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Protective Effects of Medicinal Plant-Based Foods against Diabetes: A Review on Pharmacology, Phytochemistry and Molecular Mechanisms

A peer-reviewed version of this preprint was published in:
Nutrients 2023, 15(14), 3266. https://doi.org/10.3390/nu15143266

Submitted:

29 June 2023

Posted:

30 June 2023

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Abstract
Diabetes mellitus (DM) comprises a range of metabolic disorders characterized by high blood glucose levels caused by defects in insulin release, insulin action, or both. DM is a widespread condition that affects a substantial portion of the global population, causing high morbidity and mortality rates. The prevalence of this major public health crisis is predicted to increase in the forthcoming years. Although, several drugs are available to manage DM, these are associated with adverse side effects, which limits their use. In underdeveloped countries, where such drugs are often costly and not widely available, many people continue to rely on alternative traditional medicine, including medicinal plants. The latter serve as a source of primary healthcare and plant-based foods in many low and middle-income countries. Interestingly, many of the phytochemicals they contain have been demonstrated to possess antidiabetic activity such as lowering blood glucose levels, stimulating insulin secretion and alleviating diabetic complications. Therefore, such plants may provide protective effects that could be used in the management of DM. The purpose of this article was to review the medicinal plant-based foods traditionally used for the management of DM, including their therapeutic effects, pharmacologically-active phytoconstituents and antidiabetic mode of action at the molecular level. It also presents future avenues for research in this field.
Keywords: 
medicinal plants-based foods
;  
pharmacology
;  
diabetes
;  
insulin
;  
phytoconstituents
Subject: 
Medicine and Pharmacology  -   Complementary and Alternative Medicine

1. Introduction

Diabetes mellitus (DM) is a severe medical condition that affects how the body processes glucose in the blood. It can develop following either a deficiency in the production of the anabolic hormone insulin or a lack of insulin sensitivity from cells or both. The resulting excess sugar in the blood leads to abnormalities in the metabolism of carbohydrates, lipids, and proteins. An insufficient production of insulin can also lead to these disruptions [1,2]. Diabetes is a widespread condition that affects a substantial portion of the global population, causing high morbidity and mortality rates and resulting in a major public health crisis. In 2021, it was estimated that over half a billion people have diabetes. This number is predicted to continue to rise, with 783.2 million people expected to live with diabetes by 2045 [3]. Diabetes is considered as one of the five most severe diseases worldwide. The main symptoms of diabetes include increased blood glucose, excessive thirst, frequent urination, impaired vision, hyperphagia, weight loss, nausea, and vomiting [2,4].
Type 1 and Type 2 are the two most widespread forms of diabetes. Type 2 diabetes mellitus (T2DM) accounts for the majority of diabetes cases (approximately 90-95% of cases). Among type 1 diabetes patients, about 85% are reported with islet cell antibodies which act against cells from the islets of Langerhans, affect glutamic acid decarboxylase (GAD) function [2]. Type 1 diabetes (T1DM) is generally associated with insulin insufficiency due to the autoimmune destruction of pancreatic β-cells by CD4+ and CD8+ T cells and macrophages. The abnormal functioning of pancreatic ɑ-cells also contributes to worsen of the insulin insufficiency. The ɑ-cells produce an excessive amount of glucagon which further leads to metabolic disorders. The decreased insulin and glucose metabolism in peripheral tissues contributes to raising the level of free fatty acids in the blood by triggering lipolysis. As a result, the target tissues fail to exhibit normal insulin responsiveness due to a deficiency in the glucokinase enzyme in the liver and glucose transporter (GLUT)-4 protein in adipose tissues [2]. On the other hand, the progression of T2DM is usually genetic and associated with obesity triggering a low capacity of β-cells to secrete insulin and insulin resistance [4]. In T2DM, chronic hyperglycemia is frequently observed in blood vessels of the cardiac, renal, and retinal circulation. The excess fat deposition in the blood vessels, heart, or peripheral tissues exacerbates insulin resistance and contributes to cardiovascular diseases [2]. Gestational diabetes is another type of diabetes that refers to glucose intolerance during pregnancy and heightened fetal-maternal complications [5]. Diabetes is interconnected to both micro- and macrovascular complications, including retinopathy, nephropathy, neuropathy, ischemic heart disease, peripheral vascular disease, and cerebrovascular disease. This results in organ and tissue damage in one-third to one-half of all diabetic patients. The precise etiology of this damage remains elusive, although growing evidence suggests that oxidative stress and the generation of free radicals play a significant role [6].
Insulin therapy and several classes of antidiabetic drugs (i.e., biguanides, dipeptidyl peptidase-4 (DPP-4) inhibitors, meglitinides, sodium-glucose cotransporter-2 (SGLT2) inhibitors, sulfonylureas, and thiazolidinediones (TZDs) are currently available to treat diabetes and reduce the incidence of vascular complications [7,8,9]. However, many people in low and middle-income countries find it difficult to get reasonably priced and widely accessible diabetes treatment options due to the unexpected rise in diabetes prevalence and associated medical expenses [3]. Another, more holistic approach to the treatment of diabetes is the use of alternative medical systems such as Chinese Medicine, Unani, Ayurveda, and homeopathy [10]. Such traditional systems often use medicinal plants (e.g., turmeric, cardamom, garlic, onion, ginger, tulsi and cloves) and other natural remedies which have become integral components of daily diets and are believed to possess antidiabetic properties [11]. Microorganisms have also presented a promising opportunity for the discovery of antidiabetic drugs. One such example is acarbose, a pseudo-oligosaccharide derived from various actinomycetes [11]. Recent studies have found that venom-derived compounds from cone snails, sea anemones, bees, scorpions, snakes, and spiders also possess effective antidiabetic properties [12]. The World Health Organization (WHO) has estimated that traditional medicine is used as a primary healthcare option by almost 80% of the global population. Over 800 plants have been reported to have antidiabetic properties and these plants are often considered to have fewer side effects than synthetic drugs and contain bioactive compounds or phytochemicals with various biological properties [13,14,15]. The aim of this review is to discuss the medicinal plants-based foods traditionally used for the management of diabetes, including their active phytochemical constituents, therapeutic effects, molecular mode of action and future prospects.

2. Methods

An extensive search was conducted using Google Scholar and PubMed databases to write this comprehensive review article. The keywords that were used included "Pathophysiology of diabetes," "Prevalence of diabetes," "Diabetes types and mechanisms," " Diabetes epidemiology," " Diabetes risk factors and management," " Diabetes and Plant active components," " Diabetes and plant dietary components," "Antidiabetic properties of medicinal plants," and others relevant to the topic. Over 400 articles were evaluated and half of them were selected and incorporated into this article, ensuring only the most up to date, ranging from year 1998-2022 and relevant information was included.

3. The Pathophysiology of Diabetes

Diabetes mellitus is a dysregulation of glucose homeostasis either caused by the inability to produce insulin (in Type 1 diabetes) or an insufficient response to insulin (in Type 2 diabetes). DM occurs when the delicate balance of insulin and glucagon secretion in the pancreatic islets of Langerhans is disrupted, due to alterations in the functioning of the insulin-producing β cells and glucagon-producing α cells [16]. Diabetes usually develops when fasting plasma glucose levels increases due to insulin resistance in the peripheral tissues (also known as the prediabetes stage). It further progresses to hyperinsulinemia which is characterized by increased insulin production. The long-term overproduction of insulin causes cell failure, in turn contributing to hyperglycemia [17].
The increase in blood glucose levels beyond the normal physiological range in individuals with diabetes can lead to various complications including renal, neural, ocular, and cardiovascular disorders, emphasizing the need for an early diagnosis of diabetes [17]. Polyuria serves as a crucial diagnostic hallmark for the early detection of diabetes and as an underlying factor in the pathogenesis of DM [18]. Hyperglycemia has also been shown to activate certain metabolic pathways, which contributes to the pathogenesis of diabetic complications [19]. Among these metabolic pathways, protein kinase C (PKC) activation plays a significant role in hyperglycemia-induced atherosclerosis. PKC activation is implicated in a variety of cellular responses, including growth factor expression, signaling pathway activation, and oxidative stress amplification. Hyperglycemia generally stimulates metabolic processes and increases ROS (reactive oxygen species) generation by activating the polyol and hexosamine pathways resulting in diabetes-induced atherosclerosis. The upregulation of the receptor for advanced glycation end products (RAGE) gene, which regulates cholesterol efflux, monocyte recruitment, macrophage infiltration and lipid content in diabetic patients, triggers diabetes-induced inflammation [17]. Studies have shown that in diabetic mice, there is an increase in multiple PKC isoforms in the vasculatures of the renal glomeruli and retina. It has been observed that the activation of β- and δ-isoforms appears to be preferential. The activation of PKC in various tissues, including the retina, heart, and renal glomeruli, accompanied by the rise in blood glucose levels, exacerbates diabetic complications [20]. An increase in the total diacylglycerol (DAG) content has also been observed in various diabetic vascular complications, including in "insulin sensitive" tissues like the liver and skeletal muscles in diabetic animals and patients [21]. As a result of their production from glucose-derived dicarbonyl precursors, advanced glycation end products (AGEs) frequently accumulate intracellularly. AGEs are key triggers for the activation of intracellular signaling pathways and alteration in protein activity [22]. Glycation disrupts the normal function of proteins by modifying their molecular shapes, affecting enzymatic activity, lowering breakdown capacity, and interfering with receptor recognition. Upon AGEs degradation, highly reactive AGE intermediates (e.g. methylglyoxal, glyoxal) are formed. These reactive species are able to produce additional AGEs at a faster rate than glucose itself, fueling the production of AGEs and contributing to the pathogenesis of DM [23]. The pathogenesis of DM also involves the generation of pro-inflammatory mediators and ROS with elevated levels of cyclo-oxygenase (COX)-2, a crucial regulator in the conversion of arachidonic acid into prostaglandins that mediate inflammation, immunomodulation, apoptosis, and blood flow and elevated levels of antioxidant enzymes (glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT)) counteracting the exacerbated oxidative stress [24].
T1DM is an autoimmune disease, primarily seen in children and adolescents. T1DM is associated with the selective destruction of β cells, with no damage to other islets cells such as α cells (that secrete glucagon), δ cells (that secrete somatostatin), and pancreatic polypeptide cells (that modulate the rate of nutrient absorption). The development of T1DM is largely influenced by the rate of immune-mediated apoptosis of pancreatic β-cells. A strong connection has been established between damage to pancreatic β cells and genetics as studies have revealed that variations at genes of the Human Leukocyte Antigen (HLA) complex increases T1DM susceptibility. In T1DM, mutations in such genes override self-tolerance mechanisms and result in the production of autoantibodies and T-cell cytotoxic to pancreatic β cells. This immune-mediated β-cell destruction, and ultimate failure, triggers diabetic ketoacidosis (DKA), typically considered as the initial symptom of the disease. The presence of autoantibodies is an identifying trait of T1DM. These include autoantibodies to Glutamic Acid Decarboxylase (GADs) such as GAD65, autoantibodies to Tyrosine Phosphatases IA-2 and IA-2α, autoantibodies to the Islet-Specific Zinc Transporter Isoform 8 (ZnT8), Islet Cell Autoantibodies (ICAs) to β-cell cytoplasmic proteins like ICA512, and Insulin Autoantibodies (IAAs) [19,25].
T2DM is a metabolic disorder, characterized by increased glucose levels, ROS generation and inflammation, and all of which are linked to obesity. The poor glycemic control in T2DM provokes ROS generation resulting in the stimulation of the redox pathway. Antioxidant enzymes (e.g. SOD, CAT, GST) as well as COX are produced. In T2DM, the β Langerhans cells are hypersensitive to glucose in blood plasma. As a result, they produce higher than normal insulin levels. This hyperinsulinemia serves to counteract the hyperglycemia which impairs β cell functions. The chronic hyperglycemia further induces microvascular complications resulting in higher morbidity and mortality [20]. Moreover, the accumulation of AGEs is a primary mediator in the progression of non-proliferative retinopathy in T2DM. The pathophysiological cascades triggered by AGEs also play a significant role in the development of diabetic complications. The accumulation of AGEs in the myocardium, observed in 50-60% of diabetic patients with microalbuminuria, has been linked to diastolic dysfunction and highlights the complex interplay between AGEs, oxidative stress and diabetic complications [21]. Fatty liver, characterized by fat deposition in hepatocytes, is another key feature of T2DM. The high amounts of dietary lipids and abundance of free fatty acids from adipose tissues to the liver as well as lipogenesis are the main reasons for this metabolic imbalance [16]. Insulin resistance predominates in the liver and the muscles. The liver produces glucose from non-glucose substances (gluconeogenesis) in fasting periods to maintain a constant availability of carbohydrates. Increased gluconeogenesis is seen in hyperinsulinemia, suggesting that hepatic insulin resistance is an indicator of fasting hyperglycemia. The accumulation of fat in pancreatic islets ultimately contributes to β-cell dysfunction, leading to an increase in plasma glucose levels and a reduction in insulin response to ingested glucose [19].
Other types of diabetes include Maturity-Onset Diabetes of the Young (MODY) and gestational diabetes. In MODY, mutations occur in certain genes involved in insulin secretion by pancreatic β cells. This leads to a reduction in insulin secretion capacity. Gestational diabetes only occurs during pregnancy as a result of an increase in anti-insulin hormones, leading to insulin resistance and elevated blood sugar levels in the mother [19,26]. The presence faulty insulin receptors can also result in a range of pathophysiological symptoms and complications associated with diabetes, including polydipsia, polyuria, weight loss due to calorie loss in urine, increased appetite (polyphagia), impaired wound healing, susceptibility to gum and other infections, cardiovascular disease, eye damage, kidney damage, nerve damage, and the risk of developing diabetic foot, diabetic ketoacidosis and non-ketotic hyperosmolarity [26].

5. Discussion

DM is a disease primarily attributed to a deficiency in insulin production or action, with oxidative stress and inflammation being the main mediators of its progression [16,17,185]. Several epidemiological studies have shown that dietary habits have a significant impact on the prevention of diseases, with plant-derived constituents in vegetables, fruits, spices and condiments possessing beneficial health properties (e.g. antioxidant, immunomodulatory, anti-hyperlipidemic, anti-inflammatory, anti-hyperglycemic effects) [27,28]. In the typical western diet, which comprises mostly processed foods, red meat, and fast-acting carbohydrates, these phytoconstituents are lacking and this has been demonstrated to contribute to the development of DM [1,4]. Understanding the relevance of dietary plant-based constituents to DM, including their pharmacological properties and mode of actions, can be an effective strategy to better manage and prevent DM, potentially reducing the demand for medications and preventing diabetic complications [6,11].
Vegetables (e.g. cabbage, lentils, onions), fruits (e.g. grapes), herbs (e.g. dill, thyme), spices (e.g. black pepper, cinnamon, garlic, ginger, cumin) and nuts (e.g. walnuts, pistachios, pine nuts) contain a wide variety of phytochemicals (e.g. flavonoids, anthocyanins, saponins, tannins and carotenoids) that have been shown to possess antidiabetic properties. Olive oil and honey also provide natural chemicals that have demonstrated antidiabetic activity. The aforementioned plant-derived foods exert their antidiabetic activity on multiple organs (e.g. liver, intestine, pancreas, skeletal muscle, adipose tissue) and via different mechanistic pathways [28,141,156,168] (Figure 1).
Previous studies have established the antidiabetic and antihyperlipidemic effects of a diverse range of phytochemicals in plant-based foods. This includes the organosulfur compound allicin from garlic, flavonoids (genistein, formononetin, biochanin A and quercetin) from chickpeas, cinnamaldehyde from cinnamon, isothiocyanates and anthocyanidins from cabbage, carotenoids (crocetin, crocin) and safranal from saffron, thymoquinone from black cumin, organic acid (linolenic acid, oleic acid, arachidic acid and palmitic acid) in chilgoza nuts , procyanidins from pistachios, the sesquiterpene β-caryophyllene and the alkaloid piperine from black pepper, the stilbene resveratrol from grapes and curcuminoids (6-gingerol, 6-shogaol) from ginger.
In animal models of DM, the consumption of these plant-based food product has been shown to reduce oxidative stress-induced damage and increase insulin secretion as well as exhibit hypolipidemic, hypoglycemic, and anti-inflammatory activities. The consumption of such products also helps to maintain a normal lipid profile, regulate blood glucose levels, inhibit ROS generation, decrease LDL and increase HDL cholesterol [74,80,124].
The vast array of bioactive compounds found in medicinal plants continues to be an important resource for drug discovery and development and structure-activity relationship (SAR) studies are important to understand how minor modifications in chemical structures can modulate antidiabetic or antioxidant activity [186,187]. SAR analysis has demonstrated that alkaloids found in medicinal plants such as Coptis chinensis, Commelina communis, Zingiber officinale, Nigella sativa, Cuminum cyminum, Anemarrhena asphodeloides and Piper nigrum can improve postprandial hyperglycemia by inhibiting maltase-glucoamylase, which is becoming increasingly important as a target in antidiabetic drug discovery [84,121,137,156,188]. Such studies help researchers to design and develop compounds with improved activity and selectivity and also highlight the role of plant-based foods in the development of new drugs to control diabetes. However, further extensive studies are warranted to better understand the mechanistic pathways through which plants may elicit their antidiabetic effects.

6. Conclusion

Many of the medicinal plant-based foods protecting against diabetes mentioned in this review have been safely consumed since ancient times in various parts of the world. There is, however, a lack of sufficient scientific research on their protective effects in humans, particularly understanding the impact of high-dose and long-term consumption on health, and what happens when they are combined with conventional antidiabetic medications as this may lead to unwanted side effects and interactions. Thus, it is important to practice caution when consuming such plants in the context of managing DM. Future studies should focus on conducting high-quality clinical trials to validate the efficacy and establish the therapeutic index of the phytochemicals that have already demonstrated promising antidiabetic activity in vitro and in vivo. Such studies will provide a better understanding of the effectiveness, mechanisms of action, pharmacokinetic, and potential adverse effects of active constituents from medicinal plant-based foods. This has the potential to lead to the development of novel, safer, and more cost-effective plant-based medicines to tackle the rising prevalence of diabetes, particularly in low- and middle-income countries.

Author Contributions

Conceptualisation, P.A., V.S. and Y.H.A.A.W.; formal Analysis, P.A., V.S. and J.T.K; funding acquisition, P.A. and Y.H.A.A.W.; investigation, resources, writing, and editing, P.A., V.S., J.T.K., J.F.S., M.R.R, and S.R.; Visualization, V.S., P.A., A.B.R. and Y.H.A.A.W.; supervision and reviewing, P.A. and V.S. All authors have reviewed and approved the final version of the manuscript.

Funding

This study received no external sponsorship.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We would like to express our gratitude to Prof. Peter R Flatt, School of Biomedical Sciences, Ulster University, UK, for his assistance, direction, and support in developing the narrative strategies.

Conflicts of Interest

The authors declare that this paper does not include any conflicts of interest.

Abbreviations

AchE Acetylcholinesterase
Akt Serine/threonine kinase
BW Body weight
cAMP Cyclic adenosine monophosphate
CVDs Cardiovascular disorders
CREB cAMP-response element protein
FBG Fasting blood glucose
GSH Glutathione
GLUT2 Glucose transporter 2
HbA1c Glycated hemoglobin
HDL High density lipoprotein
LDL Low density lipoprotein
PEPCK Phosphoenolpyruvate carboxykinase
PKA Protein kinase A
ROS Reactive oxygen species
TC Total cholesterol
TG Triglyceride
VLDL Very low-density lipoprotein

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Preprints 78025 g001
Figure 1. Antidiabetic effects of 20 medicinal plant-based foods on body weight and cells and organs associated with diabetes (pancreas, blood vessels, intestine, liver, skeletal muscle, adipose tissue, β-cells). Medicinal plants decrease body weight and body fat by initiating lipolysis; decrease glucose production by inhibiting gluconeogenesis and glycolysis in liver; decrease blood glucose levels by binding to insulin receptor substrate (IRS-1); decrease blood lipid levels by inhibiting HMG-CoA reductase; promote glucose uptake and enhance GLUT-4 expression by activating the AMPK pathway in skeletal muscles; inhibit α-glucosidase and α-amylase enzymes and decrease glucose absorption in the small intestine; improve insulin sensitivity/secretion, improve β-cell function and lower insulin resistance by activating PPAR-γ expression in the pancreas; decrease IL-6/TNF-α and enhance glucose uptake by activating AMPK in adipose tissues; decrease ROS/free radicals/AGEs, oxidative stress and inflammatory cytokines in β-cells through antioxidant/radical scavenging activity.
Figure 1. Antidiabetic effects of 20 medicinal plant-based foods on body weight and cells and organs associated with diabetes (pancreas, blood vessels, intestine, liver, skeletal muscle, adipose tissue, β-cells). Medicinal plants decrease body weight and body fat by initiating lipolysis; decrease glucose production by inhibiting gluconeogenesis and glycolysis in liver; decrease blood glucose levels by binding to insulin receptor substrate (IRS-1); decrease blood lipid levels by inhibiting HMG-CoA reductase; promote glucose uptake and enhance GLUT-4 expression by activating the AMPK pathway in skeletal muscles; inhibit α-glucosidase and α-amylase enzymes and decrease glucose absorption in the small intestine; improve insulin sensitivity/secretion, improve β-cell function and lower insulin resistance by activating PPAR-γ expression in the pancreas; decrease IL-6/TNF-α and enhance glucose uptake by activating AMPK in adipose tissues; decrease ROS/free radicals/AGEs, oxidative stress and inflammatory cytokines in β-cells through antioxidant/radical scavenging activity.
Preprints 78025 g001
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