Mechanism of Anti-Diabetic Activity from Sweet Potato (Ipomoea batatas): A Systematic Review

This study aims to provide an overview of the compounds found in sweet potato (Ipomoea batatas) that contribute to its anti-diabetic activity and the mechanisms by which they act. A comprehensive literature search was conducted using electronic databases, such as PubMed, Scopus, and Science Direct, with specific search terms and Boolean operators. A total of 269 articles were initially retrieved, but after applying inclusion and exclusion criteria only 28 articles were selected for further review. Among the findings, four varieties of sweet potato were identified as having potential anti-diabetic properties. Phenolic acids, flavonols, flavanones, and anthocyanidins are responsible for the anti-diabetic activity of sweet potatoes. The anti-diabetic mechanism of sweet potatoes was determined using a combination of components with multi-target actions. The results of these studies provide evidence that Ipomoea batatas is effective in the treatment of type 2 diabetes.


Introduction
The prevalence of diabetes in 2021 was 537 million people [1]. This number is anticipated to rise by 10.2% by 2030 and 10.9% by 2045 [2]. Diabetes mellitus (DM) and its complications were responsible for 12.2% of fatalities worldwide in the age group from 20 to 79 years old in 2021 [1].
The most prevalent form of diabetes is type 2, which is characterized by impaired hepatic glucose metabolism, reduced pancreatic beta cell function, and peripheral insulin resistance [3]. The American Association of Clinical Endocrinologists (AACE) recommend α-glucosidase inhibitors as the first-line therapy because they are safe, effective, have a low incidence of hypoglycemia, and have tolerance in the cardiovascular system [4]; however, it has been claimed that this medication produces undesirable side effects [5]. Therefore, an investigation of natural ingredients that are both effective and safe has the potential to mitigate the risk of type 2 diabetes and its associated complications.
Sweet potato (Ipomoea batatas) is the sixth most grown food worldwide [6]. Its leaves are renowned for their antioxidant capabilities, surpassing those of ascorbic acid, tea, and grape seed polyphenols by a factor of 3.1, 5.9, and 9.6, respectively [7]. Remarkably, the leaf parts of 40 sweet potato cultivars contain a significant amount of polyphenols ranging from 7.39 to 14.66 g/100 g dry weight (DW) [8]. Within sweet potato leaves, phenolic acids, anthocyanins, and caffeoylquinic acid derivatives were identified as contributors to the observed hypoglycemic effects [9]. Sweet potato leaf ethanol extract obtained from Aan village, Klungkung, Bali consists of diverse flavonoids, such as anthocyanins, flavonols, and flavones, whose concentrations in the extract exhibited a linear correlation with the decrease in blood glucose and malondialdehyde levels [10]. Additionally, the type and concentration of phytochemicals found in sweet potatoes affect their anti-diabetic action [11]. Despite numerous studies investigating the anti-diabetic effects and mechanisms of Ipomoea batatas, comprehensive documentation is lacking. Therefore, this systematic review aims to provide an overview of the compounds responsible for the anti-diabetic activity and to elucidate their mechanisms of action. This review will function as a comprehensive database, aiding other researchers in identifying the subsequent steps for the development of Ipomoea batatasbased products.

Literature Search
The Preferred Reporting Items for Systematic Reviews (PRISMA) served as the foundation for the search approach [12]. The literature search in this systematic review aimed to find relevant articles about the potential of Ipomoea batatas for type 2 diabetes treatment. We comprehensively selected electronic databases such as PubMed, Scopus, and Science Direct. Boolean operators were used to conduct the literature search [13]. The keys included (1) Ipomoea batatas OR sweet potato AND (2) diabetic OR type 2 diabetes.

Inclusion Criteria
For an article to be included in this study the anti-diabetic potential, chemical components, and mode of action of Ipomoea batatas needed to be covered in research articles based on in vitro and in vivo experiments. The selected article had to be written in English and should have evaluated at least the following: (1) Ipomoea batatas, (2) chemical components, (3) anti-diabetic effects, and (4) mechanisms of action involved.

Exclusion Criteria
Articles not included in the systematic review were in the form of proceedings; theses; dissertations; review articles; articles not written in English; articles with titles, abstracts, and keywords that did not meet the inclusion criteria; and articles that focused on other diseases.

Study Selection
The full text of the relevant published article was then reviewed. The articles that were chosen to be included in this study were compiled using Mendeley, a reference manager.

Data Extraction and Management
The articles that met the inclusion criteria were then analyzed, and the data collected included (1) type/cultivar, (2) material used, (3) detected phytochemical compound, (4) predicted bioactive compound, (5) type of study, (6) dose, (7) action and mechanism of anti-diabetic activity of Ipomoea batatas.

The Literature Search
A literature search was able to identify 269 articles relevant to the topic. After duplication detection, 41 papers were deleted. Based on the title, abstract, keywords, and inclusion criteria mentioned above, an additional 198 articles were excluded. Two reports could not be accessed in the full paper version, so finally 28 papers were discussed in depth in this review. A flow diagram summarizing the filtering, identification, and reasons for exclusion  Table 1. sion criteria mentioned above, an additional 198 articles were excluded. Two re not be accessed in the full paper version, so finally 28 papers were discussed this review. A flow diagram summarizing the filtering, identification, and rea clusion is shown in Figure 1. Data extraction was performed based on the completed articles, as shown in Table 1.
In vitro Crude extract (0.1 mg/mL) pure compounds (0.01 mg/mL) were • Increased glucose uptake, most likely via activation of Glut4 and regulation of the PI3K/AKT pathway [22] Glucosidase inhibition:

Types and Concentrations of Phytochemicals Contained in Ipomoea batatas Which Have Anti-Diabetic Effects
The leaves of white sweet potato have a total polyphenol concentration of 6.4 g/100 g, which is greater than that of the orange varieties as well as Japanese green sweet potatoes [16,25,38]. The plant parts used also have an impact on the variation in polyphenol concentration. The total polyphenols in the leaves are more significant when compared to the tuber [43]. Green leaves have higher total phenolics than green or purple leaves [44]. Different maturity stages of sweet potato plants exhibit a significant amount of variation in flavonols and phenolic acids of the sweet potato leaves. The quantity of bioactive compounds rises as the plant ages [45]. Anthocyanin concentrations are more significant in purple than orange tuber sweet potatoes. The concentration of phenolic acids in purple tubers is ten times greater than that in orange and white sweet potatoes [46].

Protects the Integrity of Islet Structures and Modulates Pancreatic β Cell Function
β-pancreatic cells are responsible for insulin secretion. Therefore, maintaining the islet structure of pancreatic β cells is essential for treating diabetes. The results of the pancreatic histopathological analysis showed that the administration of white sweet potato ethanol extract at doses of 80 and 150 mg per kg BW of mice for four weeks could improve the islet structure by enlarging the islet area and inhibiting apoptosis of β-pancreatic cells [47,48]. In addition, administering purple sweet potato extract containing anthocyanins and protein at a dose of 200 mg/kg body weight reduced oxidative stress and pancreatic damage in diabetic mice [20]. However, a larger dose of cloned B 0059-3 sweet potato extract obtained from Bandungan, West Java, Indonesia was required to protect β-pancreatic cells [19]. The ability to protect and modulate the function of pancreatic β polyphenols contained in ethanol extracts of white and purple sweet potato is more significant than resveratrol and polyphenols contained in Ginger (Zingiber officinale) rhizome [49,50]. The administration of polyphenol or protein-bound anthocyanins and free anthocyanins induced the expression of AMP-activated protein kinase (AMPK) in the liver, significantly increased levels of glucose transporter type 2 (GLUT2), glucokinase protein (GK), and insulin receptor α (INSR) [20,51].

Increased Insulin Secretion and Improved Insulin Sensitivity
In vivo studies have demonstrated that the administration of Caiapo, glycoprotein acid, and 3,4,5-tricaffeoylquinic results in an increased insulin sensitivity [15,24,25,52]. The effectiveness of Caiapo as an antidiabetic was proven by conducting clinical trials on 30 patients given Caiapo 4 g/day orally, once a day, in the morning before meals. Caiapo administration led to a significant reduction in HbA1c compared to the placebo group after 2 and 3 months of the administration. In addition, from the study's results, it was found that the administration of Caiapo caused the average fasting blood glucose level to reach 126 mg/dl, weight loss, and a significant decrease in postprandial glucose levels and cholesterol [14]. The caffeoylquinic derivative significantly increased glucagon-like peptide-1 (GLP-1) secretion [25,53] and glycoprotein acid increased modulation of insulin sensitivity (adiponectin) [28,54]. Similar results were obtained from the administration of polyphenols, such as phenolic acids and flavonoids, from the sweet potato leaf extract, with an improved insulin sensitivity through activation of insulin signaling in the skeletal muscles [23]. Flavonoids, such as methyl decanoate, have the potential to increase insulin sensitivity in skeletal muscles [22,[55][56][57]. The increased insulin sensitivity is due to Akt phosphorylation, thereby activating insulin signals in the skeletal muscles of phosphatidylinositol 3-kinase/protein kinase B/glucose transporter 4 (PI3K/AKT/GLUT-4) and liver (PI3K/AKT/GSK-3β) [23,31,47,[58][59][60].

Inhibition of Glucose Transport in the Intestine and Increased Uptake of Tissue Glucose
The administration of hexane and a water fraction of purple sweet potato leaf methanol extract increased the glucose uptake in 3T3-L1 adipocyte tissue and rat hepatocytes. Flavonoids, such as quercetin, have a more remarkable glucose uptake ability than other components such as 3-O-β-D-sophoroside, benzyl β-D-glucoside, and 4-hydroxy-3-methoxy benzaldehyde. The ability of some of these active compounds in glucose uptake in adipocyte tissue is most likely through the activation of GLUT4 and regulation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway [22,65]. However, the administration of 5% white sweet potato powdered leaves increased the expression of p-IR, p-AKT, and M-GLUT4, but had no significant effect on the PI3K/AKT pathway [23].

Repair of Insulin Signals and Glycogen Synthesis
There was an increase in mRNA insulin receptor (IR) expression, insulin receptor substrate 2 (IRS-2), PI3K, and AKT genes, and a decrease in glycogen synthase kinase-3β (GSK-3β) expression with white sweet potato extract administration [16]. This proved that these extracts promote liver glycogen synthesis by activating the insulin-mediated PI3K/AKT/GSK-3β signaling pathway [47,66]. Moreover, the administration of ethyl acetate fraction from white sweet potato ethanol extract and flavonoids contained in the water fraction of the extract was able to activate GLUT4 and regulate the phosphatidylinositol 3-kinase (PI3K)/AKT pathway [36].

Inhibition of Inflammatory Pathways
The commercial administration of anthocyanins from purple sweet potato decreased the expression of cyclooxygenase-2, tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. Anthocyanins can inhibit the phosphorylation induction/activation of extracellular signalregulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) [67]. The administration of 5 g/kg BW/day Caiapo significantly decreased p38 MAPKs and TNF-α production in diabetic rats. These findings imply that the inhibition of oxidative stress and the creation of pro-inflammatory cytokines, followed by an increase in the pancreatic cell mass, are what cause the hypoglycemic effects of Ipomoea batatas [27].

Conclusions and Perspective
Sweet potatoes that have the potential to be anti-diabetic include white, purple, orange, and Japanese green sweet potatoes. Phenolic acids, flavonols, flavanones, and anthocyanidins are responsible for the anti-diabetic activity of sweet potatoes. The antidiabetic mechanism of sweet potatoes is determined by a combination of components with multi-target actions.
Given the increasing prevalence of diabetes, it is crucial to conduct research on the utilization of unstudied sweet potato varieties and cultivars. Additionally, implementing quality control measures to ensure product uniformity during production is imperative for medicinal purposes. A comprehensive approach must be taken to ensure consistency in the quality, efficacy, and safety of sweet potatoes as an anti-diabetic treatment. Although numerous studies have described the benefits of the bioactive compounds of Ipomoea batatas as anti-diabetic agents, there are still some limitations. The type and concentration of the bioactive compounds of Ipomoea batatas are influenced by many factors such as genetics, the time of harvest, the post-harvesting process, and the extraction process. Standardization and quality control are necessary to guarantee the consistency of the type and amount of bioactive components responsible for the anti-diabetic effect. Standardized, validated, and characterized herbal drugs, along with their identified biochemical compounds, can be used in clinical trials and, subsequently, could contribute to advancements in the pharmaceutical industry. The quality marker (Q-marker) concept emphasizes the relationship between chemical components, manufacturing processes, and the efficacy and safety of herbal medicines. Similarly, there needs to be an accurate determination of the pharmacokinetics and dynamics of polyphenols contained in sweet potatoes. Therefore, further studies are required to determine the Q-marker for quality control of Ipomoea batatas as an anti-diabetic agent, as well as to investigate the bioavailability of its active components.

Data Availability Statement:
The data used to support the findings of this study can be made available by the corresponding author upon request.