Introduction

Diabetes is a heterogeneous metabolic disease that is described by hyperglycemia as a result of impaired insulin secretion, insulin action or both (Punthakee, Goldenberg, & Katz, 2018). Impaired insulin secretion and insulin resistance contribute more or less jointly to the development of pathophysiological conditions. Impaired insulin secretion is a drop in insulin release, observed before the disease’s clinical onset. Mainly, impaired glucose tolerance is caused by lowered early-phase insulin release as well as decreased postprandial insulin secretion causing hyperglycemia. Progression of the impaired pancreatic β-cell functions influences the blood glucose control on the long-term, as it subsequently causes permanent elevation of blood glucose as depicted in Figure 1.

Insulin resistance is when insulin does not perform sufficiently in the body, proportional to its blood level. Impaired insulin activity in main target organs; for instance, liver and muscles is a common diabetic pathophysiological attribute which was revealed to be related to genetic and environmental factors (Kaku, 2010).

Morbidities and mortalities

Globally, about 5.1 million deaths of people between 20-79 years old occurred from diabetes in 2013, with a mortality of 8.4% in people from this age group (Fareed, Salam, Khoja, Mahmoud, & Ahamed, 2017). Based on (WHO, 2016), diabetes caused the death of 1.5 million people worldwide in 2012; moreover, it was the 8^th chief death cause among both genders and the 5^th chief death cause in females. Additionally, the higher-than optimal blood glucose resulted in 2.2 million deaths. The diagnostic standard is fasting blood glucose (≥7.0 mmol/L, a diagnostic point for microvascular complications). However, the risk of macrovascular diseases, e.g. stroke begins to increase yet before the diagnostic point.

Prevalence

Diabetes percentage was observed to rise rapidly in countries with low and middle income. The prevalence worldwide among the adults has increased from 4.7% in 1980 up to 8.5% in 2015. By 2030, it’s estimated that prevalence will rise from 366 million up to 552 million (Sherif, 2015).

The International Diabetes Federation revealed that Egypt is the ninth country for the highest numbers of patients with diabetes. At the last two decades, diabetes percentage in Egypt was tripled due to elevation in risk factors for type II diabetes. In Egypt, diabetes prevalence around 15.6%, including all adults from age 20 up to 80 years old. The prevalence was estimated to increase from 3.24 million in 1995 to 3.8 million in 2025 with increasing 3.6 times in patients less than 65 years old (Hegazi, El-Gamal, Abdel-Hady, & Hamdy, 2016).

Risk Factors

Demographic risk factors

According to (Ley, Schulze, Hivert, Meigs, & Hu, 2015), the prevalence of diabetes escalates with age, as in most populations, its incidence is low before the age of 30 years but rises quickly and continuously with older age. Risk of diabetes is more significant in males compared with females as observed consistently in various European countries. In a study, a self-reported Asian, Hispanic, and black ethnicities were related to a greater risk of diabetes compared to whites.

Genetic risk factors

There are individual variations regarding the susceptibility towards environmental risk factors which can affect modifiable risk factors for T2DM (Ley et al., 2015). Development of Type II diabetes is associated with a family history of diabetes. The pathogenesis has been assumed to involve a genetic abnormality in molecules related to the regulatory system of glucose metabolism; for instance, genetic abnormalities in insulin receptor and glucokinase genes (Kaku, 2010).

Behavioural and lifestyle risk factors

Diet was believed to be the primary lifestyle risk factor for T2DM. Still, several studies concerning diet associated with the incidence of diabetes investigated the roles of nutrients, foods, and dietary patterns on its progression. Physical inactivity and sedentary behaviours are also a risk factor. Exercises (moderate to high intensity) are shown to have advantageous effects on T2DM prevention (Ley et al., 2015). Excess body fat is the most decisive risk factor in which overweight and obesity, together with physical inactivity, are estimated to cause a large proportion of the global diabetes burden (WHO, 2016).

Moreover, babies who suffered intrauterine exposure to maternal diabetes (i.e. gestational diabetes) are most probable of experiencing several problems in their early adulthood, like childhood overweight and impaired glucose tolerance.

Given that obesity and impaired glucose tolerance are risk factors for gestational diabetes in young adults, which is expected to contribute to the elevating rates of gestational diabetes and consequently, T2DM (Ley et al., 2015).

Also, studies indicated a link between income and prevalence of diabetes (higher income indicates having better access to goods and services, leading to an affordable and healthier lifestyle). Active smoking increases the risk of diabetes (highest risk among heavy smokers). The risk remains elevated for about ten years after smoking cessation, which decreases rapidly for lighter smokers (WHO, 2016).

Complications

Microvascular complications

According to (Møller, 2016), microvascular complications may arise such as;

Hyperosmolar Hyperglycemic State

Resulting from insulin deficiency or complete absence of insulin secretion, characterized by increasing in glucagon release.

Diabetic Retinopathy

Occurs due to many pathological mechanisms, including elevation of oxidative stress and hyperglycemia, stimulates sugar molecules flux through the polyol pathway.

Diabetic Neuropathy

Precise mechanism is still unclear but may be related to oxidative stress and accumulation of polyol due to advanced glycation products.

Diabetic Nephropathy

Occurs due to glomerular proteins glycosylation, leading to the proliferation of mesangial cells, damage of vascular endothelium.

Macrovascular complications

It includes angina, high blood pressure, heart attacks and stroke. This results from resistance of insulin and excess free fatty acids which causes protein kinase activation and advanced glycation end products receptor activation. This could be expressed in gastroparesis -which leads to damage of vagus nerves- and peripheral vascular disease “The diabetic foot” that occurs due to alteration in coagulation pathway, serum protein glycation, and modulation in levels of insulin/proinsulin. In addition to, healing impairment, as hyperglycemia leads to impairment in white blood cells function, reduced immunity, and low blood circulation.

Signs and symptoms

According to (Ambady, Snehalatha, Shetty, & Nanditha, 2013), early signs include weight loss, irritability, frequent fatigue and infections (especially in the oral cavity, genital tract, urinary tract, and skin), the appearance of dark patches on the neck, and groin (an indication for insulin resistance). The symptoms extend to extreme tiredness, polyuria, polydipsia, polyphagia, genital itching and regular episodes of thrush, delayed wound healing, tingling, or numbness, in the hands or feet, and blurred vision.

Diagnosis and monitoring

The diagnosis of DM comprises blood glucose concentration, fasting blood sugar test, glucose tolerance test and glucose in urine. In addition to tests for gestational diabetes, i.e. the initial glucose challenge test. It could be monitored by Glycated Hemoglobin (A1C) test as a widely used marker of chronic glycaemia, reflecting average blood glucose levels over a 2 to 3 months’ period of time. As well as, Serum Fructosamine, which is a glycated serum protein, giving a reliable estimate of blood glucose level during preceding 1-3 weeks (Wild, Roglic, Green, Sicree, & King, 2004).

Conventional treatments for T2DM

Biguanides

The first line of T2DM treatment is Metformin. Biguanides reduce glucose absorption from the intestine, enhance uptake of glucose peripherally, increase sensitivity to insulin and inhibit gluconeogenesis as depicted in Figure 2.

Thiazolidinediones

TZDs are insulin sensitizers acting on insulin-sensitive tissues (liver, adipose tissues and muscle cells) to decrease glucose production and increase its utilization as shown in Figure 2. TZDs bind to specific nuclear receptor Peroxisome Proliferator Activator Receptor-Gamma (PPAR-γ) which induces the synthesis of insulin signalling cellular molecules, e.g. GLUT-4 and Lipoprotein lipase enzyme.

Sulphonylureas and Glinides (Insulin releasers)

These are oral hypoglycemic acting by stimulating pancreatic β-cells to release insulin as illustrated in Figure 2. Mechanism of both classes depends on potassium ATP-sensitive channel (KATP-potassium channel) localized in beta cells of the pancreas. Both have different binding sites on the receptor, but they stimulate cell depolarization and channel closure leading to an increase in calcium level in cytoplasm and insulin secretion consequently (Marín-Peñalver, Martín-Timón, Sevillano-Collantes, & Cañizo-Gómez, 2016).

Dipeptidyl peptidase-4 inhibitors

Incretin hormones (GLP-1 and GIP), as shown in Figure 2, are secreted by L-cells in the intestine, stimulates insulin secretion and inhibit the release of glucagon. Agents that block DPP-4 action (known as gliptins) inhibit this enzyme which inactivates the incretins rapidly, increasing the duration of active incretin level which in turn enhances β-cell function and T2DM glycemic control (Barnett, 2006).

Alpha-glucosidase inhibitors

Agents from this class comprise Acarbose, Miglitol and Voglibose. They reversibly inhibit alpha-glucosidase hydrolase enzyme; inhibiting carbohydrates digestion and absorption in the brush border membrane of the small intestine as shown in Figure 2, which reduces postprandial hyperglycemia (Marín-Peñalver et al., 2016).

Sodium-glucose co-transporter-2 inhibitors

Such as Canagliflozin, Dapagliflozin and Empagliflozin. It is the most recent class in T2DM treatment, works by inhibition of renal glucose reabsorption, increase glucose excretion and reduce hyperglycemia as shown in Figure 2. They block, in the proximal tubule, SGLT2 transporter which is responsible for 90% reabsorption of glucose (Kalra, Sahay, & Gupta, 2015).

Herbal treatments for T2DM

Plants possessing anti-diabetic potentials

According to Prabhakar and Doble (2011), there are quite a variety of mechanisms and pathways that could be targeted while considering the treatment of T2DM; ranging from acting on pancreatic insulin, decreasing carbohydrates digestion, to inhibiting enzymes responsible for this disease.

Another aspect to focus on in diabetes treatment is insulin resistance, which is mainly to increase the sensitivity of insulin receptors in cells to insulin by insulin sensitizers. However (Alam, Shafique, Amjad, & Asad, 2019) mentioned other ways of treatment which are acting on pancreatic β-cells (Malviya, Jain, & Malviya, 2010; Patel, Prasad, Kumar, & Hemalatha, 2012; Ríos, Francini, & Schinella, 2015) and increasing insulin secretion, β-cell regeneration, enzymatic modulation and other different activities as shown in Table 1 and Figure 3 (Choudhury et al., 2018; Hawary, Saad, Halawany, Ali, & Bishbishy, 2016; Verma, Gupta, Popli, & Aggarwal, 2018).

Recently, discovering and investigating enzymes that are directly involved in the diabetic pathway has been taken into full consideration. Thus, they are modulated (inhibited/stimulated) to treat and manage the disease (Alam et al., 2019) as shown in Figure 4.

Bioactive metabolites possessing anti-diabetic activity

In-depth study of the plants leads to the identification of the bioactive metabolites that are responsible for the anti-diabetic effect. These metabolites belong to different classes including, phenolic compounds, flavonoids, alkaloids and saponins.

Phenolic compounds and flavonoids act by several pathways including the inhibition of renal glucose reabsorption, decreasing oxidative stress leading to protection of β-cells, stimulating insulin secretion and decreasing its resistance, enhancing glucose consumption and homeostasis, stimulating glycolysis, inhibition of gluconeogenesis, improving the signalling of cAMP, increasing glucose tolerance. Also, they act through the inhibition of α-glucosidase, maltase fructose-1,6-bisphosphatase, G6Pase and PTP1B enzymes and increasing GLUT-2 and GLUT-4 translocation (Ezzat et al., 2018). Similar mechanisms were also reported (Venable et al., 2000) for the alkaloids isolated from different plants (Table 2) (Ali, Jung, & Choi, 2015; Trojan-Rodrigues, Alves, Soares, & Ritter, 2012; Vanitha et al., 2014). In addition to some saponins like pseudoprototinosaponin AIII and prototinosaponinsAIII and gymnemic acid, which stimulate insulin synthesis and release from pancreatic β-cells, and lupine and protopanaxadiol, which inhibit PTP1B.

Discussion

T2DM is a metabolic condition that is known by high blood glucose levels because of insulin resistance as well as impaired insulin secretion from pancreatic β-cells. This disease caused the death of approximately 5.1 million people aged between 20-79 years in 2013, accounting for 8.4% mortality of people from this age group (Fareed et al., 2017). Its incidence was estimated to increase up to 552 million in 2030 (Sherif, 2015). It was observed to rise rapidly in countries of low and middle income. At the same time, the prevalence in Egypt in the last two decades was tripled due to the spread of wrong lifestyle and risk factors. Egypt was categorized by international diabetes federation as a ninth country having the highest numbers of diabetic patients (Hegazi et al., 2016). However, diabetes involves various risk factors, including demographic, genetic and, behavioural and lifestyle risk factors (Ley et al., 2015).

According to (Møller, 2016), diabetes complications are divided into microvascular and macrovascular. Microvascular complications include diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and hyperosmolar hyperglycemic state. Diabetic neuropathy mechanism is still unclear, but it may be due to polyol accumulation and oxidative stress. Diabetic nephropathy occurs due to glycation of glomerular protein. Diabetic retinopathy occurs due to oxidative stress elevation and polyol pathway that causes sugar molecule flux. The hyperosmolar hyperglycemic state occurs due to deficiency of insulin and stimulation of glucagon release, while macrovascular complications include angina, stroke, heart attacks and high blood pressure. They result from an excess free fatty acid that causes activation of protein kinase. In addition to advanced glycation end products. Signs and symptoms of diabetes include irritability, weight loss, fatigue, skin patches, polyuria, polydipsia, polyphagia, genital itching, delayed wound healing, tingling, or numbness, and blurred vision (Ambady et al., 2013). Diabetes can be diagnosed by blood glucose concentration, fasting blood sugar test, glucose tolerance test and glucose in urine. However, it can be monitored via glycated haemoglobin and serum fructose-amine levels tests (Wild et al., 2004).

As genetic and environmental factors such as insulin resistance and beta-cell overwork lead to the risk of T2DM, current conventional treatment target the multiple pathophysiological defects including insulin sensitizers, insulin releasers, GLP-1 analogues, alpha-glucosidase inhibitors and SGLT-2 inhibitors. Insulin sensitizers include biguanides and thiazolidinediones that increase tissues sensitivity to insulin and reduce glycolysis. Insulin releasers include sulphonylureas that work by beta cell stimulation releasing insulin (Marín-Peñalver et al., 2016). Alpha-glucosidase inhibitors work by decreasing glucose absorption from the intestine; while DDP-4 inhibitors stimulate insulin production (Barnett, 2006). SGLT-2 inhibitors excrete excess glucose in urine (Kalra et al., 2015).

Plants have several anti-diabetic mechanisms that they work by, including insulin secretagogues, insulin sensitization, β-cells regeneration, enzyme modulation and multimodal activity (Prabhakar et al., 2011). Most medicinal plants act by unique mechanisms which are not found in conventional treatments (Choudhury et al., 2018). Regarding enzyme modulation, some plants act on enzymes which are involved in the diabetic pathway and either inhibits or stimulates them; for example, inhibiting α-glucosidase and stimulating hexokinase enzyme (Alam et al., 2019). Herbs that act as enzyme modulators (i.e. modify enzymes that contribute to glucose and insulin levels) include Momordica charantia, Brassica juncea, and Andrographis paniculata. Some herbs act through inhibition of α-glucosidase and α-amylase, which is similar to some conventional drugs. Glucosidase and amylase are enzymes that help in the breakdown of carbohydrates, thus preventing the elevation of postprandial glucose. Phyllanthus urinaria, Panex ginseng and Glycine max are examples of α-glucosidase and α-amylase inhibitors (Malviya et al., 2010).

Furthermore, herbs which stimulate the release of insulin from pancreatic β-cells include Acacia arabica, Ocimum sanctum and Aegle marmelos. Also, other herbs increase insulin sensitivity such as Cinnamomum cassia, Momordica charantia and Trigonella foenumgraecum. Both actions insulin-sensitizing and insulin secretagogues actions are found in conventional treatment; however, herbs such as Gymnema Sylvestre, Elephantopus scaber and Coriandrum sativum which improve and regenerate pancreatic β-cells function is one of the mechanisms that are not found in the conventional treatment (Verma et al., 2018).

In-depth study of the plants leads to the identification of the bioactive metabolites that are responsible for the anti-diabetic effect. These constituents belong to different classes including, phenolic compounds, flavonoids, alkaloids and saponins. For example, morin, a phenolic compound and the alkaloid vindoline act by inhibition of PTP1B enzyme, this action cannot be done by conventional treatment (Vanitha et al., 2014; Venable et al., 2000). There are also some flavonoids such as daidzein, catechin and pinobanksin, which stimulate GLUT-4 translocation (Kim et al., 2014). Besides, several constituents which act by increasing insulin release such as diosmin, kaempferol-3-neohesperidoside, apigenin and tangeretin (Trojan-Rodrigues et al., 2012).

Conclusion

The active metabolites in different plants could act by unique mechanisms of action in the treatment of T2DM, thus, providing for novel targets for anti-diabetic molecules. Further studies in this area should be enhanced to evaluate the use of these metabolites either solely or as adjunctive therapies in anti-diabetic medications. Ethnopharmacological studies could aid in the selection of medicinal plants to be employed in these preliminary studies. However, the exact bioactive metabolite, along with the definite mechanism of action, should be studied before experimental and clinical studies.

Acknowledgement

There are no acknowledgements to state.

Funding Support

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest

The authors declare no conflict of interest for this study.