Knowledgebase Development and Review for the Function of Omega-3 Polyunsaturated Fatty Acid and Polysaccharide in Diabetes

Jing Li1, Teng Liu2, Fangli Ma3, Renhuai Cong3, Xiangliang Yang1, Hai Yang1*, An-Yuan Guo2* 1National Engineering Research Center for Nano medicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, P. R. China 2Department of Bioinformatics and Systems Biology, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR. China. 3Functional Oil Laboratory Associated by Oil Crops Research Institute, Chinese Academy of Agricultural Sciences and Infinitus (China) Company Ltd. International Journal of Pharmacovigilance Open Access Mini review


Introduction
Diabetes Mellitus (DM) is a chronic disease characterized by the absolute or relative shortage of insulin, leading to chronic hyperglycemia [1,2].There were 366 million people with DM in 2011 [3], and a lower life expectancy by approximately 12 years has been expected in people with DM [4].Type 2 Diabetes Mellitus (T 2 DM) causes macro vascular and micro vascular complication such as cardiovascular, cerebrovascular, retinopathy, nephropathy and neuropathy diseases [5].It is well known that both environmental and genetic factors led to DM.The predominant cause of T 2 DM is due to lifestyle factors including diet, insufficient physical activity, overweight and stress [2].The genetic susceptibility to T 2 DM has been demonstrated with at least 36 diabetes-associated genes identified, yet only about 10% of the heritability of T 2 DM can be explained [6].Medical nutrition

Omega-3 PUFA Ameliorate the Insulin Resistance
Insulin resistance is a sign of diabetes, and its development involves several adipokines, including leptin, tumor necrosis factor-α (TNF-α), interleukin-6, adiponectin, and resistin [27].Adiponectin regulates the lipid and glucose metabolism, increases insulin sensitivity, and protects against a chronic inflammation [28].Leptin is an adipokine involved in the regulation of satiety and energy intake [29].Haugen [30] reported that ALA could reduce resistin mRNA levels in 3T3-L1 adipocytes.Thus omega-3 PUFA could make the levels of adipokines increase or decrease, which all contributed to ameliorate insulin resistance.Kazemian [31] proposed that omega-3 PUFA could bind to a G-protein coupled receptor, resulting in reduced cytokine production and thus improving signaling in adipocytes, leading to a reduction in insulin resistance.

Omega-3 PUFA Can Exert Anti-Inflammatory Effects
T 2 DM is considered as an inflammatory disease [32].Increasing evidences have demonstrated that EPA and DHA can suppress inflammation and have a beneficial role in a variety of inflammatory diseases including diabetes, atherosclerosis, and arthritis [33].It has been reported that stimulation of macrophages with omega-3 PUFA abolished NLRP3 inflammasome activation and reduced the production of interleukin-1/ 2/ 6 (IL-1/ 2/ 6) and TNF-α [34,35].EPA and DHAderived resolvins and protectins are key inflammation resolution agonists [36].It also has been demonstrated that EPA and DHA exert anti-inflammatory effects through several mechanisms, including activation of AMPK [37] and PPARG [38], as well as suppression of toll-like receptors (TLRs) and NF-κB pathway [39,40].Omega-3 also can reduce blood pressure and oxidative stress in T 2 DM patients [41,42].
As discussed above, omega-3 PUFA can prevent or ameliorate DM and its complications through multiple mechanisms, such as increasing insulin secretion, improving lipid or glucose metabolism.Omega-3 PUFA also can exert anti-oxidant and antiinflammatory activity in DM and its complications.The number of publications on the effects of omega-3 PUFA on DM was summarized in Figure 2a, which showed a gradually increasing trend in last fifteen years.The allocation of publications for different omega-3 PUFA components was shown in Figure 2b.

Polysaccharide on DM
Polysaccharides such as APS and Lycium barbarum polysaccharide (LBP) can not only inhibit hyperglycemia and oxidative stress, but also improve insulin sensitivity.Here, we focused on the two polysaccharide components which have beneficial effects on DM.

The Beneficial Effects of LBP on DM
LBP as one of the traditional oriental medicines can significantly reduce the blood glucose levels and serum total cholesterol and thyroglobulin concentrations in alloxan-induced diabetic animals [43,44].The effects of LBP on the improvement of insulin resistance were investigated in a rat model of Non-Insulin Dependent Diabetes Mellitus (NIDDM) [45].The mechanism involved was that LBP increased the level of Glucose Transporter 4 (GLUT4), improving GLUT4 trafficking and intracellular insulin signal.Additional study also indicated LBP could control the blood glucose levels and modulate the metabolism of glucose, leading to significant decrease of Malonaldehyde (MDA) and increase of SOD (Superoxide Dismutase).Furthermore, LBP could decrease levels of DNA damage possibly through decreasing in oxidative stress levels in rats with NIDDM [46].

The Beneficial Effects of APS on DM
Protein tyrosine phosphatase 1B (PTP1B) was a key negative

Knowledgebase Development and Review for the Function of Omega-3 Polyunsaturated Fatty Acid and Polysaccharide in Diabetes
Copyright: © 2016 Yang and Guo, et al.
regulator of insulin signaling and emerged as an attractive target for therapeutic intervention of T 2 DM [47].APS increased the insulin sensitivity by decreasing the expression of PTP1B [48,49] and two other pathways including ROS-ERK-NF-κB [50] and PKB/GLUT4 [51].APS exerted anti-inflammatory effects by inducing IL-10 gene expression and inhibiting IL-1β protein production and most of the pro-inflammatory genes expression [52].APS showed beneficial effects to lower body weight, blood glucose and triglyceride levels in mice with insulin resistance and DM [53].Besides, APS partially improved myocardial glucose and lipid metabolism disorders in diabetic hamsters and protected myocardium [54].
Thus, polysaccharides exert anti-diabetes effect or have beneficial effects on DM complications through different ways.
The number of publications on the effects of polysaccharides on DM was summarized in Figure 2c, which showed a gradually increasing trend in recent years.The allocation of publications for different polysaccharide components was shown in Figure 2d.

The development of DOPD database
The database interface includes the following sections: HOME, SEARCH, SUMMARY 1, SUMMARY 2, SUMMARY 3, and HELP.
In the search interface, there are three methods for search: 1) search by a specific omega-3 PUFA and polysaccharide components; 2) search by one or two functions which both omega-3 PUFA and polysaccharide have; and 3) search by article information, such as PMID, title, publication time and so on.Furthermore, a combination search of the components and functions can also be carried out.
To better understand the function and mechanism of omega-3 PUFA and polysaccharide on DM, we categorized the potential functions into 7 types [Figure 2e].The SUMMARY 1 section includes some basic statistics of the publications in the database [Figure 2].The SUMMARY 2 and SUMMARY 3 sections are the combined article information of both PUFA and polysaccharide in each function category showed in different way [Figure 2e], which may indicate the study trend and status of omega-3 PUFA and polysaccharides on DM and its complications intuitively.Users can click the article number to browse the detail information.On SUMMARY 2 page, users can filter by keywords or rank each column by the number.

Knowledgebase Development and Review for the Function of Omega-3 Polyunsaturated Fatty Acid and Polysaccharide in Diabetes
Copyright: © 2016 Yang and Guo, et al.

The prediction of combined effects of omega-3 PUFA and polysaccharide
Amir Abdolahi [55] reported that the ingestion of fish oil, both alone and in combination with aspirin, reduced Lysophosphatidylcholine (LPC) and Lysophosphatidic Acids (LPA) plasma concentrations, which may reduce cardiovascular disease risk in diabetic adults.Canetti [56] demonstrated that Essential Fatty Acids (EFA) mainly concluding Linoleic Acid (LA) and ALA can not only reduce pancreas damage, insulin and glucose plasma levels, but also restore the Delta6 desaturase activity in streptozotocin-induced diabetes mice.Iancu [57] pointed out that only the diet supplemented with both flaxseed (which was very rich in omega-3 PUFA) and vitamin E resulted in the significant reduction of platelet aggregation and adhesiveness as compared to diabetic animals fed with control diet in diabetic hamsters.You-Gui Li [58] reported that Deoxynojirimycin-Polysaccharide Mixture (DPM) decreased blood glucose and reversed the damage to pancreatic β-cells in diabetic mice, thus the anti-hyperglycemic efficacy of this combination was better than that of 1-Deoxynojirimycin (DNJ) or polysaccharide alone.However, whether the combination of omega-3 PUFA and polysaccharides can exert synergistic effects on DM is unknown.Thus, based on our developed DOPD database, we predicted the potential synergistic effects on DM combining omega-3 PUFA and polysvaccharides.
In our database, SUMMARY 2 and SUMMARY 3 both show the potential effects on preventing and ameliorating DM and its complications by combining omega-3 PUFA and polysaccharide but with different strategies.Take SUMMARY 3 for an example [Figure 3], each row of the form represents the component of polysaccharides while each column is different components of omega-3 PUFA.In the cross-cell, A, B, C, D, E, F, G represent seven different functions [Figure 2e], numbers in brackets represent the articles number that omega PUFA and polysaccharide have effects on DM respectively.In the cross-cell of EPA and APS, "A" represents function "Increase insulin secretion", so there are 7 articles about EPA and 9 articles about APS on "Increase insulin secretion" in DM, others are as the same principle.Also the numbers take on different color, it is set up according to the number of omega-3 PUFA which the gradient is 10, followed by gray, green, bright green and red.If the number is gray, it indicates that omega-3 PUFA and polysaccharide has no same function.Furthermore, the number can link to related articles.
On the basis of database, several potential combinations of omega-3 PUFA and polysaccharides were suggested to prevent and ameliorate DM [Figure 3].First, the combination of APS with EPA, DHA or ALA: APS was the most studied polysaccharide on DM, and it shared at least four same functions with EPA, DHA and ALA, including increasing insulin secretion, hypoglycemic activity, and anti-inflammatory activity and decreasing endothelial dysfunction as well as decreasing myocardial injury.Furthermore, APS and EPA, DHA as well as ALA can regulate NF-κB, AMPK, PPAR-ˠ or other translational factors or proteins that involved in DM.Second, the combination of Ganoderma lucidum polysaccharide (PSG-1) and each of EPA, ALA and DHA: PSG-1 had the most same functions with EPA, DHA as well as ALA, which could reach to seven functions with EPA and ALA.Third, the combinations of MDG-1 with EPA, both of them had four same functions.All the suggested combinations of omega-3 PUFA and polysaccharides have not been proposed and reported.It was worth pointing out that the database has the capability to find out whether both omega-3 PUFA and polysaccharide can regulate the same genes and the related signal pathways in DM if the deposited sources contain genetic information that omega-3 PUFA or polysaccharide regulated in DM.

Figure 1 :
Figure 1: The schematic representation of architecture of database DOPD

Figure 2 :
Figure 2: The number of articles of different years and components of omega-3 PUFA and polysaccharides on DM a.The number of annual articles for omega-3 PUFA on DM after 2000.The number of the year 2014 is only for the first two months.b.The number of publications for different omega-3 PUFA components on DM.Omega-3 column means the article only mentioned omega-3 and no specific components.c.The number of annual article for polysaccharides on DM after 2000.(The number of 2014 is only for the first two months) d.The number of publications for different polysaccharide components on DM. e.The number of articles correlated with different functions.

Figure 3 :
Figure 3: The combination of omega-3 PUFA and polysaccharide connected by functions The rectangle colored with red is an example of the supported article number of APS and EPA in each function.