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Flavonoids as Promising Lead Compounds in Type 2 Diabetes Mellitus: Molecules of Interest and Structure-Activity Relationship
Abstract
There is evidence that hyperglycemia results in the generation of reactive oxygen species, leading to oxidative stress in various tissues, including vascular system. An important link between oxidative stress, inflammatory response and insulin activity is now well established. The ability of antioxidants to protect against the deleterious effects of hyperglycemia and also to improve glucose metabolism and intake must be considered as leads of choice in diabetes treatment. In addition to their antioxidative activity, many flavonoids were demonstrated to act on biological targets involved in type 2 diabetes mellitus such as: α-glycosidase, glucose cotransporter or aldose reductase. In this context, flavonoids behaving as antioxidants were studied as potential drugs by acting as biological targets involved in diabetes development. In this review, we propose to shed light on antioxidants flavonoids investigated as antidiabetics. A special focus was made to address the structure-activity relationship related to the effect of these naturally occurring molecules on different targets involved in diabetes development.
... The substitutional pattern of flavonoids such as hydroxylation, methylation, acetylation, prenylation and glycosylation etc. showed a vital role in several biological activities [19,193,194]. Therefore, "structural amendments" might be substantial keynotes in the design and development of new drug moiety/moieties as in the structure-based drug design. ...
... Thus, further studies are needed to address the effect of glycosylation of flavonoids and their positional effects. Further, the prenylation/geranylation at C-8 of ring A of flavonoid showed remarkable antidiabetic activities, while at C-6 its illustrations showed uncertain effects [193,206]. Also, the presence of methylation or absence of 4′-hydroxylation of ring B of flavonoids showed an extremely decrease in the activities of compounds [193,200,207]. Similarly, the methylation of C-5/C-7/C-8 and C-3′ leads to reduction in the activity of flavonoids, but its effect of proportion is dependent on the neighboring substitution pattern of the compounds. ...
... Further, the prenylation/geranylation at C-8 of ring A of flavonoid showed remarkable antidiabetic activities, while at C-6 its illustrations showed uncertain effects [193,206]. Also, the presence of methylation or absence of 4′-hydroxylation of ring B of flavonoids showed an extremely decrease in the activities of compounds [193,200,207]. Similarly, the methylation of C-5/C-7/C-8 and C-3′ leads to reduction in the activity of flavonoids, but its effect of proportion is dependent on the neighboring substitution pattern of the compounds. ...
... Altogether, the oral bioavailability of flavonoids is very low, being importantly affected by membrane transporters, metabolic enzymes, and intestinal microbiota, representing a great obstacle to getting the maximal health benefits from the intake of food products rich in these natural agents [6]. In recent years, several novel strategies have been proposed to improve the oral bioavailability of flavonoids, including the use of absorption enhancers and inclusion complexes, such as mucoadhesive and mucoadhesive guided systems [7,8]. In addition, changing the absorption site from the large intestine to the small intestine has been suggested to be another possibility for promoting the bioavailability of some flavonoids [6]. ...
Cite this article: Sak K. Could flavonoid aglycones prevent the absorption of flavonoid glycosides by inhibiting sodium-dependent glucose transporter-1 in the small intestine? Explor Drug Sci. 2023;1:287-91. https://doi. Abstract Flavonoids present a large group of natural polyphenols with numerous important health benefits for preventing and treating a diverse variety of pathological conditions. However, the actual therapeutic use of these phytochemicals is impeded by their low oral bioavailability. In this commentary article, an interesting paradox is presented: while the ingested flavonoid glycosides can be absorbed by means of sodium-dependent glucose transporters (SGLTs; SGLT1) located in the brush border membrane facing the lumen of the small intestine, certain flavonoid aglycones are able to inhibit these shuttle proteins. It is expected that avoiding the co-intake of such SGLT1 inhibitors concomitantly with flavonoid-rich foods might provide a new option for enhancing the oral bioavailability of flavonoids, thereby preventing the transport of unabsorbed compounds to the large intestine and conversion into catabolites by the colonic microbiota. Altogether, the administration of flavonoids in appropriate combinations is highlighted for getting the maximal health benefits from consuming these bioactive compounds.
... The WHO appraised that more than 80% of people worldwide are estimated to use traditional medicine (WHO, 2023). In the last years, the high cost of prescription medications, particularly for impoverished populations, especially in developing countries, and in particular, their detrimental side effects have led to an increase in herbal medicine use (Nicolle et al., 2011;Yuan et al., 2016). In rural areas, financial barriers to accessing medications and to achieving optimal health are even greater; most of the population in the Adrar region cannot easily access modern medicines and prefer to use herbal medicine as the first line treatment. ...
Moringa oleifera Lam. leaves are commonly used for diabetes worldwide. To date, there has been no research study done to investigate its effect on lipid and carbohydrate profile in Algerian diabetic patients. This pilot clinical study aimed to evaluate its long term-effect on lipid and carbohydrate profile in Algerian diabetic patients in preparation for a larger trial. 44 diabetic patients from Adrar city were administrated with 3600 mg of MO leaves powder twice a day at breakfast and at 7 p.m. for a period of 90 consecutive days, along with their regular hypoglycemic medications, in order to evaluate their serum lipid (TC, C-HDL, C-LDL and TG) and carbohydrate profile (blood sugar and HBA1c), weight, BMI and blood pressure, across five time-points (on days 0, 3, 7, 30, and 90). The results showed that oral administration of Moringa oleifera powder had a statistically significant effect on blood sugar (HBA1c), LDL-C, HDL-C levels in diabetic patients (p<0.05). Moringa oleifera leaf powder seemed reduced LDL-C, and HBA1c and elevated HDL-C, in diabetic patients. No side effect was reported by any participant. However, it did not have a statistically significant effect on weight, BMI and blood pressure. The data from the present clinical trial provide persuasive, although preliminary evidence supporting the therapeutic potential of Moringa oleifera leaf powder for managing chronic hyperglycemia and dyslipidemia in Algerian patients with diabetes. A more extensive trial is necessary to determine the Moringa oleifera leaf powder optimal dose and evaluate if its effect results into long-term advantages. In addition, further investigations are required to clear the underlying mechanisms involved with these effects.
... ALR1 is also engaged in the metabolism of methylglyoxal and 3-deoxyglucosone, producing lethal glycation products [10]. ALR1 and ALR2 inhibitors are in dire need, which can normalize the polyol pathway and fight secondary diabetic problems [11]. ...
Mechanochemistry is an eco-friendly and solventless method. In the present study, the surface of a custom-made closed mortar and pestle is used as a catalyst to synthesize thiazolidinone-triazole derivatives successfully. The compounds were subjected to potential antidiabetic activity. The results showed that para-chloro-substituted derivative (9c) is most active with IC50 values of 10±1.56. All three compounds 9a-9c with a maximum of 20% inhibition for ALR1 represent superior selectivity toward the targeted ALR2 to act as a lead in the search for new antidiabetic agents.
... Meanwhile, Lauro et al. [51] explained that the steroid derivative compound pregnenolone-dihydrotestosterone conjugate induces changes in glucose levels similar to glibenclamide. The antidiabetic activity of flavonoids acts on targets involved in type 2 diabetes mellitus, such as aldose reductase, α-glucosidase, and DPP-4 [52], and in insulin-dependent diabetes mellitus, the flavonoid compound quercetin has been reported to increase insulin release by increasing the regeneration of pancreatic islet cells [53]. Groups of phenols and flavonoids are those found in higher plants. ...
Seaweed belongs to marine biota and contains nutrients and secondary metabolites beneficial for health. This study aimed to determine the antidiabetic activity of extracts and fractions of green seaweed Halimeda tuna. The H. tuna sample was extracted with the maceration method using methanol and then partitioned using ethyl acetate and water to obtain ethyl acetate and water fractions. The methanol extract, ethyl acetate fraction, and water fraction of H. tuna were tested for their inhibitory activity against α-amilase and α-glucosidase. The methanol extract and the fractions with the highest inhibitory activity were phytochemically tested and analyzed using gas chromatography–mass spectrometry (GC-MS). The results showed that the ethyl acetate fraction (IC50 = 0.88 ± 0.20 mg/mL) inhibited α-amylase relatively similar to acarbose (IC50 = 0.76 ± 0.04 mg/mL). The methanol extract (IC50 = 0.05 ± 0.01 mg/mL) and the ethyl acetate fraction (IC50 = 0.01 ± 0.00 mg/mL) demonstrated stronger inhibitory activity against α-glucosidase than acarbose (IC50 = 0.27 ± 0.13 mg/mL). Phytochemical testing showed that the methanol extract and the ethyl acetate fraction contained secondary metabolites: alkaloids, flavonoids, steroids, and phenol hydroquinone. The compounds in methanol extract predicted to have inhibitory activity against α-amylase and α-glucosidase were Docosanol, Neophytadiene, Stigmasta-7,22-dien-3-ol,acetate,(3.beta.,5.alpha.,22E), Octadecanoic acid,2-oxo-,methyl ester, and phytol, while those in the ethyl acetate fraction were n-Nonadecane, Phytol, Butyl ester, 14-.Beta.-H-pregna, Octadecenoic acid, and Oleic acid.
... Esto puede ser atribuido principalmente al contenido de flavonoides totales de cada uno de los tratamientos. Como se mencionó anteriormente, el extracto optimizado presenta una concentración mayor de estos compuestos, de los cuales se ha reportado ampliamente su impacto en el tratamiento de afecciones relacionadas con la diabetes, incluyendo el control de la hiperglicemia [52][53][54] . ...
El presente libro es fruto de la investigación interdisciplinaria entorno a los fines medicinales de las hojas de Passiflora ligularis (granadilla), realizada entre los grupos de investigación Principios Bioactivos de Plantas Medicinales, del Departamento de Farmacia, y Estudio y Aprovechamiento de Productos Naturales Marinos y Frutas de Colombia, del Departamento de Química, ambos de la Universidad Nacional de Colombia; y el Grupo de Investigación en Fitoquímica de la Pontificia Universidad Javeriana, con apoyo del Ministerio de Ciencia, Tecnología e Innovación de Colombia. A lo largo de estas páginas se resumen algunos de los resultados y avances más destacados de estos grupos de investigación en cuanto a la caracterización química de las hojas de esta especie. Además, se da énfasis a los flavonoides y saponinas; al estudio in silico, in vitro e in vivo de su actividad farmacológica, principalmente como hipoglicemiante y antinflamatorio; y al desarrollo de metodologías analíticas precisas, exactas y reproducibles que permitan la completa caracterización del extracto optimizado obtenido como un ingrediente activo promisorio para el desarrollo de productos fitoterapéuticos (etapa actualmente en progreso). Esta publicación pretende la divulgación técnica y científica de los resultados de varios años de estudio con el fin de dar valor agregado a los cultivos de Passiflora ligularis, una planta de gran interés comercial debido a sus frutos, cuyas hojas en la actualidad son simplemente un subproducto de su cosecha, a causa del desconocimiento de su potencial terapéutico y de la posibilidad de convertirse en una materia prima para la obtención de productos fitoterapéuticos estables, seguros y eficaces.
... Quercetin, a flavonoid, has been shown to improve pancreatic islet cell regeneration in people with insulin-dependent diabetes mellitus, increasing insulin release. [23]. Fiestin has been demonstrated to boost the islets' calcium uptake in non-insulin-dependent diabetic mellitus. ...
Flavonoids, a naturally occurring substance that is extensively spread across the plant kingdom, are what give plants their diverse hues in the form of leaves, flowers, fruits, and seeds. These have strong antioxidant effects and are secondary metabolites of plants. Sedative, antioxidant, anticonvulsant, antidepressant, anti-inflammatory, anti-cancer, anti-microbial, antihypertensive, Vasorelaxant, cardiac protective, antidiuretic, antiulcerogenic, anti-fungal, antiviral, Antineoplastic, Neuroprotective, and Hepatoprotective properties are all possessed by flavonoids. Numerous studies have shown that its antioxidant property is primarily responsible for the pharmacological effects indicated above. As a result of their influence on mammalian enzymes such protein kinases, aldose reductase, and alpha-glucosidase flavonoids regulate a number of cellular signaling pathways that get disrupted under pathological situations. Due to their many health benefits, flavonoids are the subject of numerous ongoing studies. A variety of flavonoids are sold as pharmaceutical goods on the market due to their advantages in terms of cost-effective mass manufacture and health advantages. The classification, metabolic, pharmacological, and biological effects of flavonoid supplements sold on the market are the main topics of the current review.
The present study evaluated the antioxidant and antidiabetic properties of Medicago sativa and Solidago virgaurea extracts enriched in polyphenolic compounds. The extracts were obtained by accelerated solvent extraction (ASE) and laser irradiation. Then, microfiltration was used for purification, followed by nanofiltration used to concentrate the two extracts. The obtained extracts were analyzed to determine their antioxidant activity using DPPH radical scavenging and reducing power methods. The antidiabetic properties have been investigated in vitro on a murine insulinoma cell line (β-TC-6) by the inhibition of α-amylase and α-glucosidase. M. sativa obtained by laser irradiation and concentrated by nanofiltration showed the highest DPPH• scavenging (EC50 = 105.2 ± 1.1 µg/mL) and reducing power activities (EC50 = 40.98 ± 0.2 µg/mL). M. sativa extracts had higher inhibition on α-amylase (IC50 = 23.9 ± 1.2 µg/mL for concentrated extract obtained after ASE, and 26.8 ± 1.1), while S. virgaurea had the highest α-glucosidase inhibition (9.3 ± 0.9 µg/mL for concentrated extract obtained after ASE, and 8.6 ± 0.7 µg/mL for concentrated extract obtained after laser extraction). The obtained results after evaluating in vitro the antidiabetic activity showed that the treatment with M. sativa and S. virgaurea polyphenolic-rich extracts stimulated the insulin secretion of β-TC-6 cells, both under normal conditions and under hyperglycemic conditions as well. This paper argues that M. sativa and S. virgaurea polyphenolic-rich extracts could be excellent natural sources with promising antidiabetic potential.
Flavonoids are a group of low molecular weight plant products, based on the parent compound, flavone (2-phenylchromone) and have shown potential for application in a variety of pharmacological targets. By using random screening techniques flavones have been proposed as inhibitors of aldose reductase, an enzyme crucial in the treatment of diabetic complications such as cataract formation. On the other hand, a large number of natural and synthetic flavonoids are being tested as specific inhibitors of protein tyrosine kinase (PTK). Kinetic analyses of the PTK inhibition indicate that flavonoids are competitive inhibitors with respect to the nucleotide ATP. A thorough investigation of the available experimental data base by using both classical and quantum chemical descriptors has been performed in order to develop quantitative structure-activity relationships for these enzyme systems. Relevance of the descriptors to binding proper-ties of both enzyme receptors active site is proposed and the obtained results demonstrate in detail which specific electronic as well as the hydrophobic and steric properties of the substituents play a significant role in their differential binding.
Genistein is an isoflavone that is known to be contained in soybean. It was proved that genistein plays a pivotal role in homeostasis in the human body. In the course of screening for useful α-glucosidase inhibitors, we isolated and identified genistein as a candidate for α-glucosidase inhibitor from fermentation broths of a Streptomyces sp. Genistein was shown to be a reversible, slow-binding, non-competitive inhibitor of yeast α-glucosidase with a Ki value of 5.7×10−8 M when the enzyme mixture was pretreated with genistein. These results show a possibility that genistein could be a useful tool for metabolic disorders.
The role of SGLT2 (the gene for a renal sodium-dependent glucose transporter) in renal glucosuria was evaluated. Therefore, its genomic sequence and its intron-exon organization were determined, and 23 families with index cases were analyzed for mutations. In 21 families, 21 different SGLT2 mutations were detected. Most of them were private; only a splice mutation was found in 5 families of different ethnic backgrounds, and a 12-bp deletion was found in two German families. Fourteen individuals (including the original patient with 'renal glucosuria type 0') were homozygous or compound heterozygous for an SGLT2 mutation resulting in glucosuria in the range of 14.6 to 202 g/1.73 m(2)/d (81 - 1120 mmol/1.73 m(2)/d). Some, but not all, of their heterozygous family members had an increased glucose excretion of up to 4.4 g/1.73 m(2)/d (24 mmol/1.73 m(2)/d). Likewise, in index cases with glucosuria below 10 g/1.73 m(2)/d (55 mmol/1.73 m(2)/d) an SGLT2 mutation, if present, was always detected in the heterozygous state. We conclude that SGLT2 plays an important role in renal tubular glucose reabsorption. Inheritance of renal glucosuria shows characteristics of a codominant trait with variable penetrance.
a-Glucosidase inhibitors are used in the treatment of non-insulin-dependent diabetes mellitus. We attempt to isolate a-glucosidase inhibitors from 24 traditional Thai medicinal plant samples. Potent a-glucosidase inhibitory activity was found in aqueous methanol extract of dried Devil tree (Alstonia scholaris) leaves. Active principles against a-glucosidase, prepared from rat small intestine acetone powder, were isolated and identified. The structures of these isolated compounds were found to be quercetin 3-O-b-D-xylopyranosyl (1 000 ? 2 00)-b-D-galactopyranoside and (À)-lyoniresinol 3-O-b-D-glucopyranoside on the basis of chemical and spectral evidence. The lat-ter exhibited an inhibitory activity against both sucrase and maltase with IC 50 values of 1.95 and 1.43 mM, respectively, whereas the former inhibited only maltase with IC 50 values of 1.96 mM. This preliminary observation will provide the basis for further examination of the suitability of Alstonia scholaris as a medicinal supplement that contributes toward the treatment and prevention of diabetes.
This article has been retracted at the request of the Editor-in-Chief and author. Please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).Reason: A detailed study of extracts of the Russian knapweed Acroptilon [Centaurea] repens roots has failed to establish the presence of 7,8-benzoflavone, which therefore remains unknown as a plant natural product. The above authors therefore wish to retract the original publication which previously reported its existence, and deeply regret any inconvenience to the scientific readership.
The aim of the current study was to investigate the oral antidiabetic activity of six structurally related flavonoids: flavone (1), 3-hydroxyflavone (2), 6-hydroxyflavone (3), 7-hydroxyflavone (4), chrysin (5) and quercetin (6). Normoglycemic and STZ-nicotinamide diabetic rats were treated with these flavonoids (50 mg/kg) and the hypoglycemic and antidiabetic effects in acute and sub acute (five days of treatment) experiments were determined. Compounds 1, 5 and 6 were found most active in both experiments in comparison with control group (p<0.05). After five days of administration to STZ-nicotinamide diabetic rats, flavonoids induced a significantly diminishing of total cholesterol, TG and LDL and an augment of HDL compared with the control group (p<0.05). The in vitro inhibitory activity of the compounds against 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) was also evaluated. Quercetin, the most active compound, was docked into the crystal structure of 11beta-HSD1. Docking results indicate potential hydrogen bond interactions with hydroxyl groups of catalytic amino acid residues.
Historically, the incidence of type 2 diabetes has been lower in Asian populations compared with those in Western countries. One possible reason for the lower incidence among Asians is that they consume fermented soybean products, which are unique to the traditional Asian diet. Some have hypothesized that dietary phytoestrogens and soy peptides in fermented soybean foods consumed in traditional Asian diets may help prevent and slow the progression of type 2 diabetes. This review evaluates the existing evidence from animal studies and clinical and epidemiologic investigations on fermented soybeans in the prevention and treatment of type 2 diabetes. Nutritional studies performed in animals and intervention studies with humans suggest that the ingestion of soy protein with isoflavones improves glucose control and reduces insulin resistance. Korean fermented soybean products such as doenjang, kochujang, and chungkookjang contain alterations in the structures and content of isoflavonoids and small bioactive peptides, which are produced during fermentation. Several studies revealed improvements in insulin resistance and insulin secretion with the consumption of these fermented products. Therefore, fermented soybean products may help prevent or attenuate the progression of type 2 diabetes. Although the lack of human intervention trials does not permit definitive conclusions, the evidence does suggest that fermented soy products may be better for preventing or delaying the progression of type 2 diabetes compared with nonfermented soybeans.
The alpha-glucosidase inhibitor acarbose is administered to control blood glucose levels in type 2 diabetic patients and, in several countries, in those with impaired glucose tolerance. The efficacy and safety of the drug has been well established in these patient populations. Acarbose shows no weakening of efficacy in long-term diabetes treatment, reduces the development of type 2 diabetes in those with impaired glucose tolerance, and also appears to reduce the risk of cardiovascular disease. The underlying mechanisms of its effect on the risk of developing macrovascular complications have still to be elucidated. The mode of action of acarbose, which precedes all other metabolic processes involved in blood glucose regulation, inhibits high increases in postprandial blood glucose. Due to this early mode of action, acarbose also modifies insulin and proinsulin secretion which are both involved in ss-cell dysfunction and insulin resistance and may be independent risk factors for cardiovascular mortality. Based on the literature available the present state of knowledge on insulin and proinsulin as risk factors for cardiovascular mortality is reviewed as well as the effect of acarbose on the regulation of the ss-cells as monotherapy and in combination regimens. Possible associated interactions with the cardiovascular system are identified.