Flavonoids, alkaloids and terpenoids: a new hope for the treatment of diabetes mellitus

Abstract

Diabetes mellitus is a metabolic syndrome characterized by a hyperglycemic state and multi-organ failure. Millions of people worldwide are suffering from this deadly disease taking a hit on their pocket and mental health in the name of its treatment. Modern medical practices with new technological advancements and discoveries have made revolutionary changes in the treatment. But, unfortunately, Glucose-lowering drugs used have many accompanying effects such as chronic vascular disease, renal malfunction, liver disease and, many skin problems. These complications have made us think about alternative treatments for diabetes with minimum or no side effects. Nowadays, in addition to modern medicine, herbal treatment has been suggested to treat diabetes mellitus. These herbal medicines contain biological macromolecules such as flavonoids, Terpenoids, glycosides, and alkaloids, which show versatile anti-diabetic effects. These phytochemicals are generally considered safe, and naturally occurring compounds have a potential role in preventing or controlling diabetes mellitus. The underlying mechanism of their anti-diabetic effects includes improvement in insulin secretion, decrease in insulin resistance, enhanced liver glycogen synthesis, antioxidant and anti-inflammatory activities. In this review, we have focused on the mechanism of various phytochemicals targeting hyperglycemia and its underlying pathogenesis.

Introduction

Diabetes mellitus is a metabolic syndrome with presenting feature of hyperglycemia, associated with multiple vascular and non-vascular complications [14]. The disease is widely contributing to the socioeconomic burden of 174 billion US$ in developing and developed countries [23]. A recent study reveals that 415 million people currently surviving with this disease, and more than 1.6 million people die every year; 642 million people could have diabetes by the end of 2040 [26, 35]. Inflammation and oxidative stress are the chief contributing factors involving pathological processes of both type-1 and type-2 diabetes mellitus. Chronic hyperglycemia is the key player behind increased polyol pathway, hexosamine pathway, protein kinase activity, protein glycosylation, and decreased antioxidant mechanism resulting in excessive production of reactive oxygen (ROS) and nitrogen (NOS) species [59]. Oluwafemi Omoniyi Oguntibeju has shown that hyperglycemia-induced oxidative stress caused vascular damage, the release of Proinflammatory cytokines, and growth factors. Activated inflammatory markers are significant factors to initiate and develop diabetes-associated complications, including retinopathy, renal malformation, neuropathy, cardiovascular and cerebrovascular disease, etc. [18]. Moreover, the various drugs approved by different regulatory bodies used in diabetes mellitus are associated with secondary complications like cardiovascular complications, kidney disease, liver injury, and skin disease [26]. So, it is thought essential to investigate some natural plant-derived bioactive compounds in the treatment and management of diabetes mellitus with fewer complications and side effects. In this review, we will understand the mechanism of various phytochemicals targeting hyperglycemia and underlying pathogenesis.

Pathogenesis of type 2 diabetes mellitus

There are four major elements in the pathogenesis of Diabetes mellitus which are; (1) Oxidative stress, (2) Inflammation, (3) mitochondrial dysfunction, (4) Autophagic dysfunction.

Oxidative stress and diabetes

Oxidative stress in the body is caused by free radicals and non-radicals reactive derivatives called oxidants. Oxidants in cells are divided into two categories, i.e., Reactive oxygen species (ROS) and reactive nitrogen species (RNS). O2, OH, H2O2, HOCl is reactive oxygen species, whereas NO, NO2, OONO- are the reactive nitrogen species mainly responsible for oxidative stress [28]. Biological free radicals are generated due to regular cellular metabolism, having unpaired electrons, making them highly unstable and reactive. These radicals damage biomolecules such as lipids, proteins, and also DNA. Free radicals can either be beneficial or detrimental for the living system [69].

From previous studies, it is evident that a high concentration of radicals causes oxidative stress, damaging cell structure. A set of experiments conducted on both humans and rodents has shown elevated oxidative stress markers establishing a direct link between diabetes and oxidative stress. The hyperglycemic state not only increases lipid peroxidation product (MDA), proteins carbonyl, 8-(OH)-2-deoxyguanosine but also reduces antioxidant enzyme GPX, CAT, and reduced glutathione activity [47]. A significant elevated oxidative stress was seen in cell culture studies using pancreatic beta cells, along with decreased expression in mRNA of insulin gene [21, 41]. Oxidative stress is highly suspicious with chronic hyperglycemia-induced insulin resistance. Experimental and clinical studies have shown that oxidative stress is involved in the pathogenesis of DM and several other diseases such as cardiovascular diseases and carcinogenesis and neurodegenerative disorders (Parkinson’s, Alzheimer’s, Huntington’s, etc.) [28]. Prolonged exposure of both human and animal cells and tissues to hyperglycemia is known to result in non-enzymatic glycation of proteins, and the end products such as Schiff base and Amadori products culminates in the production of reactive oxygen species (ROS) [31, 57, 60]. Chronic hyperglycemia is a principal factor in promoting the development of microvascular and macro-vascular complications in diabetes, and hyperglycemia is known to be responsible for the damage of DNA, lipids, and proteins. There is a link between the degree of damage and hyperglycemic-induced production of reactive oxygen species and, consequently, oxidative stress [4].

Studies on the level of 8-hydroxy-2-deoxyguanosine modified proteins in GK-rats and Tucker diabetic rats by Akash et al. and Tanaka et al. [60, 64] respectively showed that hyperglycemia is a leading potential factor of oxidative stress in pancreatic beta-cells and that glucose-induced oxidative stress explains the mechanism behind glucotoxicity. To study the effect of oxidative stress in type-2 diabetes, the diabetic clinic at Charles sturt university, Australia, recruited 309 persons with diabetes and compared them with a control group that included non-diabetic individuals. The control group was normoglycemic, normotensive, and had no history of diabetes and cardiovascular disease. The comparison showed an increased level of glycosylated Hb, lipid biomarkers in individuals who have diabetes concerning the non-diabetic group. Thus, this study supported both direct and indirect links between diabetes mellitus and oxidative stress induced by hyperglycemia and the progression of diabetes due to the hyperglycemic state of cells [58].

Inflammation and diabetes

Insulin resistance, T2DM, has been a well-known inflammatory state involving innate and acquired immunity [14]. Various studies have shown that blood glucose levels and anti-inflammatory agents can improve pancreatic β-cell function in T2DM. The primary link between T2DM and inflammation are inflammatory cytokines, i.e., macrophage mediators, tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6). Previous studies have confirmed the increased amounts of these cytokines in diabetes mellitus [63].

Thus, type-2 DM is related to increased expression of markers of chronic inflammation in a diabetic patient who has a severe complication of both the micro and macrovascular system. Macrovascular complications from cardiovascular disease are life-threatening; about 80% of diabetic patients lose their life from coronary artery and other complications associated with it [12, 22]. Adipocytes, when acted upon by macrophages and endothelial cells, release key chemokines known as MCP-1. MCP-1 circulating in adiposity contributes to increased expression of the Proinflammatory cytokines prevents inflammation related to type-2 diabetes [16].

White adipose tissue release very crucial anti-inflammatory cytokine adiponectin. Its level decreases due to obesity and inflammation during type-1 diabetes [40]. Advanced glycation end products (AGEs) were known as oxidative derivatives formed due to diabetic hyperglycemia. It is believed that AGEs can be a risk factor for pancreatic islet cell injury and type-2 diabetes. They significantly increase the expression of inflammatory markers and oxidative markers in diabetes. It also impairs the production, function of insulin [70].

Many clinical and preclinical studies suggest that significant sites of inflammation in diabetes are adipose tissue, liver, muscles, and pancreas Mellitus (T1DM) [39]. In diabetes-induced animal models and obese patients who have diabetes, infiltration of macrophages into adipose tissue, liver, muscle, and pancreas is seen. Macrophages play an essential role in producing proinflammatory cytokines, i.e., TNF-α, IL-6, IL-1β, and other inflammatory mediators. These mediators work in both autocrine and paracrine ways and stimulate insulin resistance as they interfere with insulin signalling in peripheral tissues by activating different inflammatory associated pathways like nuclear factor-kappa B (NF-κB) and c-JUN N-terminal kinase (JNK) pathways [3, 10]. The NF-κB is the principal inflammatory switch that controls the active protein series such as Iβ, IL-1α, IL-1, and TNF-α for the activation and maintenance of the inflamed state. Thus, researchers have proven that inflammation is a marker and is also a disease mediator.

There are two separate categories of immune cells, macrophage activated classically are M1 phenotype that helps in the formation of the majority of proinflammatory cytokines TNF-α, IL-6, IL-1β, and the “alternatively activated macrophages” phenotype, termed M2, which produces major anti-inflammatory cytokines, IL-10 [7]. Furthermore, infiltration of macrophages to adipose tissue switch M2 phenotype to M1 phenotype, associated with insulin resistance in animals and humans [11]. The M1 macrophages can modify insulin signalling pathways and adipogenesis. M2 macrophages seem to protect against insulin resistance induces by obesity [3].

Increased expression/production of TNF-α in adipose tissue is observed in obese individuals, and it is playing a vital role in obesity-induced insulin resistance [55]. Previous findings have confirmed a specific up-regulation of inflammatory genes and an over-production of numerous proinflammatory cytokines and chemokines in inflamed adipose tissue [39]. Furthermore, improvement in insulin sensitivity induced by weight loss is accompanied by a reduction in the expression of multiple proinflammatory genes [5, 39]; Therefore, inflammation in adipose tissue is considered as a necessary consequence leading to T2DM and its complications.

Mitochondrial dysfunction and diabetes

It is suggested that mitochondrial dysfunction is one of the underlying reasons contributing to insulin resistance and T2DM. Mitochondrial dysfunction leads to lipids intermediate accumulation fallowed by desensitizing insulin signalling and ultimately causing insulin resistance.

Obesity, which is characterized by fat deposition in non-adipose tissues like the liver, heart, and muscles, harms health. For individuals with a sedentary lifestyle, fat deposition in the liver and skeletal muscles is related to insulin resistance, inclining towards the development of T2DM [23]. In 2002, the issue of mitochondrial dysfunction in T2DM was raised by Kelly et al. The authors observed alteration in morphology of mitochondria, reduced size, increased no, of damaged mitochondria in T2DM. A positive correlation was found between mitochondrial surface area and insulin-stimulated glucose disposal. Additionally, they reported the reduced activity of rotenone sensitive NADH, O2 oxidoreductase that reflects the overall activity of the respiratory chain and citrate synthesis in a patient with T2DM [47]. Micro-array studies shown that mRNA expression of genes encoding for proteins involved in mitochondrial metabolism was slightly but gradually less expressed in muscles of T2DM patients or their Ist degree relatives, most of these genes are controlled by transcription co-activator PGC1α, which was also found reduced in T2DM patient and family history positive non-diabetic [21, 41].

A group of proteins known as uncoupling proteins (UCPs) plays a significant role in reducing proton gradients. UCP-1 is exclusively expressed in brown adipose tissue, UCP-2 is commonly present, while UCP-3 shown expression in skeletal muscles. UCP-1 makes up to 10% of membrane proteins and regulates adaptive thermogenesis; mice, when subjected to UCP-2,&3 genetic ablation, show a normal response to cold, average basal proton conductance, and normal body weight [25, 63]. Although over-expressed UCP-2&3 lower the production of ROS, these also stimulate metabolic rate & provides protection against weight gain and insulin resistance [12]. In addition, severe oxidative damage is seen in UCPs knockout mice [16]. These findings suggest that UCPs play a vital role in mitochondrial function by regulating heat & ROS production. The functioning of mitochondria for energy balance is crucial for normal physiology and cellular function.

Autophagic dysfunction and diabetes mellitus

Autophagy is a molecular mechanism that maintains the physiology of cells & and promotes survival. Autophagic defects lead to the etiology of numerous diseases, such as diabetes mellitus, cancer, neurodegenerative disorders, aging, and infectious disease. Diabetes mellitus is a chronic metabolic disease with higher frequency in the world as well as in India. Recent studies show the involvement of Autophagic machinery in the pathophysiology of type-2 DM. & regulation of beta cells to function normally. On the other hand, enhanced autophagy is an important protective mechanism against oxidative stress on insulin-targeted tissue such as adipose tissue, liver, and skeletal muscles [31, 72]. Autophagy is characterized by an increase of double-membrane vesicles (also known as autophagosomes or Autophagic vesicles) and degradation of Golgi. Autophagy promotes cell survival in response to stress; however, once autophagy is overstimulated, cells can progress to autophagic cell death. There are four stages in the autophagic process: (1) induction, (2) vesicle nucleation, (3) autophagosome membrane elongation, and (4) termination/fusion and degradation. Autophagy regulates the function of pancreatic beta cells and insulin-target tissues (skeletal muscle, liver, and adipose tissue). T2D progression through impaired pancreatic beta-cell function and development of insulin resistance is associated with autophagy [34, 53]. Many studies suggest that enhanced autophagy acts as a protective mechanism against oxidative stress in pancreatic beta cells [34, 61]. In vivo studies demonstrated that Atg7-deficient mice showed a decrease in the number of pancreatic beta cells, glucose tolerance impairment, and insulin secretion reduction [43]. The insulin-resistant mice (beta-cell-specific Atg7 knockout mice) model shows that autophagy plays a crucial role in the development of Diabetes and in preserving the structure and function of pancreatic beta cells. Accumulation of autophagosomes in the pancreatic beta-cell was demonstrated in the db/db mouse model [24, 46, 50]. Fujitaniet al. showed that reduced insulin secretion was associated with pancreatic beta-cell degeneration and impaired glucose in autophagy-deficient mice [20, 24]. However, constitutively activated autophagy has injurious effects on pancreatic beta cells, and chronic activation of autophagy causes autophagic cell death [15, 46, 54].

Phytochemicals vs. diabetes

Lots of glucose-lowering drugs are used in the management of Diabetes mellitus. They worked on different mechanisms like stimulating insulin secretion, increasing peripheral absorption of glucose, delay in the absorption of carbohydrates from the intestine, and reducing hepatic gluconeogenesis [32]. However, these drugs had many disadvantages like drug resistance, side effects, and toxicity [17]. So nowadays addition to these drugs, herbal treatments are also suggested for diabetes management. These herbal drugs contain carotenoids, flavonoids, terpenoids, alkaloids, and glycosides which showed anti-diabetic effects [1, 45]. The mechanism of these drug’s actions is usually improving insulin secretions or reducing the intestinal absorption of glucose. Following are the categories of phytochemicals, having a potential role in controlling and preventing diabetes mellitus.

Flavonoids

The phenolic compound isolated from the medicinal plant has excellent hypoglycemic effects shown in Table 1. are also having other pharmacological responses like antiviral, antioxidant, antihistamine, anticancer, and anti-inflammatory properties [71]. The primary underlying mechanism of the anti-hyperglycemic effect of isolated flavonoids are via the binding to peroxisome proliferator-activated receptor gamma (PPARγ) and glucose transporter 1 (GLUT1) receptors stimulating lipid metabolism, glucose uptake, increased insulin action on glucose utilization, and improved glucose tolerance in diabetic animals and humans [42].

Table 1.

Hypoglycemic flavonoids and underlying effects

Medicinal plant	Flavonoid Compound	Mechanism/ effects
Ampelopsis grossedentata (Vitaceae) [9]	Semi-synthesized myricetin analog	• Help to inhibit the action of α-glucosidase activity by competitive inhibition and also help to improve post-prandial blood glucose levels.
Ficusracemose L. (Moraceae) [42]	Kaempferol (FR6), quercetin (FR7), naringenin (FR8) and baicalein (FR9)	• Help to maintain normal BMI and blood glucose levels • Enhanced glycogen synthesis in the liver and also help to improve SGOT and SGPT levels.
Glycyrrhizaglabra L. and glycyrrhiza sp. (Fabaceae). [75]	Glabridin	• Help to maintain BMI, glucose tolerance and SOD activities in the liver, kidney and pancreas • Significantly reduced FBG levels and MDA content in the liver, kidney and pancreas
Jatrophagossypifolia L. (Euphorbiaceae) [27]	5,7,40-trihydroxy-30,50-dimethoxyflavanone	• Increase glucose intake in insulin-resistant cells • Flavanone-containing fraction treatment significantly reduced the curve of glucose tolerance in diabetic mice
Malustoringoides (Rosaceae) [48]	Flavonoid extract	• Significantly increased serum insulin and c-peptide • Significantly elevated SOD activity and reduced MDA level in the liver.
Mangifera Indica L. (Anacardiaceae) [29, 62, 81]	Mangiferin	• Improves glucose and lipid metabolism by increasing the number of insulin-positive b cell mass. • Increased phosphorylation of AMPK in 3T3-L1 cells help to uptake glucose. • Activates AMPK in both LKB1-dependent and -independent manner • decreases in protein expression of type IV collagen and smooth muscle actin in the kidney of this help to prevent renal glomerulus fibrosis. • Reduced the levels of IL-1β in the serum and kidney.
Myricarubra (Lour.). (Myricaceae) [80]	Cyanidin-3-O-glucoside, quercetin-3-O-galactoside, quercetin-3-O-glucoside and quercetin-3 Orhamnoside	• increased glucose uptake in the cells
Oxytropis falcate Bunge (Fabaceae) [76] Puerarialobata (Fabaceae) [33] Vexibiaalopecuroides (Fabaceae) [78]	Total flavonoid	• Improve FBG and postprandial 2-h plasma glucose. • Increased insulin level. • Reversed the changes in increased MCP-1, TNF-α, IL-6, IRS-1 and p-IRS-1 in diabetic rats • Reversed the changes in decreased of PKB, p-PKB, PI3Kp85 and p-PI3K expression in diabetic rats • Reduced serum MDA level • Increased the lactic-pyruvic acid redox potential and liver glycogen level, Lipid metabolism, antioxidant protection system and peroxidation processes showed a distinct tendency to normalize

Alkaloids

Alkaloids are nitrogenous chemical compounds with two carbon atoms and a heterocyclic structure. Alkaloids Compounds like Berberine, Nigelladines, coptisine, palmatine, epiberberine, Vindogentianine, Vindoline, vindolidine, vindolicine, and vindolinine, and jatrorrhizine is summarized in Table 2.

Table 2.

Hypoglycemic alkaloids isolated from medicinal plants

Medicinal plant	Alkaloids isolated	Mechanism/ effects
Catharanthusroseus (Apocynaceae) [66, 67, 79]	Total alkaloid extract Vindogentianine, Vindoline, vindolidine, vindolicine and vindolinine	• Enhanced the insulin level and helps to decrease FBG • Improve ALT, AST and ALP levels • Enhanced the action of GSH, SOD, CAT. • Increase the cellular uptake of glucose
Coptischinensis Franch (Ranunculaceae) [13, 19, 38, 51]	Berberine,coptisine, palmatine, epiberberine jatrorrhizine,and Berberine nano-suspension	• Enhanced the secretion of insulin • Improved impaired glucose tolerance and decreased plasma Hyperlipidemia • Decreased fasting plasma insulin and homeostasis model assessment of insulin resistance • Up-regulated protein expression of liver kinase, AMPK, p-AMPK and p-TORC2 • Down-regulated protein expression of gluconeogenic Enzymes Inhibited high glucose-elevated nitrotyrosine level, reduced SOD-1 and UCP2 expression and AMPK phosphorylation in INS-1E cells • decreased insulin secretion in diabetic islet • Promoted glucose uptake of HepG2 cells • Improve BMI
Morus alba L. (Moraceae) (US9066960B2 - Use of the effective fraction of alkaloids from mulberry twig in preparing hypoglycemic agents - Google Patents [68]	Effective fraction of alkaloids, SZ-A	• Significant inhibits the action of sucrase and maltase • Significantly decreased HbA1c, 1- and 2-h postprandial plasma glucose levels • Have less gastro-intestinal adverse effects.
Nigella glandulifera Freyn&Sint. (Ranunculaceae) [8, 65]	Nigelladines A-C and Nigellaquinomine	• Exhibited potent PTP1B inhibitory activity • No apparent cytotoxicity on the A431 cell line at 100 l M • Increased glucose consumption, lactic acid production, glycogen synthesis and hexokinase activity in L6 myotube • Activated PI3 K-dependent Akt phosphorylation Induced insulin receptor substrate-1 and glycogen synthase kinase-3b

Terpenoids

Terpenoids are the most diverse class of phytochemicals with various functions, like light-harvesting pigments, hormones, phytoalexins, and semi-chemicals. They are obtained from the universal five-carbon building blocks. The summary of some Terpenoids is shown in Table 3.

Table 3.

Hypoglycemic terpenoids isolated from medicinal plants

Medicinal plant	Terpenoids isolated	Mechanism/Effects
Momordicacharantia L. (Cucurbitaceae) [6, 37, 77]	Ginseng extract and ginsenosides	• Improve pancreatic β cell function • Increased the secretion of insulin from islet β-cell and promoted β-cell migration•
	Compound K16, Cucurbitanetriterpenoids 3β,25-dihydroxy 7βmethoxycucurbita- 5,23(E)-diene 3β,7β,25-trihydroxycucurbita-5,23(E)- dien-19-al	• Helps to improve glucose tolerance. Up-regulated the expression of the insulin receptor, insulin receptor substrate 1, glycogen synthase kinase 3β, Akt serine/ threonine kinase, and the transcript levels of GLUT4 and AMP-activated protein kinase. • Shows α-glucosidase inhibitory activity • Increased the tyrosine phosphorylation of insulin receptor substrate isoform 1 and the phosphorylation of Akt only in the presence of insulin • Enhanced phosphorylation of Akt substrate, migration of GLUT4 and the glucose uptake in the absence of insulin
Prosopisjuliflora (Fabaceae) [30]	24-methylencycloartan-3-one	• Help to decrease blood glucose levels and also non-toxic to red blood cells
Salvia urmiensis Bunge (Lamiaceae) [2]	Essential oil from aerial parts	• Inhibits α-amylase and α-glucosidase activities
Common aglycone of many saponins [36, 56, 73]	Oleanolic acid	• Improves hepatic insulin resistance • Inhibits mitochondrial oxidative stress via activation of Nrf2-GCLc signal • Suppresses hepatic lipid accumulation and inflammation • Increased p-glycogen synthase expression in the skeletal muscle of diabetic rats and decreased glycogen phosphorylase expression • Significantly decreased villus height in the duodenum of diabetic rats • Decreased diabetic-induced elevated alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase activities

Phytochemicals and toxicity

Consuming Phytochemicals are believed to be safe because they are naturally occurring compounds. However, this is not always true for every plant-origin chemical compound. Some of them may act as a pro-oxidant, on further metabolism in the body, they can show some potential toward oxidative damage leading to the development of cancers or tumors. Since there is no published report on the toxic potential of plant-derived biomolecules in the relevance of type 2 diabetes mellitus, there is a growing body of evidence supporting the safety of these phytochemicals in the treatment of type 2 diabetes mellitus.

Phytochemicals as future antidiabetic agents

Phytochemicals have low absorption and are limited in nature, so researchers may implant several strategies to increase the stability and bioavailability of phytochemicals, i.e., absorption enhancer, self-microemulsion, and solid lipid nanoparticles [49, 74]. Furthermore, phytochemicals are the natural compounds from which new and more effective drugs can be formulated for DM treatment in the place of metformin which is considered as the first-line drug for the management of type 2 DM because metformin had many side effects, including gastrointestinal disorders like diarrhoea, flatulence, and abdominal discomfort [44] (Fig. 1).

Fig. 1.

Mechanistic pathways of diabetes and management by Photochemicals

Declarations

Conflict of interest

The authors declared that they have no conflict of interest. 

Ethical clearance

Not applicable.