Introduction

(Suggest starting this paragraph with “A recent study/publication from The World Health Organisation (WHO))WHO states that 300,000,000 of the total population around the world will suffer from diabetes mellitus (DM) by 2025. According to the WHO, the United States ranks third in the world for the incidence of diabetes in its population.

The way this condition progresses is a critical issue as it leads to many serious complications that need to be understood to stay under control. The goal of DM management is to control sugar levels within the normal range. Hyperglycemia causes auto-oxidation of glucose, which will increase the presence of reactive oxygen species. Excessive reactive oxygen species (ROS ) production leads to a condition defined as “oxidative stress”, which happens when the ROS production elevates till it becomes more than the antioxidant capacity.

To reduce the oxidative damage, the patient needs to be supported with exogenous antioxidants. Xanton, which is a bioactive component found in mangosteen, has an anti-diabetic action. Mangosteen showed a powerful antioxidant effect due lowering the blood glucose levels, and after testing, compounds of? The Xanton group were found to be pharmacologically active as anti-inflammatory agents as well. As a result, being anti-inflammatory and antioxidant makes mangosteen very useful in improving the pancreatic capacity in cases of hyperglycemia.¹

Understanding blood sugar levels

Glucose is mainly obtained from the diet or by synthesis in organs such as the liver. Body organs and tissues need a constant source of energy, which is why they need a constant supply of glucose, and for the same reason, decreasing blood glucose levels leads to a variety of complications, such as seizures. In contrast, elevation in glucose concentrations for a long time without control results in dangerous problems such as renal failure, neuropathy, or blindness. This is why control of glucose levels within the right limits is a must, through a process which is called glucose homeostasis. This  could be done by  controlling:

1. Hormonal regulation of peripheral glucose uptake
2. Glucose production from the liver
3. Glucose uptake during carbohydrate ingestion

Glucose is the major source of energy in all cell types in mammals. It has a hydrophilic nature, which is why it needs specific transporters to be able to move through cellular membranes. SGLT (sodium-glucose linked transporter) and GLUTs (glucose transporters) represent the cotransporter families for all body sugars:

1. Glucose
2. Galactose
3. Mannose
4. Fructose
5. Myoinositol

Whole body glucose homeostasis is understood within disease as well as normal conditions, and this requires an absolute complete understanding of SGLT and GLUT physiology.²

Diabetes mellitus: symptoms, diagnosis, and management (A brief)

Symptoms of DM are known from early times. “Diabetes” is a Greek word which means a “siphon”, while mellitus is Latin and means “honey”; the combination of both words gives the right description for the condition associated with repeated and sweet urination. Current practice considers that plasma glucose concentration over 180-200 mg/dL leads to:

1. Glomerular filtration
2. Pollakiuria
3. Glycosuria

The European Association for the Study of Diabetes (EASD) stated in 2009 that A1C level can be tested as an indication in the diagnosis of DM. Table 1 below shows the current diagnosis guidelines. Measuring A1C level helps in; diagnosis of DM clearly by physicians, with avoidance of confusion by DM patients. There are other approved tests, such as oral glucose tolerance, which are also an indicator of the possible complications that patients can face. It is used to decide the treatment options.

ADA stated that lifestyle modifications alone are not enough to overcome DM in diagnosed patients. Metformin has been included as a first-line therapy, it has many useful actions in the treatment of DM. It lowers plasma glucose (PG) and significantly shows a reduction in total blood lipids.³

^{(Table 1: the current diagnosis guidelines for diabetes mellitus and Increased risk for DM)3}

Phytotherapy in cases of DM

In recent years, many naturally occurring agents have shown some positive  effects in lowering elevated blood glucose levels by increasing glucose uptake from:

• Hepatocyte
• Myocyte
• Adipocyte(4)

In a recent study, the results show significant hypoglycemic effects of some plants in cases of DM. The use of “Eryngium longifolium,” especially the aerial parts and the rhizome of Alsophila firma, is consumed by fasting patients throughout the day to control their blood glucose levels. The phytochemical effects of both plants were studied and tested for the toxicological tests, and the in vitro and in vivo trials were performed to show if there was any effect on glucose metabolism. These components lower glucose 6-phosphatase and fructose 1,6-bisphosphatase in in vitro assays, which could be associated with the hypoglycemic effect in vivo. The assayed components are  as follows:

• Caffeic acid
• Chlorogenic acid
• Rosmarinic acid
• Isoflavones
• Glycosylated flavonoids
• Flavanones
• Dihydroflavonols⁵

Mangosteen, a valuable agent in phytotherapy for DM⁴

One of the most important tropical fruits in Southeast Asia is the Mangosteen. Recent studies show some important biological functions which have been identified in the peel extraction of mangosteen, such as anti-oxidation effect that improves osteoblast activity, antiviral, and part of solar cells. The main constituents of the bioactive extract are:

1. Tannins
2. Anthocyanins
3. Xanthones (Mangostins)
4. Additional phenolics (crude extract in the aril and skin; responsible for protein-binding and antioxidant potential)

A newly published study suggests that there is another benefit of mangosteen byproducts, instead of being just a waste, by using Mangostins, mangosteen’s xanthones (the major ingredient of mangosteen that are characterised α-, β-, and γ-mangostin, and α-mangostin is one most component of three mangostin forms).

1. α-Mangostin shows medicinal values as:
   • Anti-bacterial
   • Anti-tumor
   • Anti-aging
   • Anti-inflammation
   • Antiviral
   • Anti-diabetic
   • Hepatoprotective
2. Many biological activities have been found for γ-mangostin, such as:
   • Immunomodulation
   • Energy modulation
   • Antibacterial
   • Anti-depression
   • Anti-cancer
   • Ability to modulate cellular energy levels

In the first in-vivo study for testing the blood glucose homeostasis of γ-mangostin, a virtual screening is done and executed to search the potential anti-diabetic targets for the interaction of γ-mangostin and further evaluations for the anti-hyperglycemic effect of γ-mangostin via selection of targets for posing the acting mechanism. Results show (short term) hypoglycemic effect of γ-mangostin; by feeding γ-mangostin, blood glucose levels of diabetic mice were significantly lower than the control group that was not treated. Taking all data collected from that study into consideration, it suggests that there is an antidiabetic effect of γ-mangostin. Mangosteen’s xanthone γ-mangostin could be a new drug hit for the management of diabetic patients. Moreover, this study also highlighted the results of in-silico and in vitro studies to investigate the target protein candidates and accelerate the progress of searching for new drug discovery and development. In the future, the combination of γ-mangostin with available antidiabetic drugs such as Metformin or Pioglitazone may increase the anti-diabetic actions.

Conclusion

In conclusion, the increasing prevalence of diabetes mellitus (DM) worldwide highlights the need for a deeper understanding of its progression, complications, and management strategies. With projections from the WHO indicating a significant rise in the number of individuals affected by DM, there is an urgent need to explore new approaches to address this complex condition.

Understanding the mechanisms behind blood sugar regulation, such as glucose homeostasis, is essential for effectively managing DM. Disruptions in glucose levels can lead to serious complications, emphasising the importance of maintaining proper control through various physiological processes, including hormonal regulation, hepatic glucose production, and glucose uptake.

Diagnosis and management of DM necessitate a comprehensive approach. Conventional methods, like A1C testing, remain vital for identifying and monitoring the condition, while lifestyle modifications combined with pharmacological interventions like Metformin play crucial roles in treatment. However, there is growing interest in alternative therapies, particularly phytotherapy, which has gained momentum in recent years.

Phytotherapy offers a promising avenue for managing DM, with natural compounds demonstrating significant hypoglycemic effects. Plants such as Eryngium longifolium and Alsophila firma have shown potential in regulating glucose metabolism, providing insights into new therapeutic pathways. Additionally, the investigation of tropical fruits like mangosteen has uncovered bioactive compounds like xanthones, particularly γ-mangostin, which exhibit promising anti-diabetic properties.

Exploring the byproducts of mangosteen research reveals a potential breakthrough in DM management. γ-mangostin has demonstrated notable hypoglycemic effects in animal studies, indicating its potential as a therapeutic agent. Moreover, its diverse biological activities and potential synergies with existing anti-diabetic drugs offer promising prospects for future treatment modalities.

In summary, the pursuit of innovative approaches, including phytotherapy and the exploration of natural compounds like mangosteen-derived xanthones, shows potential in addressing DM. As the prevalence of DM continues to rise, embracing diverse therapeutic modalities becomes essential in mitigating its impact and enhancing the quality of life for affected individuals.