced platelet aggregation and activation, favouring a hypercoagulable pro-thrombotic state thus increasing the risk ofcoagulopathy due to COVID-19 [22]. Yeast BRMGs havebeen found to act on cytokine production regulating coagulation activation along with reversing diabetes-induced oxidative stress causing disturbances in the clotting parameters due
to enhanced platelet aggregation and increased thrombin
levels [23]. The diabetics are at heightened risk of disease
severity in COVID-19 because of the higher rate of inflammatory processes seen in these individuals due to constantglucose recognition by C type lectin receptors [24].
Immunomodulatory effects of BRMGs resulting in increased
resistance to both viral and bacterial infections have been attributed to their signalling mediated by CLR family of receptors [25]. Dectin-1 is a member of the CLR family [26] and wewish to reiterate that the AFO-202’s BRMG’s key receptor forexerting its biological activity is Dectin-1 [9]. It is interestingto specify that the beneficial effects of the AFO-202 BRMG asa prophylactic supplement to help combat coagulopathy associated with COVID-19, especially in vulnerable people likethose with diabetes has been recently published [27].

Author contributions NI and SA contributed to conception and design ofthe study. NI performed the literature search. SA drafted the manuscript.
MI performed critical revision of the manuscript. All the authors contributed to manuscript, read, and approved the submitted version.

Compliance with ethical standards
Potential conflicts of interest

1 Nobunao Ikewaki is an employee of Dept. of Medical Life Science,2
3

Open Access This article is licensed under a Creative Commons

Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as
you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were
made. The images or other third party material in this article are includedin the article's Creative Commons licence, unless indicated otherwise in a
credit line to the material. If material is not included in the article's
Creative Commons licence and your intended use is not permitted bystatutory regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view a copy of thislicence, visit http://creativecommons.org/licenses/by/4.0/.

References
1

2

3

Conclusions
4

Especially at this time, when there is no definite treatment for
COVID-19-infected patients or a preventative vaccine available, safe measures such as BRMGs that may provide a prophylactic effect should undergo clinical studies for further
validation so that their consumption can help high-risk individuals to keep their FPG levels under control, thereby providing them with a safety net. Further research on the specificmechanisms of BRMGs on metabolic and immune system
pathways are necessary to validate their beneficial effects in
those with co-morbidities that make them prone to COVID-19& complications.

Kyushu University of Health and Welfare, Japan & Institute of
Immunology, Junsei Educational Institute, Nobeoka, Miyazaki,
Japan.
Masaru Iwasaki is a faculty in Yamanashi University, Japan.
Samuel Abraham is a faculty in Yamanashi University, EELS,
Edogawa Hospital, Japan & NCRM, India, as well as shareholder
in GN Corporation, Japan which in turn is a shareholder in the
manufacturing company of the AFO 202 Beta Glucan & also an
inventor in several patents of relevance to the AFO 202 Beta Glucan.

5

6

7

8

Wang S, Ma P, Zhang S, et al. Fasting blood glucose at admission isan independent predictor for 28-day mortality in patients with
COVID-19 without previous diagnosis of diabetes: a multi-centre
retrospective study. Diabetologia. 2020;63(10):2102-2111.
Zhang B, Liu S, Zhang L, Dong Y, Zhang S. Admission fastingblood glucose predicts 30-day poor outcome in patients hospitalized
for COVID-19 pneumonia. Diabetes Obes Metab. 2020. https://doi.
org/10.1111/dom.14132.
Novak M, Vetvicka V. Glucans as biological response modifiers.
Endocr Metab Immune Disord Drug Targets. 2009;9(1):67–75.
Sobieralski K, Siwulski M, Lisiecka J, JĊdryczka M, Sas-Golak I,FruĪyĔska-JóĨwiak D. Fungi-Derived β-Glucans as a component offunctional food. Acta Sci Pol Hortorum Cultus. 2012;11(4):111–28.
Chen J, Raymond K. Beta-glucans in the treatment of diabetes andassociated cardiovascular risks. Vasc Health Risk Manag. 2008;4:1265–72.
El Khoury D, Cuda C, Luhovyy BL, Anderson GH. Beta glucan:
health benefits in obesity and metabolic syndrome. J Nutr Metab.
2012;2012:851362.
Cao Y, Zou S, Xu H, et al. Hypoglycemic activity of the Baker’s
yeast β-glucan in obese/type 2 diabetic mice and the underlying
mechanism. Mol Nutr Food Res. 2016;60:2678–90.
Francelino Andrade E, Vieira Lobato R, Vasques Araújo T, et al.
Effect of beta-glucans in the control of blood glucose levels of diabetic patients: a systematic review. Nutr Hosp. 2014;31:170–7.

J Diabetes Metab Disord
9

10

11

12

13

14

15

16

17

18
19

Ikewaki N, Fujii N, Onaka T, Ikewaki S, Inoko H. Immunologicalactions of Sophy beta-glucan (beta-1,3 – 1,6 glucan), currently
available commercially as a health food supplement. Microbiol
Immunol. 2007;51:861–73.
Vetvicka V, Vetvickova J. Comparison of immunological effects ofcommercially available beta-glucans: part III. Int Clin Pathol J.
2016;2:78–83.
Li X, Wang J, Wang W, Liu C, Sun S, Gu J, Wang X, Boraschi D,
Huang Y, Qu D. Immunomodulatory activity of a novel, synthetic
beta-glucan (β-glu6) in murine macrophages and human peripheral
blood mononuclear cells. PLoS One. 2013;8:e80399.
Yano et al. Sophy Beta-Glucan is effective in alleviating increased
blood sugar levels. Abstract presented at the 55th Conference of theJapanese Society of Nutrition and Dietetics 2008.
Dedeepiya VD, Sivaraman G, Venkatesh AP, et al. Potential effectsof nichi glucan as a food supplement for diabetes mellitus and hyperlipidemia: preliminary findings from the study on three patientsfrom India. Case Rep Med. 2012;2012:895370.
Type 2 diabetes: prevention in people at high risk. NICE Public
Health Guideline 38 – NICE. Published July 12, 2012. (Available
from https://www.nice.org.uk/guidance/ph38) [Accessed 1st
Oct 2020]
Kolluru GK, Bir SC, Kevil CG. Endothelial dysfunction and diabetes: effects on angiogenesis, vascular remodeling, and woundhealing. Int J Vasc Med. 2012;2012:918267.
Geerlings SE, Hoepelman AI. Immune dysfunction in patients withdiabetes mellitus (DM). FEMS Immunol Med Microbiol. 1999;26:
259–65.
Rao KS, Suryaprakash V, Senthilkumar R, et al. Role of Immune
Dysregulation in Increased Mortality Among a Specific Subset of
COVID-19 Patients and Immune-Enhancement Strategies for
Combatting Through Nutritional Supplements. Front Immunol.
2020;11:154.
Vlassara H. Advanced glycation end-products and atherosclerosis.
Ann Med. 1996;28:419–26.
Murphy EJ, Masterson C, Rezoagli E, et al. β-Glucan extracts fromthe same edible shiitake mushroom Lentinus edodes produce differential in-vitro immunomodulatory and pulmonary cytoprotective

effects - Implications for coronavirus disease (COVID-19) immunotherapies. Sci Total Environ. 2020;732:139330.
20 Cerf ME. Beta cell dysfunction and insulin resistance. Front
Endocrinol (Lausanne). 2013;4:37.
21 Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end
products and diabetic complications. Korean J Physiol Pharmacol.
2014;18:1–14.
22 Hussain A, Bhowmik B, do Vale Moreira NC. COVID-19 anddiabetes: Knowledge in progress. Diabetes Res Clin Pract.
2020;162:108142.
23 El-Kashoury, Fattah SM, Ramadan L, El-Denshary ES. The Role of
Yeast Beta Glucan on Blood Coagulation in Streptozotocin-Induced
Diabetes and Irradiated Rats. 2016. Available from https://www.
semanticscholar.org/paper/The-Role-of-Yeast-Beta-Glucan-onBlood-Coagulation-El-Kashoury-Fatah/
6f68a9067831eebb0015c2961882d1e91a89e84f. [Accessed 1st
October, 2020].
24 de Lucena TMC, da Silva Santos AF, de Lima BR, de AlbuquerqueBorborema ME, de Azevêdo Silva J. Mechanism of inflammatory
response in associated comorbidities in COVID-19. Diabetes Metab
Syndr. 2020;14:597–600.
25 Petit J, Bailey EC, Wheeler RT, de Oliveira CAF, Forlenza M,
Wiegertjes GF. Studies Into β-Glucan Recognition in Fish
Suggests a Key Role for the C-Type Lectin Pathway. Front
Immunol. 2019;10:280.
26 Adachi Y, Ishii T, Ikeda Y, Hoshino A, Tamura H, Aketagawa J,
Tanaka S, Ohno N. Characterization of beta-glucan recognition site
on C-type lectin, dectin 1. Infect Immun. 2004;72:4159–71.
27 Ikewaki N, Rao K, Archibold AD et al. Coagulopathy associatedwith COVID-19 – Perspectives & Preventive strategies using a biological response modifier Glucan. Thrombosis J 2020;18(27).
https://doi.org/10.1186/s12959-020-00239-6
Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.