In this blog, I would like to share the study, “Fucoidan Structure and Its Impact on Glucose Metabolism: Implications for Diabetes and Cancer Therapy” by Blessing Mabate et al. By linking diabetes and cancer, the study not only provides valuable insights into the relationship between the two diseases but also presents a comprehensive overview of glucose metabolism. This process plays a central role in the progression of both cancer and diabetes, and the study further identifies potential therapeutic targets that could be used for treating both conditions. Fucoidan and its derivatives are shown to be significant contenders for glucose metabolism.

Until now, there have been no studies conducted to examine how fucoidan impacts the absorption of glucose through sodium-glucose cotransporters (SGLTs). The main glucose supply to the human body is dietary carbohydrates, mainly from fructose, lactose, and starch. The breakdown of these carbohydrates relies on enzymes such as amylase and oligosaccharides. Salivary amylase begins to break down starch in the mouth into the disaccharide maltose. In the duodenum, which is the initial segment of the small intestine, the process of carbohydrate digestion advances to the next stage. Pancreatic amylase, which is the most abundant enzyme at this point, continues to break down carbohydrates further, transforming them into disaccharides.

In the duodenum, oligosaccharides cleave each oligosaccharide into monosaccharides (mainly glucose). Glucose becomes available for energy use during metabolism. Enterocytes absorb glucose, one of the monosaccharides that are formed when amylase and brush border enzymes break down food in the small intestine. Selective active transport of the D isomers (mainly D-glucose and D-galactose) occurs through a sodium (Na)-conjugated secondary active transport symporter known as Na-glucose transporter 1 (SGLT1) as shown in Figure 1.

Additionally, how quickly glucose enters the bloodstream is determined by gastric emptying, which is regulated by various nutrients and hormones. In vivo experiments have recently demonstrated that fucoidan can enhance insulin sensitivity, reduce blood sugar levels after eating, and prevent hyperglycemia. Fucoidan is believed to have an impact on the activation of pathways that lead to increased insulin production and improved movement of glucose transporter molecules. However, few studies have investigated these aspects, so fucoidan may be useful for treatment.

Fucoidan has been proposed as a potential regulator of signaling molecules, including receptor tyrosine kinases. Moreover, it has been observed to have the capacity to cause cell cycle arrest and initiate apoptosis. It is also believed that fucoidan can prevent the migration of tumor cells and improve the production of immune cells. However, recent studies have demonstrated the importance of the pathophysiology of glucose metabolism and glycolytic flux in tumor development. Despite this, there has been limited effort in the screening of fucoidan. Glycolysis occurs within the cytoplasm of cells and relies on glucose transporters (GLUTs) as its substrate importers. GLUT1 and Na-glucose Linked Transporter 1 (SGLT1) are often overexpressed in cancer cells with markedly advanced glycolysis. GLUT3 and GLUT5 are also overexpressed in tumor cells. Fucoidan inhibits these overexpressed GLUT.

Upon entering the cell, glucose undergoes phosphorylation to form glucose-6-phosphate (G6P) through the action of hexokinase. This step is crucial as it regulates the energy conservation within the cell. There are four hexokinase (HK) isoforms with high affinity for glucose that catalyze this reaction; among hexokinase, HK-1 is ubiquitously expressed, whereas HK-2 is expressed in insulin-sensitive muscle and adipose tissue. Additionally, HK-2 is overexpressed in tumor cells. However, fucoidan significantly decreases the expression of HK-2. In HK synthesis, glucose-6-phosphate is isomerized to fructose-6-phosphate with the help of glucose-6-phosphate isomerase. The conversion of fructose-6-phosphate to fructose-1,6-bisphosphate and fructose-2,6-diphosphate involves the phosphorylation process, where ATP acts as the phosphate donor. This phosphorylation is facilitated by phosphofructokinase-1 (PFK1) and PFK2, as shown in Figure 2.

Dual chemotherapy targeting both diabetes and cancer can potentially focus on any of the steps involved in glycolytic flux and glucose homeostasis, as shown in Figure 1 and Figure 2. Fucoidan, derived from marine sources, is considered to be a safer alternative with fewer side effects compared to the synthetic chemotherapy drugs currently utilized in the treatment of diabetes and cancer. However, when it comes to studying the bioactivity of fucoidan, most researchers rely on mouse models, both in vitro and in vivo. Few studies have been conducted on human participants. As a result, even though the review designs do not allow for a direct estimation of cytotoxicity, the authors reach the conclusion that fucoidan could serve as a significant and potentially dual therapeutic option for both diabetes and cancer. Thus, it is imperative to conduct more studies in order to better comprehend the correlation between their structure and biological activity.

Source: Mar. Drugs 2021, 19(1), 30; https://doi.org/10.3390/md19010030