INTRODUCTION:

Diabetes mellitus (DM) is one of the most common systemic metabolic disorders, characterized by high blood glucose levels (hyperglycemia). It is associated with decreased insulin secretion and/or insulin activity in target cells¹. Additional abnormalities in carbohydrate, lipid, and protein intermediary metabolism are also commonly observed². Diabetes is the world's leading endocrine disease, with an estimated 382 million people suffering from it in 2013, and this figure is expected to rise to 592 million by 2035.

The majority of diabetic patients live in low and middle-income countries, and the incidence of diabetes among those with low income is expected to rise over the next 22 years³. Traditionally, the presence or absence of insulin dependence in a patient determines the classification of their diabetes. Recent research has identified five types of diabetes mellitus (DM) and their etiopathogenetic mechanisms: type 1A (auto-immune mediated), type 1B (idiopathic or nonauto- immune mediated), type 2 (insulin resistance), gestational (first recognized during pregnancy but typically characterized by insulin resistance), and type 5 (other specific aetiologies; secondary to other diseases and recognized gene mutations)⁴. Although T2DM's immediate symptoms may be inconsequential and barely interfere with daily activities, the complications that result in the impairment of vital organs have the potential to be significantly more morbid and lethal^5-15.

METHODS:

Materials:

A search for articles published in peer-reviewed journals using electronic databases such as PubMed, Scopus, Science Direct, and Google Scholar. It was used to collect data on various plant-based anti-diabetic agents that have historically been used for pharmacologically based treatment, ethnomedicinal, phytochemical, and other disorders.

Patients who experience failure during initial therapy typically need medication. In general, patients who don't respond to the initial therapy need medication. No oral medication, however, can be regarded as the best course of treatment due to their extensive lists of side effects, high prices, and occasionally attenuated responses after prolonged use. For instance, sulphonylurea typically results in hypoglycemia, skin rash, or itching, whereas the widely used anti-diabetic medication metformin causes lactic acidosis, general sickness, and alcohol use. Additionally, alpha-glucosidase inhibitors have been linked to bloating, diarrhea, and hypoglycemia, meglitinides to weight gain and hypoglycemia, and thiazolidinediones to liver disease risk¹⁷.

To overcome the difficulties associated with existing synthetic oral hypoglycemic agents, a search for novel targets or newer drugs is required. As a result of their traditional use, several phytoconstituents and phyto-products have emerged as potential alternative sources for developing new antioxidant and anti-diabetic agents. There are approximately 200 pure compounds isolated from plant sources with blood glucose lowering activity, fewer side effects, and low costs¹⁸.

Polyphenols are secondary metabolites that are generally involved in the defense against ultraviolet radiation or pathogen infection. Epidemiological studies and associated meta-analyses from the early twenty-first century strongly suggested that long-term consumption of plant polyphenol-rich diets offered some resistance against the development of diabetes, cancers, osteoporosis, cardiovascular disease, and neurodegenerative diseases. Polyphenols and phenolic compounds inhibit glucose absorption, protect pancreatic cells from damage, improve insulin release and sensitivity, reduce inflammation, modulate the carbohydrate metabolism pathway, and regulate insulin dependent and independent signalling pathways in diabetic patients^15-23.

As a result, scientists are eager to learn more about the mechanisms underlying these polyphenolic compounds' anti-diabetic effects. As a result, the goal of this review is to compile all available data on polyphenols as potential anti-diabetic agents from medicinal plants, fruits, and vegetables, as well as their respective mechanisms. These compounds could be a valuable resource in the future for developing new regimens and/or improving existing synthetic anti-diabetic drugs with fewer or no side effects²³.

T1DM affects genetically susceptible people and is thought to be caused by viruses and one or more environmental agents. T1DM individuals' genetic markers, immune markers, and metabolic markers are detectable after birth, after the onset of the autoimmune process, and after the destruction of enough -cells to be detected by sensitive tests. Unfortunately, immunosuppressive drugs rarely prevent autoimmune destruction due to side effects^22-24.

Figure 1. A major pathway of Diabetes Mellites, the ROS, are formed in the Oxidative stress via NADPH pathway and the polyol pathway that leads to Nephropathy.

Pharmacological mechanism of natural polyphenols based medicinal antidiabetic agents

Table 1. Major antidiabetic natural polyphenols in natural source^25-35

Plant source	Family	Common name	Chemical constituents
Vaccinium myrtillus L.	Ericaceae	European blueberry	Anthocyanin
Ipomoea batatas cv.Ayamurasaki	Convolvulaceae	Sweet potato
Phaseolus vulgaris	Fabaceae	French bean
Lactuca sativa L.	Asteraceae	Lettuce
Solanum melongena	Solanaceae	Eggplant
Raphanus sativus	Brassicaceae	Red radish
Brassicaoleraceavar.capitata f. rubra	Brassicaceae	Red cabbage
Allium cepa	Amaryllidaceae	Red onion
Asparagus officinalis var. violetto	Asparagaceae	Purple asparagus
Solanum tuberosum	Solanaceae	Red potato
Brassica oleracea var. botrytis	Brassicaceae	Purple cauliflower
Chrysophyllumcainito	Sapotaceae	Star apple
Ficuscarica L.	Moraceae	Fig
Prunuscerasus	Rosaceae	Sour Cherry
Reynosiajamaicensis	Rhamnaceae	Blackberry
Rubusrosifolius	Rosaceae	Red raspberry
Rubusracemosus	Rosaceae	Black raspberry
Kadsuracoccinea	Schisandraceae	Black tiger
Prunusarmeniaca L.	Rosaceae	Armenian plum/ Apricot
Punica granatum L.	Lythraceae	Pomegranate	Ellagitannin
Rubus rosifolius	Rosaceae	Raspberry
Rubus fruticosus	Rosaceae	Blackberry
Dovyalishebecarpa	Salicaceae	Ceylon Gooseberry
Fragaria ananassa	Rosaceae	Strawberry
Hippo phaerhamnoides	Elaeagnaceae	Sea buckthorn berry
Actinidia deliciosa	Actinidiaceae	Kiwi	Luteolin
Psidium guajava	Myrtaceae	Guava
Olea europaea L.	Oleaceae	Olive
Citrus paradisi	Rutaceae	Grapefruit	Rosmarinic acids
Citrus sinensis	Rutaceae	Orange
Citrus limon	Rutaceae	Lemon
Ribesuva-crispa L.	Grossulariaceae	Gooseberry	Catechin
Vitisvinifera L.	Vitaceae	Black grape
Prunusarmeniaca L.	Rosaceae	Apricot
Prunuspersica	Rosaceae	Peach
Prunusdomestica	Rosaceae	Plum
Prunusavium	Rosaceae	Sweet Cherry
Vitisvinifera	Vitaceae	White Grape
Diospyros kaki	Ebenaceae	Persimmon
Prunusarmeniaca L.	Rosaceae	Apricot	Quercetin
Maluspumila	Rosaceae	Apple
Morus alba	Moraceae	Mulberry
Sorbusaucuparia	Rosaceae	Rowan
Amelanchieralnifolia	Rosaceae	Saskatoon berry
Allium cepa	Amaryllidaceae	Onion
Moringa oleifera	Moringaceae	Indigenous vegetable
Phaseolus vulgaris	Fabaceae	French bean
Pisumsativum	Fabaceae	Peas
Solanum lycopersicum	Solanaceae	Tomato
Anethumgraveolens	Apiaceae	Dill
Brassica napobrassica	Brassicaceae	Swedish Turnip
Armoracia rusticana	Brassicaceae	Horseradish
Brassica oleracea var. italica	Brassicaceae	Broccoli
Vitisrotundifolia	Vitaceae	Muscadine grapes	Resveratrol
Fragariaananassa	Rosaceae	Strawberry
Vaccinium myrtillus	Ericaceae	Bilberry
Vacciniumvitis-idaea	Ericaceae	Cowberry
Citrus paradisi	Rutaceae	Grapefruit
Prunusavium	Rosaceae	Sweet Cherry	Rutin
Allium Cepa	Amaryllidaceae	Onion
Capsicum frutescens	Solanaceae	Red pepper
Asparagus officinalis	Asparagaceae	Asparagus
Aronias sp.	Rutaceae	Aronia
Maluspumila	Rosaceae	Apple
Citrus limon	Rutaceae	Lemon	Diosmin
Citrus aurantifolia	Rutaceae	Lime	Diosmin
Maluspumila	Rosaceae	Apple	Myricetin
Fragariaananassa	Rosaceae	Strawberry
Prunusdomestica	Rosaceae	Plum
Prunusarmeniaca L.	Rosaceae	Apricot
Vitisrotundifolia	Vitaceae	Muscadine grapes
Pisumsativum	Fabaceae	Peas
Daucuscarota	Apiaceae	Carrot
Spinaciaoleracea	Spinaciaoleracea	Spinach
Brassica oleracea	Brassicaceae	Cauliflower
Brassica rapa	Brassicaceae	Turnip
Allium cepa	Amaryllidaceae	Onion
Anethumgraveolens	Apiaceae	Dill
Apiumgraveolens var. dulce	Apiaceae	Celery
Solanum lycopersicum	Solanaceae	Tomato
Brassica napobrassica	Brassicaceae	Swedish Turnip
Pisumsativum	Fabaceae	Peas	Kaempferol
Brassica napobrassica	Brassicaceae	Swedish Turnip
Armoracia rusticana	Brassicaceae	Horse Radish
Brassica oleracea	Brassicaceae	Cabbage, Cauliflower
Spinaciaoleracea	Spinaciaoleracea	Spinach
Brassica rapa	Brassicaceae	Turnip
Brassica oleracea var. italica	Brassicaceae	Broccoli

Major antidiabetic natural polyphenols

DISCUSSION:

Natural products have long been a valuable resource in the development of novel drugs due to their diverse chemical compounds and ability to act on a wide range of biological targets. Polyphenols derived from natural products are currently the focus of drug discovery and development efforts, as many of these compounds are potential therapeutics that can intervene at various stages of diabetes development. Because in vitro and animal studies show that many polyphenols have positive effects on glucose homeostasis, more research on each polyphenol is needed to provide information about their potential to be used as pharmaceutical agents in the treatment of diabetes. Polyphenols found in fruits, vegetables, green tea, and edible plants, as shown in table 1, can be used as prophylactics or as synergistic compounds^35-43.

CONFLICT OF INTEREST:

The author has no conflicts of interest.

ACKNOWLEDGMENTS:

The author would like to thank NCBI, PubMed and Web of Science for the free database services for their kind support during this study.

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Received on 22.12.2022 Modified on 04.05.2023

Res. J. Pharmacology and Pharmacodynamics.2024;16(1):42-47.

DOI: 10.52711/2321-5836.2024.00008