INTRODUCTION

Diabetes mellitus is a chronic disease afflicting 425 million individuals worldwide, and it is expected to rise inevitably in the coming decades (IDF Diabetes Atlas 9th edition 2019). Despite significant advances in monitoring and treatment, diabetic complications continue to be a key source of morbidity and mortality (Halban et al., 2010). The defects that result in diabetes are diverse, but the failure of pancreatic β-cell is a large determinant of this disorder (Kahn, 2001). The progressive deterioration of glucose control in both type 1 diabetes (T1D) and type 2 diabetes (T2D) is mainly caused by the insufficient mass of β-cells and gradual dysfunction, which leads to diminished insulin secretion (Stumvoll et al., 2005). In T1D, immunological factors, as well as T-cells activated by immune-mediated responses damage insulin-producing β-cells (Wållberg and Cooke, 2013). T2D, on the other hand, is a degenerative condition caused by both genetic and environmental factors, resulting in insulin resistance in peripheral tissues, often culminating in β-cell death, which cannot compensate for insulin resistance (Benthuysen et al., 2016).

In T2D pancreatic β-cells are compromised or become non-functional as a result of persistently high levels of glucose and lipid, a phenomenon known as glucolipotoxicity (Weir, 2020). Endoplasmic reticulum stress, Reactive oxygen species (ROS) production, islet inflammation, mitochondrial dysfunction, increased synthesis of ceramides, and increased islet amyloid polypeptide (Fig. 1a–c) have all been proposed as mechanisms for glucolipotoxicity-induced β-cell dysfunction and death (Chang-Chen et al., 2008). Furthermore, chronic hyperglycemia can induce β-cell death by increasing the expression of proapoptotic genes, while antiapoptotic gene expression B-cell lymphoma 2 (Bcl-2) remains unaffected (Tomita, 2016). The mechanisms activated by glucolipotoxicity are strongly linked, resulting in a destructive cycle that inevitably leads to the failure of β-cells. The molecular basis of the parameters regulating β-cell mass and function, on the other hand, is a key problem for understanding diabetes, which is characterized by a near total (in T1D) or relative (in T2D) insufficiency in pancreatic β-cell number (Chen et al., 2017). Thus, the discovery of new therapeutics targeting the apoptotic process to delay or reverse β-cell death/dysfunction serves as an attractive strategy for the control of the disease (Venkatesan et al., 2011).

Figure 1. (a) Glucolipotoxicity leading to decreased β-cell mass and dysfunction: β-cells become dysfunctional as a result of glucolipotoxicity several mechanisms for glucolipotoxicity-induced β-cell dysfunction have been proposed, including endoplasmic reticulum stress, mitochondrial dysfunction, ROS production, islet inflammation, and increased islet amyloid polypeptide. Chronically elevated glucose levels stimulate glucose metabolism via oxidative phosphorylation. As a result, dysfunctional mitochondria and there is an increased production of ROS. ER stress has also been linked to increased biosynthetic demand, elevated FFA levels, and chronic-cell overnutrition. (b) Role of oxidative stress in beta cell cycle: ROS inhibits cyclin D1 and D2 expression while increasing cell cycle inhibitors such as p21 and p27, resulting in decreased beta cell proliferation. Furthermore, ROS promotes nuclear translocation of FoxO1, which inhibits the expression of Pdx-1, Ngn3, and other beta-cell related gene transcription, all of which are required for beta cell proliferation and differentiation. (c) Inflammatory response causing β-cell dysfunction: inflammatory mediators increases ER stress by activating Nicotinamide adenine dinucleotide phosphate oxidase and DMT-1. Also, these mediators stimulate the transcription of various cytokines, chemokines, and other inflammatory markers, exacerbating the inflammatory response. The signaling molecules involved in mitochondrial dysfunction, ER stress, oxidative stress, and inflammation all interact extensively, leading to beta cell dysfunction. [Click here to view]

There are numerous anti-diabetic medications available today to treat hyperglycemia. Except for insulin, liraglutide, exenatide, and pramlintide, all other anti-diabetic drugs are administered orally. These drugs work through various mechanisms, including enhanced insulin release, improved insulin sensitivity, increased glucose uptake, and decreased carbohydrate absorption. The major downside of existing drugs is that they must be administered throughout one’s life and cause undesirable side effects (Hossain and Pervin, 2018). Therefore, herbal medicines that can manage diabetes and associated complications more efficiently and safely have become increasingly popular among people and scientists working in the field both in developed and emerging nations (Kumar et al., 2021). Plants have proven to be an excellent source of drugs, with many currently available drugs derived explicitly or implicitly from them. The active principles derived from plants work through a wide range of pathways, including the inhibition of several key enzymes involved in glucose metabolism. The world health organization has identified close to 21,000 plants used for a variety of medicinal purposes around the world. Nearly 800 of them have been known to possess anti-diabetic potential (Rizvi and Mishra, 2013). In a review, Salehi et al. (2019a, 2019b) described several medicinal plants, including Aloe vera, Gymnema sylvestre, Ficus benghalenesis, Hibiscus rosa-sinesis, Mangifera indica, Tinospora cordifolia, Trigonella foenum-graecum, Allium sativum, Momordica charantia, Panax ginseng, Azadirachta indica Aegle marmelose with antihyperglycemic, insulin-mimetic, anti-lipidemic, and anti-diabetic properties, with a focus on compounds of high interest from various classes such as flavonoids, terpenoids, coumarins, carbohydrates, polypeptides, and small molecules (Salehi et al., 2019a). Some of these medicinal plants and plant-derived compounds are discussed further in this systematic review.

METHODS USED FOR LITERATURE COLLECTION

Online databases such as PubMed, Science Direct, Google Scholar, Web of Science, Scopus, Clinical Trials.gov, and Wiley online library were used for the literature search for this systematic review. The strategy of search is based on the PRISMA guidelines and the major keywords used in various combinations included: Diabetes mellitus, the anti-diabetic activity of plant extracts and plant-derived compounds, β-cell function, proliferation, and differentiation. Based on the search 625 articles were identified. The full-length articles from peer-reviewed journals related to the subject of interest, published between (2000 and 2021) and written in English were included in the review process. Studies on the beneficial effects of crude extracts/isolated compounds on glucose-lowering effects via restoration of islet cells using in vivo and/or in vitro studies were selected for this review. Commercial oral-hypoglycemic agents that lacked definitive evidence on pancreatic β-cell function and mass but obliquely suggested improvement of those activities were excluded from the review. Plants that have been reported for their beneficial effects on β-cells and have undergone clinical trials were included in this review. The review excluded studies that were unrelated to the research question, duplicated, had unavailable full texts or were abstract-only. Further, only plants with reported antidiabetic phytochemicals and mechanisms of action were considered for the review work. There were no restrictions on the sample size, study design, or method of exposure and outcome measurement. Of the 625 articles, 195 articles were included in this review following the criteria for inclusion. Figure 2 summarizes the strategy for the search.

IS REGENERATION POSSIBLE?

The endocrine pancreas is known to be tissue with slow turnover and reduced renewal capacity than tissues with well-defined adult stem cell niches, such as blood, skin, and gut (Aguayo-Mazzucato and Bonner-Weir, 2018) Despite this, the low frequency of both apoptosis and proliferation allows for sustained expansion of β-cell mass in rats for the initial 7 months (Montanya et al., 2000). For about a decade, the notion of regeneration of islets by implies apart from replication of pre-existing cells was unpopular, but neogenesis/trans differentiation has regained favor. Proliferation and the formation of newer β- cells are both likely islet regeneration mechanisms, with different emphases depending on the injury and species (Aguayo-Mazzucato and Bonner-Weir, 2018). Most of the studies on the regeneration of β-cells have been carried out using various rodent models (Kodama et al., 2003), and there is significant evidence of impressive proliferation capacity of post-natal rodent β-cells in situations of higher metabolic demand (Desgraz et al., 2011). Furthermore, it has been shown in transgenic mice that the mature pancreas can recover fully from almost complete ablation of all existing β-cells (Cano et al., 2008), but it is unspecified whether a similar approach applies to humans. Although it has been hypothesized for decades that the human pancreas contains progenitor cells with the potential to regenerate islets, the regenerative capacity of the human pancreas has not been conclusively demonstrated (Ku, 2008). Diabetes Research Institute reports have shown that there are progenitor cells in the human pancreas that can be induced to develop into glucose-responsive β-cells in the presence of bone morphogenic protein-7 (Qadir et al., 2018). These cells were also distinguished by the presence of Pancreatic and duodenal homeobox-1 (Pdx-1), a protein required for β-cell development. As a result, these findings open up the possibility for the development of regenerative therapies to combat the disease (Qadir et al., 2018).

RESTORATION OF PANCREATIC Β-CELLS MASS AND ITS FUNCTION

The β-cells play a crucial role in human physiology since they are the only cells able to produce insulin, which can maintain glucose homeostasis by enhancing the uptake of glucose and its utilization in peripheral tissues. Therefore, dysfunctional β-cells or reduced β-cell mass, disrupt glucose homeostasis, leading to diabetes mellitus (Basile et al., 2019). Thus, the restoration of insulin-producing functional β-cells or transplantation of islets has been one of the major themes of treating diabetes mellitus (Tokui et al., 2006). Since β-cell dysfunction has been identified as a key factor in the development and progression of T1D and T2D, scientists are working on strategies to replace the destroyed β-cell. One way to do that is through β-cell replacement therapy (Butler et al., 2003; Rahier et al., 2008). However, the scarcity of donors, the need for immunosuppressive drugs, which are often toxic, and graft failure, which typically occurs within a few years (Halban et al., 2010) have prompted several studies on alternative means, including the use of β-cells deduced from human embryonic/induced pluripotent stem cells and/or the initiation of endogenous regeneration (Aguayo-Mazzucato and Bonner-Weir, 2018). Embryonic stem cells (ESCs) have tremendous potential for producing insulin-secreting cells because of their significant proliferation, self-renewal, and controlled differentiation capacity (D’Amour et al., 2006). Nevertheless, the clinical application of ESCs is limited due to their undesirable teratoma formation property (Wakitani et al., 2003) and the stringent ethical standards followed in their procurement (Fischbach and Fischbach, 2004). As a result, there is ongoing research into the intracellular expansion of β-cells to regenerate their mass (Bonner-Weir et al., 2004). Thus, (a) enhanced replication of existing β-cells (Dor et al., 2004) and (b) generation of new β-cells from cells not expressing insulin, either through converting from a differentiated cell type (trans differentiation) or differentiation from progenitors (neogenesis) found in regenerating pancreatic ducts, which are viewed as a possible source of β-cell regeneration, can result in increased β-cell mass (Fig. 3) (Bonner-Weir et al., 2004).

Figure 2. Search strategy. [Click here to view]

Transdifferentiation is the process through which one specialized cell type is transformed into some other mature cell type via a dedifferentiation intermediate. It has emerged as the most alluring method of generating β-cell sources for cell replacement therapies (Kim and Lee, 2016). This process is contingent on cellular reprogramming, such as the neogenesis of β-cells and alternative progenitor cells as the source for regeneration of new β-cells from the adult pancreas. Acino-ductal trans differentiation is one such example. Given their abundance, proximity, and shared developmental origin with endocrine cells, acinar cells appear to be a viable source for producing large numbers of β-cells. Acinar cell subpopulations have increased expression of the transcription factor sex-determining region Y-Box 9, a progenitor cell marker for the pancreas, indicating the existence of differentiated acinar cells (Furuyama et al., 2011). Furthermore, during the initial stages of pancreatic development in mice, the trans differentiation process was initiated by ductal cells towards the endocrine lineage, acting as a progenitor for an islet cell (Solar et al., 2009). Interestingly, ductal cells positive for immature β-cell indicators were observed in pregnant women and T2D, indicating this as a reparative mechanism to enhance β-cells mass in physiological and pathophysiological conditions with increased metabolic demand (Dirice et al., 2019).

Figure 3. Expansion of functional beta-cell mass: expansion of the population of functional β-cells represents one of the difficult strategies for compensating for insulin deficiency and improve glucose homeostasis. Cells producing insulin can be derived from either multipotent progenitor cells (hepatocytes or gastrointestinal cells), pancreatic exocrine cells, or endocrine pancreatic islet cells, by inducing cell identity switches termed as trans differentiation. Also, via enhanced replication of existing β-cells (self-replication). [Click here to view]

The potential of α-cells to differentiate into β-cells is yet another example of pancreatic trans differentiation. Some of the benefits of considering α-to-β trans differentiation as a potential intervention are the close lineage associations and extensive overlap of transcriptomes between α and β-cells, as well as the evident better resistance of α-cells to metabolic stressors (Hancock et al., 2010). It was also found that pancreatic insulin-glucagon-positive cell populations increased in response to an increase in Glucagon like peptide-1 (GLP-1) exposure via an increase in the Pdx-1 expression (Zhang et al., 2019).

Because, hepatocytes and gastrointestinal cells are obtained from the primitive foregut endoderm and share initial developmental stages, they are viewed as a plausible endogenous source of insulin-producing cells. Multiple studies have developed reliable methods for obtaining cells like β-cells from hepatocytes by increasing the expression of transcription factors that are important for β-cell development, resulting in improved expression of biologically active insulin and restoration of glycemic control in various diabetic models (Ber et al., 2003; Kojima et al., 2003). Similarly, transient transgenic expression of genes such as Pdx-1, MafA, and nuclear factor E2-related factor (Nrf2) can induce insulin expression in gastrointestinal cells in vivo (Chen et al., 2014). Another study found that demonstrated that increasing HNF-6-induced Ngn-3 expression with GLP-1 improved insulin-producing cell conversion in rodent and human intestinal epithelial cells (Suzuki et al., 2003). A large number of studies in this research area, however, are based on findings made in rodents and proof-of-concept studies on human cells in vitro. As a result, it remains a significant challenge to determine whether reprogramming of β-cells from extra-pancreatic cells can be stimulated in human patients with the ultimate goal of increasing their mass and treating diabetes.

PHARMACOLOGICAL AGENTS THAT PROMOTE Β-CELL MASS AND IMPROVE THEIR FUNCTION

The search for strategies to enhance β-cell function and its regeneration has resulted in the discovery of several small molecules that have been demonstrated to protect and stimulate human β-cell proliferation. Table 1 lists some of the molecules involved in increased islet cell mass, the proliferation of beta cells, and glucose-stimulated insulin secretion (GSIS). Once all safety concerns have been addressed, these pharmacological agents could be used as a strategic approach to reducing the amelioration of this disorder. However, the shortcomings of presently available oral hypoglycemic agents in terms of their efficacy and/or safety, short-term hypoglycemia, and the emergence of diabetes as a global epidemic have prompted the development of alternative therapies that can manage diabetes more efficiently and safely. Dietary composition is considered to be one of the stimuli for pre-existing cell multiplication; different components may trigger this differentiation individually or synergistically. As a result, it is worthwhile to research natural products that can assist in overcoming some of these limitations and alleviate this disorder.

Table 1. Pharmacological agents that aid in the regeneration and function of β –cells. [Click here to view]

TRADITIONAL MEDICINE CONTRIBUTING TO THE RESTORATION OF Β-CELL MASS AND ITS FUNCTION

Complementary or herbal medicine draws the attention of many diabetics to manage and/or prevent diabetes and its ramifications. Numerous popular herbs are asserted to lower blood glucose levels, and therefore the possibility of improving glucose control or reducing the dependency on insulin therapy via the use of traditional medicine is undeniably appealing (Dey et al., 2002). Herbal medicine is based on the comprehensive and integrated theory, that emphasizes the whole body. In contrast to conventional treatments, which typically contain a single bioactive molecule that targets a particular mechanism, herbal concoctions may include a variety of bioactive components that act synergistically through different mechanisms (Ceylan-Isik et al., 2008).

These medications can have a diverse range of beneficial effects, including increased insulin responsiveness, insulin release, β-cell regeneration, reduced carbohydrate absorption, and so on (Choudhury et al., 2018). However, caution should be exercised before administering any herbal medicine treatment (Watson and Preedy, 2012), as the selection of herbs may be dependent on a variety of factors, such as the stage of diabetes advancement, the types of comorbidities that the patients have, cost and availability, and the health impact of the herbs (Surya et al., 2014). As a result, researchers must increase their efforts in investigating alternative preventive and therapeutic measures, such as the utilization of locally accessible functional plants with novel action mechanisms. Such measures may be useful in a variety of communities where their use is accepted and considered a pivotal customary practice (Njume et al., 2019). Some of the commonly used plants and plant-derived compounds that have been researched extensively for their anti-diabetic potential, with a focus on β-cell function and β-cell preservation, and have undergone clinical trials are discussed further in the review. Table 2 summarizes the role of some of these medicinal plants in restoring pancreatic β-cells functionality in terms of T1D and T2D. In this table, animals induced with chemicals such as streptozotocin (STZ) and alloxan, which can damage pancreatic beta cells, are classified as T1D models, while diet-induced ones are classified as T2D models. Figure 4 depicts the multiple pathways by which medicinal plants and compounds derived from plants may regenerate pancreatic β-cells.

PLANTS FOR RESTORING PANCREATIC Β-CELL MASS AND ITS FUNCTION

Clinical studies

A 5-year clinical study involving 5,000 patients with coronary artery disease confirmed that including A. vera gel in the diet resulted in a significant reduction in fasting and post-prandial blood glucose levels in diabetics, as well as total serum cholesterol, TG, and an increase in HDL levels was observed (Agarwal, 1985). Surprisingly, the majority of those who benefited were diabetics who were not taking any anti-diabetic medication, and no side effects were observed during the study (Agarwal, 1985). Another study found A. vera to have anti-diabetic activity in new cases of diabetes mellitus, with improved triglyceride levels (Yongchaiyudha et al., 1996). As previously stated, dyslipidemia is known to play an important role in impaired β–cell function, which contributes to the T2D onset. Improving triglyceride, cholesterol, and total lipid levels must therefore be one of the mechanisms for improved β–cell function. Furthermore, in diabetics, oral administration of a high-molecular-weight fraction (AHM-0.05 g) containing acemannan and verectin daily thrice for 12 weeks resulted in a decrease in FBG levels (Yagi et al., 2009). Acemannan, which is digested by intestinal microbiota into oligosaccharides and is responsible for obstructing glucose absorption, was discovered to be responsible for the biological effect of AHM (Boban et al., 2006; Jain et al., 2007; Yagi et al., 2001). In addition, T2Dwho received acemannan (600 mg capsule/day) for 60 days demonstrated a decrease in blood glucose, TC, and Low-density lipoprotein (LDL) levels (Huseini et al., 2012). In a randomized trial, A. vera was considered to be superior to the placebo in reducing FBG levels HbA1c, and TC levels, and also improvement in HDL levels was observed (Alinejad-Mofrad et al., 2015; Devaraj et al., 2013). Another study observed that Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was found to be lower in an intervention group (Choi et al., 2013).

Table 2. Effects of medicinal plants on diabetes mellitus through pancreatic β–cell regeneration. [Click here to view]

Figure 4. Possible mechanism for β-cell regeneration: medicinal plants and plant-derived compounds can regenerate pancreatic beta cells through multiple pathways; Inhibition of DPP-IV and increasing shelf life of GLP-1, reduced islet inflammation potentiates GSIS; Prevents beta cell apoptosis by inhibiting Caspase-9 and increasing Bcl-2; Preventing nuclear translocation of Fox-1 increases expression of genes involved in beta cell regeneration and have protective effects on beta cells; reduced cytokine, chemokine production increases insulin synthesis and secretion. [Click here to view]

Although the antidiabetic activity of A. vera has been reported in various studies, not all of this included preparation are identical. Furthermore, the variability in daily dose makes it difficult to determine the minimum optimal dose of A. vera that can bring glucose homeostasis. Large-scale, multicenter, randomized-controlled long-term trials must be robustly designed to corroborate the recent findings and investigate the long-term impact of A. vera supplementation on managing prediabetes and T2DM with a focus on improved β–cell function (Zhang et al., 2016).

COMPOUNDS IMPLICATED IN THE RESTORATION OF PANCREATIC Β-CELL MASS AND ITS FUNCTION

Different natural compounds, such as flavonoids and alkaloids, have been shown in preclinical and clinical studies to have anti-diabetic potential.

CONCLUSION

β-cell death contributes to the progression of T1D and T2D by reducing the mass of β-cells and, as a result, endogenous secretion of insulin. Therapeutics to impede or even reverse the apoptosis and dysfunction of β-cells are urgently needed. Several studies have demonstrated that the average contributions of β-cell proliferation, neogenesis, and apoptosis to overall β-cell mass vary with age and in response to stress. We reviewed some medicinal plants and plant-derived compounds, inspired by traditional healthcare systems. Several pieces of scientific evidence suggested that these plant extracts and/or phytochemicals have anti-hyperglycemic properties. Some of these extracts such as A. vera, P. ginseng, M. charantia, and a few compounds, such as Geniposide, Baicalein, and Apigenin, demonstrated highly promising effects. The extracts and the phytochemicals described in this review are believed to ameliorate diabetic symptoms via multiple pathways including increased half-life of GLP-1 and inhibiting DPP-IV, decreasing β-cell apoptosis by inhibiting caspase 9 and increasing the expression of Bcl-2, enhancing the expression of genes involved in β-cell proliferation, decreasing islet inflammation and increasing insulin synthesis and secretion. However, the most significant limitation is the paucity of controlled clinical trials. The short duration of these studies, small sample size, lack of randomization, and dose variation. Thus, further investigation and clinical trials are needed to determine the correct dosage for diabetes prevention and its complications, as well as to better comprehend the mechanisms through which these extracts impart their therapeutic benefits. Importantly, prospective anti-diabetic plants should be evaluated for toxicity to ensure they are therapeutically safe and effective phytomedicines.

ACKNOWLEDGMENT

The lead author (ND) would like to acknowledge the Indian Council of Medical Research for providing a fellowship under grant 45/39/2018/MP/BMS. Also, the authors are thankful to VIT, Vellore for their support in the research activities.There is any other financial support to report.

LIST OF ABBREVIATIONS

AUC, Area under curve; BCL2, B-cell lymphoma 2; cAMP, Cyclic adenosine monophosphate; DPP-IV, Dipeptidyl peptidase-IV; ESCs, Embryonic stem cells; FFA, Free fatty acid; GABA, Gamma-aminobutyric acid; GLP-1, Glucagon-like peptide-1; Glut2, Glucose transported-2; Glut-4, Glucose transporter-4; GOPs, Ginseng oligopeptides; GSIS, Glucose stimulated insulin secretion; Gymnema sylvestre, G. sylvestre; HbA1c, Glycated hemoglobin; HDL, High-density lipoprotein; HFD, High fat diet; HOMA-B, Homeostasis model assessment of β-cell function; HOMA-IR, Homeostatic model assessment of insulin resistance; IRS-1, Insulin receptor substrate-1; KRG, Korean red ginseng; LDL, Low-density lipoprotein; Momordica charantia, M. charantia (MC); Nrf2, Nuclear factor E2-related factor; Panax Ginseng, P. ginseng; Pdx-1, Pancreatic and duodenal homeobox 1; PPAG, Phenylpropenoic acid glucoside; PPAR-γ, Peroxisome proliferator- activated receptor gamma; STZ, Streptozotocin; T1D, Type 1 diabetes; T2D, Type 2 diabetes; TCF7L2, T-cell factor 7-like 2; Tinospora cordifolia, T. cordifolia; TNF-α, Tumor necrosis factor alpha.

AUTHOR CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the international committee of medical journal editors (ICMJE) requirements/guidelines.

CONFLICTS OF INTEREST

The authors report no financial or any other conflicts of interest in this work.

ETHICAL APPROVALS

This study does not involve experiments on animals or human subjects.

DATA AVAILABILITY

All data generated and analyzed are included in this research article.

PUBLISHER’S NOTE

This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.

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