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Bioactive Constituents, Metabolites, and Functions
Homoisoflavonoids are potent glucose transporter 2 (GLUT 2) inhibitors – a potential mechanism for the glucose-lowering properties of Polygonatum odoratum Huijun Wang, Mark Fowler, David Messenge, Leon A. Terry, Xuelan Gu, Luxian Zhou, Ruimin Liu, Juan Su, Songshan Shi, José Ordaz-Ortiz, Guoping Lian, Mark Berry, and Shunchun Wang J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.8b00107 • Publication Date (Web): 13 Mar 2018 Downloaded from http://pubs.acs.org on March 13, 2018
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Journal of Agricultural and Food Chemistry
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Homoisoflavonoids are potent glucose transporter 2 (GLUT 2) inhibitors – a
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potential mechanism for the glucose-lowering properties of Polygonatum odoratum †,‡,∇ ,
Mark I. Fowler ‡, David J. Messenger ‡, Leon A. Terry §, Xuelan Gu ║, Luxian
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Huijun Wang
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Zhou ║, Ruimin Liu †, Juan Su†, Songshan Shi †, José Juan Ordaz-Ortiz O, Guoping Lian ‡, Mark J.
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Berry *,‡, Shunchun Wang *,†
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†
The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key
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Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese
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Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road,
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Shanghai 201203, P. R. China;
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‡
Unilever R&D Colworth, Colworth Science Park, Sharnbrook, Bedford MK44 1LQ, U.K.;
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§
Plant Science Laboratory, Cranfield University, MK43 0AL, U.K.;
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║
Unilever R&D Shanghai, 5/F, 66 Lin Xin Road, Shanghai 200335, P. R. China;
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∇
Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 4, 898 Halei Road, Shanghai 201203, P. R. China;
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O
National Laboratory of Genomics for Biodiversity, CINVESTAV IPN, 36824 Irapuato, Guanajuato, Mexico.
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CORRESPONDING AUTHORS
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* Mark J. Berry, Unilever R&D Colworth, Colworth Science Park, Sharnbrook, Bedford MK44 1LQ,
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U.K. Tel.: +44 1234222180; E-Mail:
[email protected] ; ORCID: 0000-0002-6211-6151
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* Shunchun Wang, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese
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Medicine, 1200 Cailun Road, Shanghai 201203, P. R. China; Tel.: +86-21-5132-2511; Fax:
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+86-21-5132-2519; E-Mail:
[email protected] ; ORCID: 0000-0003-0384-1350 1
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Journal of Agricultural and Food Chemistry
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ABSTRACT
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Foods of high carbohydrate content such as sucrose or starch increase postprandial blood glucose
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concentrations. The glucose absorption system in the intestine comprises two components:
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sodium-dependent glucose transporter-1 (SGLT1) and glucose transporter 2 (GLUT2). Here five
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sappanin-type (SAP) homoisoflavonoids were identified as novel potent GLUT2 inhibitors, with
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three of them isolated from the fibrous roots of Polygonatum odoratum (Mill.) Druce. SAP
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homoisolflavonoids had a stronger inhibitory effect on 25 mM glucose transport (41.6±2.5%,
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50.5±7.6%, 47.5±1.9%, 42.6±2.4%, and 45.7±4.1% for EA-1, EA-2, EA-3, MOA, and MOB) than
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flavonoids (19.3±2.2%, 11.5±3.7%, 16.4±2.4%, 5.3±1.0%, 3.7±2.2%, and 18.1±2.4% for apigenin,
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luteolin, quercetin, naringenin, hesperetin, and genistein) and phloretin (28.1±1.6%) at 15 mM. SAP
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homoisoflavonoids and SGLT1 inhibitors were found to synergistically inhibit the uptake of glucose
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using an in vitro model comprising Caco-2 cells. This observed new mechanism of the
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glucose-lowering action of P. odoratum suggests that SAP homoisoflavonoids and their combination
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with flavonoid monoglucosides show promise as naturally functional ingredients for inclusion in
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foods and drinks designed to control post-prandial glucose levels.
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KEYWORDS: Polygonatum odoratum, homoisoflavonoids, GLUT2 inhibitors, synergy, glucose
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control
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Journal of Agricultural and Food Chemistry
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INTRODUCTION
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As a very common chronic disease, diabetes is becoming one of the greatest global health burdens
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along with cancer, cardiovascular and cerebrovascular diseases because of its high prevalence,
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morbidity and mortality1. The prevalence of diabetes for all adults worldwide was estimated to be
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415 million in 2015 and this number is expected to increase to ca. 642 million by 20402-42-4. Diabetes
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is characterized by hyperglycemia resulting from a defect in insulin secretion, insulin action, or both5.
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Consumption of foods high in available carbohydrate such as sucrose or starch increases postprandial
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blood glucose concentrations6. It has been reported that an elevated postprandial glucose level is
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associated with the development of diabetes. Node et al.2 reported high post-prandial plasma glucose
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‘‘spikes’’ are associated with an increased risk of developing type 2 diabetes. Controlling the
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post-meal glucose level is known to be important in both diabetic patients as well as normal healthy
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subjects7, 8. Unregulated glycemic excursions are undesirable, and any reduction or ‘‘blunting’’ of the
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post-prandial glucose concentration in blood is potentially beneficial.
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The glucose absorption system in the intestine comprises two components. One is a
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well-established component mediated by the apically located, sodium-dependent glucose
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transporter-1 (SGLT1), a high-affinity, low-capacity, active transport protein. The other component is
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glucose transporter 2 (GLUT2), a low-affinity, high-capacity, facilitated transport protein9, 10. Kellett
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et al.11 described the potential interplay of these transporters during the consumption of a
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carbohydrate rich meal. We have illustrated this interplay schematically in Figure S1. Before the
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meal, the concentration of free glucose in the lumen of the intestine is low (
