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Polyphenols for Diabetes

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A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Phytochemicals and Human Health".

Deadline for manuscript submissions: closed (20 May 2023) | Viewed by 37212

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Dr. Regina Menezes

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CBIOS-Research Center for Biosciences and Health Technologies, Universidade Lusófona, Campo Grande 376, 1749-024 Lisboa, Portugal
Interests: diabetes; dietary polyphenols; nutrition
Special Issues, Collections and Topics in MDPI journals

Dr. María-Teresa García Conesa

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Quality, Safety and Bioactivity of Plant Foods, Food Science and Technology Department, CEBAS-CSIC, P.O. Box 360, Campus de Espinardo, Espinardo, 30100 MURCIA, Spain
Interests: bioactive compounds; cardiometabolic diseases; interindividual variability; mechanisms of action; nutritional genomics; Mediterranean diet
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Prof. Dr. Paulo Matafome

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Coimbra Institute for Clinical and Biomedical Research (iCBR) and Institute of Physiology, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
Interests: glycation; insulin sensitivity; gut hormones; diabetic vascular complications
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The latest IDF Diabetes Atlas warned that in 2019, the diabetes pandemic had reached 463 million people worldwide, and over the years, we have seen a failure of estimates to predict the number of cases for years to come. It is now clear that only multidisciplinary efforts have the power to reverse this trend.

Diet plays a pivotal role in diabetes management, and varied evidence has revealed the potential of dietary bioactives toward minimizing disease complications. In particular, the pleiotropic action of (poly)phenols has been associated with the improvement of diabetes clinical signs, such as impaired insulin secretion and sensitivity, amyloidogenesis, oxidative stress, glycation, and inflammation. Although these are encouraging facts, there are still gaps in knowledge that need to be fulfilled for an effective exploitation of dietary (poly)phenols as allies in the fight against diabetes and co-morbidities. Interindividual variability in the response to these compounds and identification of the factors that may influence this response, including the specific bioactive compounds and (or) metabolites that may benefit a particular group of people, remains essential to progress in the battle against this disease.

Therefore, we invite authors to contribute with high-quality original or review papers highlighting the power of (poly)phenols to modulate diabetes pathophysiology, with particular attention to microbial metabolites and host-derived conjugates for an accurate characterization of the health benefits of these compounds.

Potential topics include but are not limited, to:

- Identification of active molecules;

- Mechanistic studies on the modus operandi of protective (poly)phenols;

- Synergistic interaction of (poly)phenols and established diabetes therapies;

- Chemical manipulation enhancing bioactivity;

- Controlled delivery systems for nutraceutical applications;

- Clinical intervention trials with a focus on interindividual variability.

Prof. Dr. Regina Menezes
Dr. María-Teresa García Conesa
Prof. Dr. Paulo Matafome
Guest Editors

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Keywords

Metabolic syndrome and diabetes
Dietary polyphenols
Polyphenol metabolites
Polyphenol bioactivity
Interindividual variability in response to polyphenols and factors involved

Published Papers (11 papers)

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Research

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14 pages, 1243 KiB

Open AccessArticle

Increased Intake of Both Caffeine and Non-Caffeine Coffee Components Is Associated with Reduced NAFLD Severity in Subjects with Type 2 Diabetes

by Margarida Coelho, Rita S. Patarrão, Inês Sousa-Lima, Rogério T. Ribeiro, Maria João Meneses, Rita Andrade, Vera M. Mendes, Bruno Manadas, João Filipe Raposo, M. Paula Macedo and John G. Jones

Nutrients 2023, 15(1), 4; https://doi.org/10.3390/nu15010004 - 20 Dec 2022

Cited by 8 | Viewed by 7798

Abstract

Coffee may protect against non-alcoholic fatty liver disease (NAFLD), but the roles of the caffeine and non-caffeine components are unclear. Coffee intake by 156 overweight subjects (87% with Type-2-Diabetes, T2D) was assessed via a questionnaire, with 98 subjects (all T2D) also providing a 24 h urine sample for quantification of coffee metabolites by LC–MS/MS. NAFLD was characterized by the fatty liver index (FLI) and by Fibroscan^® assessment of fibrosis. No associations were found between self-reported coffee intake and NAFLD parameters; however, total urine caffeine metabolites, defined as Σ_caffeine (caffeine + paraxanthine + theophylline), and adjusted for fat-free body mass, were significantly higher for subjects with no liver fibrosis than for those with fibrosis. Total non-caffeine metabolites, defined as Σ_ncm (trigonelline + caffeic acid + p-coumaric acid), showed a significant negative association with the FLI. Multiple regression analyses for overweight/obese T2D subjects (n = 89) showed that both Σ_caffeine and Σ_ncm were negatively associated with the FLI, after adjusting for age, sex, Hb_A1c, ethanol intake and glomerular filtration rate. The theophylline fraction of Σ_caffeine was significantly increased with both fibrosis and the FLI, possibly reflecting elevated CYP2E1 activity—a hallmark of NAFLD worsening. Thus, for overweight/obese T2D patients, higher intake of both caffeine and non-caffeine coffee components is associated with less severe NAFLD. Caffeine metabolites represent novel markers of NAFLD progression. Full article

(This article belongs to the Special Issue Polyphenols for Diabetes)

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16 pages, 6050 KiB

Open AccessArticle

Thymus serpyllum Exhibits Anti-Diabetic Potential in Streptozotocin-Induced Diabetes Mellitus Type 2 Mice: A Combined Biochemical and In Vivo Study

by Jahanzaib Azhar, Peter John and Attya Bhatti

Nutrients 2022, 14(17), 3561; https://doi.org/10.3390/nu14173561 - 29 Aug 2022

Cited by 3 | Viewed by 2238

Abstract

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder that is characterized by hyperglycemia, insulin resistance, and lack of insulin production. It has been previously reported that Thymus serpyllum has therapeutic potential against many diseases. To investigate the antidiabetic action of Thymus serpyllum, this study aimed to analyze its restorative impact in diabetic mice, in which it was administered in diet. Diabetes was induced in BALB/c mice fed with a high-fat diet and two intraperitoneal injections of streptozotocin. With the onset of diabetes, the mice were administered daily with aqueous extract of Thymus serpyllum (500 mg/kg/d and 800 mg/kg/d) for 4 weeks. Body weight and fasting blood glucose levels were measured after every 1 week of the treatment. Subsequently, intraperitoneal glucose tolerance and insulin tolerance tests were conducted. In addition, liver tissue was isolated for assessment in terms of levels of gene expression of the AMPK, IRS1, and GLUT2 gene. Treatment with the aqueous extract of Thymus serpyllum was found to be significantly effective in controlling hyperglycemia and improving glucose and insulin tolerance. Predictable with these impacts, the extract of Thymus serpyllum upregulated the AMPK expression at the mRNA level, as well as upregulating the expression of IRS1 and GLUT2 gene. Histopathological examination of the liver, kidney, and pancreas also revealed the restorative impact in terms of cellular morphology. The results hence demonstrated that oral administration of aqueous extract of Thymus serpyllum can potentially attenuate hyperglycemia in the liver muscle of streptozotocin (STZ)-induced diabetic mice via AMPK and IRS1 upregulation. Full article

(This article belongs to the Special Issue Polyphenols for Diabetes)

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14 pages, 3032 KiB

Open AccessArticle

Investigation of the Renal Protective Effect of Combined Dietary Polyphenols in Streptozotocin-Induced Diabetic Aged Rats

by Yassine Chtourou, Maram Morjen, Rahma Ammar, Rania Mhiri, Mohamed Jemaà, Ines ELBini-Dhouib, Hamadi Fetoui, Najet Srairi-Abid, Naziha Marrakchi and Jed Jebali

Nutrients 2022, 14(14), 2867; https://doi.org/10.3390/nu14142867 - 13 Jul 2022

Cited by 5 | Viewed by 2171

Abstract

Natural polyphenols are widely reported to have a large range of pharmacological properties, especially antioxidant activities and free radical scavenging capacities. In this study, we investigate the effects of naringin, chlorogenic acid, and quercetin mixtures (NCQ) on renal fibrosis in streptozotocin (STZ)-induced diabetic aged rats and its underlying mechanisms for ten consecutive weeks. The oxidative defense system in the kidneys of treated rats was found to be improved. Several biomarkers were investigated including the blood urea nitrogen, creatinine, and uric acid. Moreover, antioxidant parameters were evaluated and we found that superoxide dismutase, catalase, glutathione peroxidase, Na⁺-K⁺-ATPase activities, the nitric oxide production, the protein carbonyl, the advanced oxidation protein products, lipid peroxidation, and reduced glutathione levels were all significantly balanced and close to control values. In addition, NCQ restored renal injuries and fibrosis as assessed by histological method and molecular biology investigation of the matrix metalloproteinase, the transforming growth factor-beta TGF-β, the tumor necrosis factor TNFα, and p53 expression. Our study proposes the NCQ combination as potential plant-derived bioactive compounds to prevent diabetic nephropathy. Full article

(This article belongs to the Special Issue Polyphenols for Diabetes)

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23 pages, 5817 KiB

Open AccessArticle

An In Silico and an In Vitro Inhibition Analysis of Glycogen Phosphorylase by Flavonoids, Styrylchromones, and Pyrazoles

by Sónia Rocha, Natália Aniceto, Rita C. Guedes, Hélio M. T. Albuquerque, Vera L. M. Silva, Artur M. S. Silva, Maria Luísa Corvo, Eduarda Fernandes and Marisa Freitas

Nutrients 2022, 14(2), 306; https://doi.org/10.3390/nu14020306 - 12 Jan 2022

Cited by 7 | Viewed by 2427

Abstract

Glycogen phosphorylase (GP) is a key enzyme in the glycogenolysis pathway. GP inhibitors are currently under investigation as a new liver-targeted approach to managing type 2 diabetes mellitus (DM). The aim of the present study was to evaluate the inhibitory activity of a panel of 52 structurally related chromone derivatives; namely, flavonoids, 2-styrylchromones, 2-styrylchromone-related derivatives [2-(4-arylbuta-1,3-dien-1-yl)chromones], and 4- and 5-styrylpyrazoles against GP, using in silico and in vitro microanalysis screening systems. Several of the tested compounds showed a potent inhibitory effect. The structure–activity relationship study indicated that for 2-styrylchromones and 2-styrylchromone-related derivatives, the hydroxylations at the A and B rings, and in the flavonoid family, as well as the hydroxylation of the A ring, were determinants for the inhibitory activity. To support the in vitro experimental findings, molecular docking studies were performed, revealing clear hydrogen bonding patterns that favored the inhibitory effects of flavonoids, 2-styrylchromones, and 2-styrylchromone-related derivatives. Interestingly, the potency of the most active compounds increased almost four-fold when the concentration of glucose increased, presenting an IC₅₀ < 10 µM. This effect may reduce the risk of hypoglycemia, a commonly reported side effect of antidiabetic agents. This work contributes with important considerations and provides a better understanding of potential scaffolds for the study of novel GP inhibitors. Full article

(This article belongs to the Special Issue Polyphenols for Diabetes)

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32 pages, 4804 KiB

Open AccessArticle

Blueberry Counteracts Prediabetes in a Hypercaloric Diet-Induced Rat Model and Rescues Hepatic Mitochondrial Bioenergetics

by Sara Nunes, Sofia D. Viana, Inês Preguiça, André Alves, Rosa Fernandes, João S. Teodoro, Patrícia Matos, Artur Figueirinha, Lígia Salgueiro, Alexandra André, Sara Silva, Ivana Jarak, Rui A. Carvalho, Cláudia Cavadas, Anabela P. Rolo, Carlos M. Palmeira, Maria M. Pintado and Flávio Reis

Nutrients 2021, 13(12), 4192; https://doi.org/10.3390/nu13124192 - 23 Nov 2021

Cited by 10 | Viewed by 3709

Abstract

The paramount importance of a healthy diet in the prevention of type 2 diabetes is now well recognized. Blueberries (BBs) have been described as attractive functional fruits for this purpose. This study aimed to elucidate the cellular and molecular mechanisms pertaining to the protective impact of blueberry juice (BJ) on prediabetes. Using a hypercaloric diet-induced prediabetic rat model, we evaluated the effects of BJ on glucose, insulin, and lipid profiles; gut microbiota composition; intestinal barrier integrity; and metabolic endotoxemia, as well as on hepatic metabolic surrogates, including several related to mitochondria bioenergetics. BJ supplementation for 14 weeks counteracted diet-evoked metabolic deregulation, improving glucose tolerance, insulin sensitivity, and hypertriglyceridemia, along with systemic and hepatic antioxidant properties, without a significant impact on the gut microbiota composition and related mechanisms. In addition, BJ treatment effectively alleviated hepatic steatosis and mitochondrial dysfunction observed in the prediabetic animals, as suggested by the amelioration of bioenergetics parameters and key targets of inflammation, insulin signaling, ketogenesis, and fatty acids oxidation. In conclusion, the beneficial metabolic impact of BJ in prediabetes may be mainly explained by the rescue of hepatic mitochondrial bioenergetics. These findings pave the way to support the use of BJ in prediabetes to prevent diabetes and its complications. Full article

(This article belongs to the Special Issue Polyphenols for Diabetes)

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17 pages, 4790 KiB

Open AccessArticle

Hypoglycaemic and Antioxidant Properties of Acrocomia aculeata (Jacq.) Lodd Ex Mart. Extract Are Associated with Better Vascular Function of Type 2 Diabetic Rats

by Tamaeh Monteiro-Alfredo, Sara Oliveira, Andreia Amaro, Daniela Rosendo-Silva, Katia Antunes, Ana Salomé Pires, Ricardo Teixo, Ana Margarida Abrantes, Maria Filomena Botelho, Miguel Castelo-Branco, Raquel Seiça, Sónia Silva, Kely de Picoli Souza and Paulo Matafome

Nutrients 2021, 13(8), 2856; https://doi.org/10.3390/nu13082856 - 20 Aug 2021

Cited by 9 | Viewed by 3056

Abstract

Oxidative stress is involved in the metabolic dysregulation of type 2 diabetes (DM2). Acrocomia aculeata (Aa) fruit pulp has been described for the treatment of several diseases, and recently we have proved that its leaves have phenolic compounds with a marked antioxidant effect. We aimed to assess whether they can improve metabolic, redox and vascular functions in DM2. Control Wistar (W-Ctrl) and non-obese type 2 diabetic Goto–Kakizaki (GK-Ctrl) rats were treated for 30 days with 200 mg.kg⁻¹ aqueous extract of Aa (EA-Aa) (Wistar, W-EA-Aa/GK, GK-EA-Aa). EA-Aa was able to reduce fasting glycaemia and triglycerides of GK-EA-Aa by improving proteins related to glucose and lipid metabolism, such as GLUT-4, PPARγ, AMPK, and IR, when compared to GK-Ctrl. It also improved viability of 3T3-L1 pre-adipocytes exposed by H₂O_2. EA-Aa also increased the levels of catalase in the aorta and kidney, reduced oxidative stress and increased relaxation of the aorta in GK-treated rats in relation to GK-Ctrl, in addition to the protective effect against oxidative stress in HMVec-D cells. We proved the direct antioxidant potential of the chemical compounds of EA-Aa, the increase in antioxidant defences in a tissue-specific manner and hypoglycaemic properties, improving vascular function in type 2 diabetes. EA-Aa and its constituents may have a therapeutic potential for the treatment of DM2 complications. Full article

(This article belongs to the Special Issue Polyphenols for Diabetes)

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Review

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20 pages, 1897 KiB

Open AccessReview

Nurturing through Nutrition: Exploring the Role of Antioxidants in Maternal Diet during Pregnancy to Mitigate Developmental Programming of Chronic Diseases

by Mariana S. Diniz, Carina C. Magalhães, Carolina Tocantins, Luís F. Grilo, José Teixeira and Susana P. Pereira

Nutrients 2023, 15(21), 4623; https://doi.org/10.3390/nu15214623 - 31 Oct 2023

Cited by 2 | Viewed by 1848

Abstract

Chronic diseases represent one of the major causes of death worldwide. It has been suggested that pregnancy-related conditions, such as gestational diabetes mellitus (GDM), maternal obesity (MO), and intra-uterine growth restriction (IUGR) induce an adverse intrauterine environment, increasing the offspring’s predisposition to chronic diseases later in life. Research has suggested that mitochondrial function and oxidative stress may play a role in the developmental programming of chronic diseases. Having this in mind, in this review, we include evidence that mitochondrial dysfunction and oxidative stress are mechanisms by which GDM, MO, and IUGR program the offspring to chronic diseases. In this specific context, we explore the promising advantages of maternal antioxidant supplementation using compounds such as resveratrol, curcumin, N-acetylcysteine (NAC), and Mitoquinone (MitoQ) in addressing the metabolic dysfunction and oxidative stress associated with GDM, MO, and IUGR in fetoplacental and offspring metabolic health. This approach holds potential to mitigate developmental programming-related risk of chronic diseases, serving as a probable intervention for disease prevention. Full article

(This article belongs to the Special Issue Polyphenols for Diabetes)

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15 pages, 1061 KiB

Open AccessReview

Updated Information of the Effects of (Poly)phenols against Type-2 Diabetes Mellitus in Humans: Reinforcing the Recommendations for Future Research

by Regina Menezes, Paulo Matafome, Marisa Freitas and María-Teresa García-Conesa

Nutrients 2022, 14(17), 3563; https://doi.org/10.3390/nu14173563 - 30 Aug 2022

Cited by 7 | Viewed by 2181

Abstract

(Poly)phenols have anti-diabetic properties that are mediated through the regulation of the main biomarkers associated with type 2 diabetes mellitus (T2DM) (fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), insulin resistance (IR)), as well as the modulation of other metabolic, inflammatory and oxidative stress pathways. A wide range of human and pre-clinical studies supports these effects for different plant products containing mixed (poly)phenols (e.g., berries, cocoa, tea) and for some single compounds (e.g., resveratrol). We went through some of the latest human intervention trials and pre-clinical studies looking at (poly)phenols against T2DM to update the current evidence and to examine the progress in this field to achieve consistent proof of the anti-diabetic benefits of these compounds. Overall, the reported effects remain small and highly variable, and the accumulated data are still limited and contradictory, as shown by recent meta-analyses. We found newly published studies with better experimental strategies, but there were also examples of studies that still need to be improved. Herein, we highlight some of the main aspects that still need to be considered in future studies and reinforce the messages that need to be taken on board to achieve consistent evidence of the anti-diabetic effects of (poly)phenols. Full article

(This article belongs to the Special Issue Polyphenols for Diabetes)

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19 pages, 828 KiB

Open AccessReview

Urolithins: Diet-Derived Bioavailable Metabolites to Tackle Diabetes

by Ana F. Raimundo, Sofia Ferreira, Francisco A. Tomás-Barberán, Claudia N. Santos and Regina Menezes

Nutrients 2021, 13(12), 4285; https://doi.org/10.3390/nu13124285 - 27 Nov 2021

Cited by 16 | Viewed by 5096

Abstract

Diabetes remains one of the leading causes of deaths and co-morbidities in the world, with tremendous human, social and economic costs. Therefore, despite therapeutics and technological advancements, improved strategies to tackle diabetes management are still needed. One of the suggested strategies is the consumption of (poly)phenols. Positive outcomes of dietary (poly)phenols have been pointed out towards different features in diabetes. This is the case of ellagitannins, which are present in numerous foodstuffs such as pomegranate, berries, and nuts. Ellagitannins have been reported to have a multitude of effects on metabolic diseases. However, these compounds have high molecular weight and do not reach circulation at effective concentrations, being metabolized in smaller compounds. After being metabolized into ellagic acid in the small intestine, the colonic microbiota hydrolyzes and metabolizes ellagic acid into dibenzopyran-6-one derivatives, known as urolithins. These low molecular weight compounds reach circulation in considerable concentrations ranging until micromolar levels, capable of reaching target tissues. Different urolithins are formed throughout the metabolization process, but urolithin A, isourolithin A, and urolithin B, and their phase-II metabolites are the most frequent ones. In recent years, urolithins have been the focus of attention in regard to their effects on a multiplicity of chronic diseases, including cancer and diabetes. In this review, we will discuss the latest advances about the protective effects of urolithins on diabetes. Full article

(This article belongs to the Special Issue Polyphenols for Diabetes)

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Other

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8 pages, 945 KiB

Open AccessOpinion

The (Poly)phenol-Carbohydrate Combination for Diabetes: Where Do We Stand?

by Ana Marta de Matos and Regina Menezes

Nutrients 2023, 15(4), 996; https://doi.org/10.3390/nu15040996 - 16 Feb 2023

Viewed by 1360

Abstract

The type 2 diabetes epidemic is real and hardly coming to an end in the upcoming years. The efforts of the scientific community to develop safer and more effective compounds for type 2 diabetes based on the structure of natural (poly)phenols are remarkable and have indeed proven worthwhile after the introduction of gliflozins in clinical practice. However, low-quality reports on the antidiabetic potential of plant-derived lipophilic (poly)phenols continue to pile up in the literature. Many of these compounds continue to be published as promising functional nutrients and antidiabetic pharmaceutical leads without consideration of their Pan-Assay Interference Compounds (PAINS) profile. This evidence-based opinion article conveys the authors’ perspectives on the natural (poly)phenol artillery as a valuable and reliable source of bioactive compounds for diabetes. Ultimately, in light of the already established membrane-perturbing behavior of lipophilic (poly)phenols, together with the multiple benefits that may come with the introduction of a C-glucosyl moiety in bioactive compounds, we aim to raise awareness of the importance of contemplating the shift to (poly)phenol–carbohydrate combinations in the development of functional nutrients, as well as in the early stages of antidiabetic drug discovery. Full article

(This article belongs to the Special Issue Polyphenols for Diabetes)

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26 pages, 708 KiB

Open AccessSystematic Review

A Systematic Review of the Cardiometabolic Benefits of Plant Products Containing Mixed Phenolics and Polyphenols in Postmenopausal Women: Insufficient Evidence for Recommendations to This Specific Population

by Lorena Sánchez-Martínez, María-Jesús Periago, Javier García-Alonso, María-Teresa García-Conesa and Rocío González-Barrio

Nutrients 2021, 13(12), 4276; https://doi.org/10.3390/nu13124276 - 27 Nov 2021

Cited by 9 | Viewed by 3167

Abstract

Menopause is characterized by endocrine and physiological changes and is often accompanied by increased body weight and cholesterol, glucose intolerance, and/or hypertension. These alterations are associated with increased risk for cardiovascular diseases (CVDs) and Type II diabetes mellitus (T2DM) that may be moderate by dietary plant phenolic compounds. In this review, we examine the current evidence of the impact of a variety of plant products (foods, extracts, beverages) rich in a mixture of phenolics and polyphenols on: (i) glucose and insulin levels; (ii) lipid profile; (iii) blood pressure; and (iv) biomarkers of inflammation and oxidative stress in postmenopausal women. We critically evaluate both the results of a range of intervention studies conducted in this specific subpopulation and the level of evidence supporting the benefits of consuming those products after the menopause. Overall, the current available evidence does not allow for specific dietary recommendations of these plant products rich in phenolics and polyphenols in this high-risk subpopulation. Our data show rather variable and small effects of the different products examined on the cardiometabolic biomarkers and further support the need to: (1) improve the quality of the study designs and data reporting; and (2) understand the variability in the response of the different biomarkers and establish clear differences between healthy and cardiometabolic disease levels. Full article

(This article belongs to the Special Issue Polyphenols for Diabetes)

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