Stephanie Tan

THE EFFECT OF PHILIPPINE MEDICINAL PLANTS ON THE GLYCEMIC CONTROL AND CARDIOVASCULAR RISK FACTORS​ ​IN TYPE 2 DIABETES: A SYSTEMATIC REVIEW Authors​: Antonio, Dominic Martin L. Aportadera, Emma Teresa Carmela L. Cadiz, Renarose Angela J. Chan, Stefanie Robyn S. Coronel, Maria-Kassandra E. Diño, Jose Paolo A. Tabuno, Angelette F. Tan, Rochelle Anne R. Tan, Stephanie M. Ver, Abbygail Therese M. INSTITUTION​: University of Santo Tomas, Faculty of Medicine and Surgery PRESENTER​: Maria-Kassandra E. Coronel E-Mail Address​:- 1 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM TABLE OF CONTENTS ABSTRACT Background 4 4 Objective/s 4 Methods 4 Key Findings and Discussion 5 Conclusion and Recommendations 5 INTRODUCTION Objectives Significance of the Study METHODOLOGY Eligibility Criteria 6 6 6 7 7 Outcome Measures 7 Methodological Approach 7 Data Extraction 8 Critical Appraisal 8 RESULTS AND DISCUSSION Abukado - Persea sp. 9 10 Ampalaya - Momordica charantia 11 Balbas-pusa - Orthosiphon stamineus 11 Banaba - Lagerstroemia speciosa 11 Bawang and Sibuyas - Allium cepa and Allium sativum 12 Bayabas - Psydium guajava 12 Caimito - Chrysophyllum cainito L. 12 Dalanghita – Citrus reticulata 13 Duhat - Syzygium cumini 13 Guyabano - Annona muricata 13 Kalingag - Cinnamomum zeylanicum 14 Kamatsile - Pithecellobium dulce or Feuillia dulcis or Inga camatchilii 14 Kasuy - Anacardium occidentale 14 Lagundi - Ventix negundo 15 Luya (Ginger) – Zingiber officinale Roscoe 15 Malunggay - Moringa oleifera 15 Mangosteen - Garcinia mangostana 16 Okra - Abelmoschus esculentus (Hibiscus esculentus) and Basil (Ocimum basilicum) 16 Sabila - Aloe vera 16 2 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM Saging - Musa paradisiaca 17 Other plants 17 Outcome Measures 17 Hemoglobin A1C 18 Glucose Level 19 Weight 19 Total Cholesterol & Triglycerides 20 HDL/LDL 21 CONCLUSION 22 RECOMMENDATION 22 3 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM ABSTRACT Background Diabetes is a worldwide predicament that is reaching epidemic proportions in the Philippines. However, the country is also endowed with abundant plant resources; many of which are said to have anti-diabetic properties. Identification and comprehensive investigation of such plants can provide a means to combat the escalating burden of the disease. Objective/s This study aimed to systematically synthesize data about Philippine medicinal plants on their effects on glycemic control and cardiovascular risk factors in Type II Diabetes. Plants of interest were abukado, akapulko, ampalaya, balanoi, balbas-pusa, banaba, bawang, bayabas, caimito, dalanghita, duhat, guyabano, kalingag, kamatsile, kasuy, lagundi, luya, malunggay, mangosteen, mankit, okra, pandan, sabila, saging, sibuyas, and sinta. Methods A thorough literature search through PubMed, Cochrane CENTRAL, HERDIN, and the Department of Science and Technology (DOST) Tuklas Lunas program, for studies on humans and animals was completed. This review investigated the effects of the twenty-six aforementioned Philippine plant groups for their impacts on HbA1c levels, fasting plasma glucose, and cardiovascular risk factors (body weight, total cholesterol, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triacylglycerol). Randomized control trials (RCTs), observational analytic studies, experimental analytic studies, mixed methodology studies, and literature reviews were included into the study, while descriptive studies, commentaries, editorials, unpublished studies, and other working papers were excluded. Literature not published in English or within 5 years were also excluded from the study. Joanna Briggs Institute Critical Appraisal checklists were used to assess the included studies, with the minimum standard or passing score at 80%. To control for bias, two researchers appraised the studies. During instances when scores resulted to both an inclusion and exclusion, a third researcher was tasked to assess the study. Any further disagreements between their ratings were resolved through discussion and consensus. 4 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM Key Findings and Discussion Data extraction identified 1258 journals reports. 2 were removed due to duplication. 1256 reports were thoroughly screened. 1163 were later removed due to pre-established exclusion criteria. A total of ninety-three journals were included in this present review. The systematic review showed that 22 of the 26 plant groups exhibited the aforementioned antidiabetic and anti-obesity properties, with the Ampalaya plant group (​Momordica charantia)​ being the most extensively studied. Specifically, nine plants were shown to control HbA1c levels, 19 plants were shown to decrease fasting plasma glucose, 12 plants were shown to decrease weight gain, 17 plants were shown to decrease total cholesterol, 19 plants were shown to decrease LDL, 14 plants were shown to increase HDL, and 18 plants were shown to decrease triacylglycerol levels. Conclusion and Recommendations The growing burden of Diabetes in the Philippines can possibly be alleviated with the archipelago’s rich plant resources. Whilst most of the included studies in this review are experimental studies on rats, there is great potential for 22 Philippine plants to be used as alternative or adjacent medications to control HbA1c levels, fasting plasma glucose, and cardiovascular risk factors amongst Type II Diabetics in the future. It is recommended that more studies on these plants, particularly RCTs amongst ​Homo sapiens​, be done. 5 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM INTRODUCTION Diabetes is a global burden and major cause of morbidity, leading to blindness, kidney failure, heart attacks, strokes and lower limb amputation, and death in populations worldwide. In 2016, an estimated 1.6 million deaths were directly caused by diabetes, with another 2.2 million deaths in 2012 due to high blood glucose. According to the World Health Organization (WHO) (2018), the number of afflicted individuals has risen almost 400%, from 108 million in 1980 to 422 million in 2014. Meanwhile, the prevalence of diabetes among adults over the age of 18 years has risen from 4.7% in 1980 to 8.5% in 2014. Globally, diabetes accounted for an estimated 12% of health expenditures in 2010, at least $376 billion—a figure expected to hit $490 billion in 2030 (Hu, 2011). Due to the increasing number of people with diabetes worldwide, its burden can be felt globally; however, the focus falls mostly on Asian countries due to increase both in its prevalence and incidence (Paz-Pacheco, 2015). As of 2016, around 6 million of the Filipino population have been diagnosed with diabetes and is predicted to rise in subsequent years. The country’s Department of Health (DOH) aims to address the issue through measures for prevention (DOH, 2017). Several studies within the country have been carried out attempting to address the disease burden. One study compiles a list of medicinal plants found in Tarlac, Philippines used as remedies for diabetes (Mina & Mina, 2017). The authors asked respondents to evaluate plants’ relative efficacy on diabetes. The listed plants are the basis of those investigated in the present study. Objectives The study aims to systematically synthesize data about Philippine medicinal plants on their effects on glycemic control and cardiovascular risk factors in type II diabetes. Significance of the Study This review elucidates greater understanding of the specified medicinal plants on their effects on glycemic control and cardiovascular risk factors in type II diabetes. While the plants included in this study may not be considered a first-line alternative to the current medication for diabetes, the study may offer insights on possible alternative or adjunct herbal medications for the management of the disease. 6 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM METHODOLOGY The systematic review was conducted in October 2018 following the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) methodology as outlined by Shamseer ​et al.​ (2015). Studies were selected according to the criteria below. Eligibility Criteria Literature screened included randomized control trials (RCTs), observational analytic studies, experimental analytic studies, mixed methodology studies, and literature reviews. Descriptive studies, commentaries, editorials, unpublished studies, and other working papers were excluded from the study. The researchers included studies involving selected Philippine medical plants of research interest through the Department. of Science and Technology (DOST) Tuklas Lunas program that were used for diabetes identified through review of literature and how the said plants ameliorate the T2DM (PCHRD-DOST, 2018; Mina and Mina, 2017). Plants of interest were abukado, akapulko, ampalaya, balanoi, balbas-pusa, banaba, bawang, bayabas, caimito, dalanghita, duhat, guyabano, kalingag, kamatsile, kasuy, lagundi, luya, malunggay, mangosteen, mankit, okra, pandan, sabila, saging, sibuyas, and sinta. Outcome Measures With regards to type II diabetes mellitus, the study focused on the management of glycosylated hemoglobin (HbA1c), blood sugar, and cardiovascular risk factors, specifically fasting plasma glucose, body weight, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triacylglycerol, which are validated risk factors for cardiovascular disease and is the main cause of death in patients. These biomarkers are the most used for T2DM patients in all clinical trials (Schiwingshackl ​et al.​, 2017). Methodological Approach Literature search strategies were elaborated using PubMed, Cochrane CENTRAL, and HERDIN. Articles of interest will be elucidated using the following search terms: 1. Diabetes OR T2DM 2. Plant Common English Name OR Plant Scientific Name 3. Glycemia OR glycaemia OR HbA1c OR body weight OR cholesterol OR lipid 7 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM 4. Meta-analysis OR Systematic Review OR Randomized Controlled Trial OR Case-control OR Cohort OR Experimental 5. Combinations of #1 AND #2 AND #3 AND #4 The search strategy was adapted for each database. The “Snowball Method” to obtaining literature was also done. Other systematic reviews and meta-analyses were also checked to search for further relevant studies. Literature not published in English or within 5 years were excluded from the study. Data Extraction The following data was extrapolated from the selected literature: first author’s last name, year of publication, study design, study population and its characteristics, plant/s of interest, outcome measure, results, and conclusions. The following outcome measures were extracted: post-intervention values and SD of HbA1c, fasting plasma glucose, blood lipid profile, and body weight. Critical Appraisal The Joanna Briggs Institute Critical Appraisal checklists for randomized controlled trials, systematic reviews, and quasi-experimental studies were used to assess the obtained studies based on the set inclusion and exclusion criteria. The researchers set the minimum standard or passing score at 80% of the total items in each of the checklists. To control for bias, two researchers appraised the studies. During instances when scores resulted to both an inclusion and exclusion, a third researcher was tasked to assess the study. Any further disagreements between their ratings were resolved through discussion and consensus. 8 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM RESULTS AND​ ​DISCUSSION As seen in Figure 1, during the Identification part of this study’s methodology, researchers identified 1258 journal reports (1255 via database searching and an additional 3 through other sources). After 2 were removed for duplication, 1256 journals were thoroughly screened. Figure 2 shows the research articles elucidated and screened for ELIGIBILITY. As seen in the pie chart, the most common of the 26 included plants are: ampalaya, kamatsile, and kasuy. 9 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM After thorough screening, 93 journal articles were included in this study. This study showed that 22 of the 26 plant groups exhibited the aforementioned antidiabetic and anti-obesity properties. The following are the summaries of each individual plant after systematic review. Abukado - ​Persea sp. Persea sp.​, ​or avocado, is an excellent source of dietary fiber, a food component strongly linked to enhancement of satiety and modulation of glucose and insulin responses to meals (Burton-Freeman, 2000; Juvonen ​et al.​ , 2009; Dreher & Davenport, 2013). It generally reduces LDL and increases HDL in the experimental setting; however, no significant difference was found in the insulin secretion and sensitivity of obese patients given avocado soybean unsaponifiables (ASU) over 3 months. ASU was composed of fractions of 1/3 avocado and 2/3 soybean oils, which were reported to have a negative effect on IL-6 and CRP, supposedly leading to increased insulin secretion and action (Martinez-Abundis ​et al.,​ 2013). 10 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM Ampalaya​ - ​Momordica charantia Momordica charantia, k​ nown as ampalaya or bitter gourd, has been the focus of numerous studies in the examination of its antidiabetic and antioxidant properties. Several studies have demonstrated the bitter gourd’s hypoglycemic actions. Preparations shown to be effective include Momordica charantia leaf and fruit extracts, herbal concoctions, and dietary supplements (Mahmoud ​et al.,​ 2017; Tahira and Hussain, 2014; He ​et al.,​ 2018). A systematic review and meta-analysis study of RCTs by Peter ​et al. have concluded that adjunct preparations had improved glycemic control and that a standard formulation is warranted to further assess its activity in future trials. Ampalaya has also proved effective in the control and mitigation of cardiovascular risk factors. The plant had demonstrated hypolipidemic effects amongst a healthy variety of studies using different preparations and populations. A possible mechanism of action may be by regulation of hepatic PEPCK, 11beta-HSD1 and AMPK phosphorylation (Shih ​et al.,​ 2014). Wang and Ryu have concluded that Momordica charantia ​extracts have anti-obesity effects alongside its hypolipidemic effect. Wilai et al. claims that this plant may also be useful in treating systemic effects of T2DM as well. Balbas-pusa -​ Orthosiphon stamineus In a study by Azam ​et al. (2017), OS aqueous extract (OSAE) showed a reversal of acetoacetate and 3-hydroxybenzotriazol (3-HBT) indicative of energy metabolism. There was also a reversal of high levels of branched-chain amino acids (BCAA) which signifies decreased ketogenesis or gluconeogenesis. In comparison with the diabetic group, the OS treated had lower body weight as well. In addition to this, an improved lipid profile as evidenced by lowered triglyceride, total cholesterol and low-density lipoprotein were noted (Seyedan ​et al.,​ 2016). Banaba - ​Lagerstroemia speciosa Banaba leaves have been used traditionally as antidiabetic treatment in the Philippines. Multiple active constituents of banaba such as corosolic acid and tannin components contribute to its hypoglycemic effects. Short-term clinical trials have reported decreased fasting blood glucose with no hypoglycemia, toxicities or adverse effects in humans (Kouzi ​et al.,​ 2015). Extracts from the flower has been found to significantly lower blood sugar dose dose-dependently against glibenclamide control. (Sharmin ​et al.​, 2018). Self micro-emulsifying formulations of the plant extract increases the hypoglycemic and hypolipidemic activity of ​Lagerstroemia speciosa leaves. (Agarwal​ et al.,​ 2018). 11 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM Bawang and Sibuyas - ​Allium cepa a​ nd ​Allium sativum ​Allium sativum (garlic) possesses hyperinsulinemic, hypoglycemic, hypocholesterolemic, hypotriglyceridemic, anti-glycation, and anti-lipid peroxidation actions and has been shown to improve insulin sensitivity and metabolic syndrome in animal models and human studies. Aged extracts show greater activity (Thomson ​et al.​, 2016; Miki ​et al.​ , 2017; Ota & Ulrih, 2017). These may be attributed to organosulfur compounds which can act as insulin secretagogues or sensitizers and variably exert hypoglycemic activity (Trio ​et al.,​ 2014). A meta-analysis of RCTs of garlic supplementation in T2DM management confirms regulation of blood glucose, total cholesterol, and lipids. (Wang ​et al.​, 2017) Sibuyas has anti-diabetic effects, with proven hypoglycemic and insulinotropic activity in multiple diabetic animal models as well as clinical studies on patients (Akash ​et al.​, 2014; Pradeep & Srinivasan, 2017; Ikechukwu & Ifeanyi, 2016; Gautam ​et al.,​ 2015; Jafarpour-Sadegh ​et al.,​ 2016). Both species are also listed as having antidiabetic properties by Bading Taika ​et al.​ (2018). Crude extracts of Allium species and cultivars inhibit α-glucosidase by over 80%. (Schmidt ​et al.,​ 2014). Species whose antidiabetic potential has been studied include ​A. ascalonicum,​ ​A. tuberosum​, and A. ampeloprasum. ​(Kongstand​ et al.​, 2015; Tang ​et al.,​ 2017; Rahimii-Madiseh ​et al.,​ 2017) Bayabas -​ Psydium guajava Rats given guava leaf extract (GLE) showed inhibition of antioxidant decline that delayed oxidative stress to tissues. The methanol extract of guava was most effective in lowering glucose levels. Reduction in fatty infiltration and destruction of pancreatic islet cells were found. It also protects hepatic and renal tissues (Jayachandran ​et al.​, 2017). ​Psydium guajava (P ​ G) can delay onset of insulin resistance, leptin resistance, hyperinsulinemia, weight gain, hypertension and hypertriglyceridemia (Mathur ​et al.​, 2015). Caimito - ​Chrysophyllum cainito​ L. Chrysophyllum cainito L., also called the star apple or caimito, is from the Sapotaceae family and has been shown to have antihypertensive, anti-inflammatory, antioxidant, antibacterial and antidiabetic properties. The stem bark decoction has been traditionally used as antidiabetics. Although several parts of C. cainito​, such as fruit, leaf and stem, have been used as alternative medicines for the treatment of diabetics in many countries, documentation on antidiabetic activity of the extract from its stem bark has been limited. Doan ​et al. (2018) conducted an investigation on the use of ​C. caimito stem barks in maintaining glucose homeostasis which showed significantly improved glucose tolerance and 12 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM enhancement of glucose uptake, positive effects on glucose absorption, glucose uptake and α-glucosidase activity. An experiment by Hegde ​et al​. (2017) on Wistar albino rats also found ​Chrysophyllum cainito to be effective against alloxan- and streptozotocin-induced diabetes possibly due to the regeneration of pancreatic β-cells, potentiating serum insulin effect by increasing either the pancreatic secretion of insulin from the existing β-cells or by increasing the peripheral utilization of glucose and inhibiting the glucose transporter activity from the intestine. Dalanghita – ​Citrus reticulata C ​ . reticulata ​ameliorates blood glucose levels in T2DM through improvements in lipid profile, weight gain, serum insulin and glucagon levels, and insulin sensitivity (Park ​et al.,​ 2013; Constantin ​et al., 2​ 014; Liu ​et al.,​ 2016; Jia ​et al.​, 2015; Guo ​et al.​, 2016; Rotimi ​et al.,​ 2018). The hypoglycemic effect of ​C. reticulata ​was associated with a marked decrease in phosphoenolpyruvate carboxykinase activity in the liver (Park ​et al., 2​ 013). Citrus pectin was shown to significantly reduce insulin resistance through upregulation of phosphorylated Akt expression and downregulation of GSK3β expression, indicating that the potential anti-diabetic mechanism might occur through regulation of the PI3K/Akt signaling pathway (Liu ​et al.,​ 2016). Duhat - ​Syzygium cumini Extracts of ​S. cumini a​ re known to reduce the risk via improving insulin secretion, regulating the enzymes involved in glucose homeostasis, maintaining lipid levels, decreasing HbA1C, and improving the activity of antioxidant enzymes (Chandran ​et al.,​ 2016; Trinh ​et al.,​ 2016; Thiyagarajan ​et al​., 2016; Ecker ​et al.,​ 2017; Sharma ​et al​., 2017; Sidana ​et al.,​ 2017; Ajiboye ​et al.​, 2018; Chagas ​et al.​, 2018). This plant also inhibits the pathway of cholesterol synthesis and increases HDL/LDL ratio (Sampath ​et al.,​ 2013). Trinh ​et al. (2016) and Franco ​et al.​ (2017) state the potential 𝞪-glucosidase and 𝞪-amylase inhibitory effects of these phenolic compounds. Lastly, ​S. cumini a​ lso contains Vitalboside A, which is a selective inhibitor of PTP1B, a major negative regulator of insulin and leptin signaling. This enhances insulin sensitivity and attenuates lipid accumulation via partial agonism to PPAR𝝲 (Thiyagarajan ​et al.,​ 2016). Guyabano - ​Annona muricata Genus ​Annona is a widely known and used as traditional medicine in tropical countries. Decrease in the total cholesterol, triglycerides, LDL, and VLDL, while increase on HDL of the diabetic were 13 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM observed. Results support previous studies on the extract’s similar activity to glibenclamide. In another study leaves extract of ​A. muricata were administered to STZ-induced diabetic rats for 28 days (Florence et al.,​ 2014). By 28 days reduced blood glucose levels and LDL-cholesterol were observed. Total cholesterol and enzymatic activity were also restored to normal. The study thus connotes that extract works long term. Kalingag - ​Cinnamomum zeylanicum The two main varieties of the genus ​Cinnamomum are Chinese cinnamon (​C. cassia or ​C. aromaticum​) and Ceylon cinnamon (​C. zeylanicum or ​C. verum​). Studies showed that cinnamon induces a significant decrease in serum glucose, HbA1c, total cholesterol, serum triglycerides, and LDL-c, and an increase in HDL-c (Askari et al., 2013; Beejmohun et al., 2014; Gupta Jain et al., 2017). Liu ​et al. (2015) further noted that cinnamon intake continued improved serum glucose level even after treatment cessation. These improvements were consistent in non-alcoholic fatty liver disease (NAFLD) patients. A systematic review and meta-analysis by Allen ​et al. (2013) reported a statistically significant decrease in levels of serum glucose, total cholesterol, LDL-c, and triglyceride, and an increase in HDL-c. Meta-analysis showed a high degree of heterogeneity among 10 RCTs dated 2003 to 2012, limiting the applicability of these results to patient care. In addition, preferred dose and therapeutic duration remain unclear. Kamatsile - ​Pithecellobium dulce o​ r ​Feuillia dulcis o​ r ​Inga camatchilii The hydroalcoholic fruit extract of kamatsile (​Pithecellobium dulce)​ is safe to use for clinical trials. Ethanolic and aqueous extracts have show effects comparable to glibenclamide (Kulkarni & Jamakhandi, 2018 and Kumar ​et al.,​ 2017). The anthocyanin-rich fraction inhibits alpha-glucosidase activity by as much as 46x that of the negative control (López-Angulo, ​et al​., 2018). Kasuy - ​Anacardium occidentale Anacardium occidentale,​ commonly known as kasuy or cashew, is a Philippine medical plant introduced from the tropical Americas and is locally used as an antibacterial and anti-inflammatory agent. Studies have shown antidiabetic potential of its nuts and leaves (Jaiswal ​et al.​, 2016 and Mohan ​et al.,​ 2018). In one study, cashew leaf extracts were concluded to be comparable to pioglitazone, a commonly used antidiabetic. This is attributed to its high phenolic content and antioxidant capacities. Its nuts also 14 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM proved effective in mitigating glycemia and CV risk factors when used as a supplement in a standard diabetic diet. Lagundi - ​Ventix negundo Lagundi or ​Vitex negundo is one of the indigenous plants in the Philippines that belongs to the Vitex genus. Many species belonging to the same genus exhibited anti-diabetic properties. While there are a number of studies on its neighboring species, studies on ​Vitex negundo are quite limited. These studies, however, showed that Lagundi may reduce triglycerides, cholesterol, and LDL and increase HDL. Since studies are few and limited, more studies should be made on this plant. Luya (Ginger) – ​Zingiber officinale ​Roscoe Zingiber officinale R ​ oscoe (Zingiberaceae), ginger, has long been used in complementary and alternative medicine for the treatment of diabetes. It is associated with increased capacity of energy metabolism reducing blood glucose levels and subsequently reducing in weight. Major findings that further strengthen the antihyperglycemic potential of ​Z. officinale are that ginger extract markedly decreased circulating insulin and prevented insulin resistance. In the study, [6]-Gingerol showed potent insulin secreting, antihyperglycemic, lipid lowering, and antioxidant properties. Data from Azarati ​et al. (2017) postulate that ginger supplementation significantly reduces serum levels of fasting blood glucose and HbA1C as well as the ratio of LDL-C/HDL-C. Wang ​et al. (2017) demonstrated that oral administration of ginger extract not only improved glucose control, but it also significantly reduced body weights and serum lipid levels. Malunggay - ​Moringa oleifera The malunggay plant, or ‘Drumstick Tree’, is a common ingredient in many Filipino dishes that exhibits anti-diabetic properties. Of the 15 articles appraised, only 2 are clinical trials, with the rest being experimental. All experimental articles were conclusive on its anti-hyperglycemic effects on diabetic rats. In all studies, mice had significant body weight increase. El Latif ​et al.​ (2014), Waterman ​et al. (2015), Olayaki ​et al. (2015), and Paula ​et al. (2017) mention that malunggay lowered levels of LDL, cholesterol and triglycerides and increased HDL. Momoh ​et al. (2013) claim that ​M. oleifera has the potential to be a more potent antidiabetic drug compared to glibenclamide; however, results are inconclusive at the level of clinical trials. One clinical trial by Taweerutchana ​et al. (2017) showed that ​M. oleifera had no effect on glycemic control on type 2 diabetes mellitus patients. ​M. oleifera presents as a potential antidiabetic drug, but further studies are needed for its approval as antidiabetic therapy. 15 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM Mangosteen​ - ​Garcinia mangostana The Mangosteen ​Garcinia mangostana Linn. (Clusiaceae) is a tropical evergreen tree in Southeast Asia, and its fruits are known as “Queen of Fruit” in Thailand. Our review consisted of one clinical trial, two systematic reviews, and two experimental studies. Generally, Mangosteen reduces glucose, triglycerides, body weight, LDL, and total cholesterol and increased HDL in experimental diabetes-induced rats. While Mangosteen is an effective antidiabetic and anti-obesity plant for diabetic rats, the clinical trial conducted did not show any significant decreases or increases in glucose, body weight, LDL, HDL, cholesterol, and triglycerides when tested on obese female patients; thus, the findings of these studies show that more experimental studies may be needed to prove the uses of this plant. Okra - ​Abelmoschus esculentus (Hibiscus esculentus)​ and Basil ​(Ocimum basilicum) Abelmoschus esculentus,​ commonly known as Okra, and ​Ocimum basilicum, commonly known as Basil, are integral food items in the Asian cuisine and have potential anti-diabetic properties. Both have been shown to lower blood glucose and TAGs (Ezeani ​et al.​ , 2017; Liu ​et al.,​ 2017). Free fatty acid reduction and significant increase in HDL/LDL was seen in ​A. esculentus (​ Huang ​et al.​ , 2017), while ​O. basilicum (Ezeani ​et al.​, 2017) has shown significant reduction in serum cholesterol. However, anti-obesity effects of both plants has shown conflicting results in literature (Chaudhary ​et al.,​ 2016; Huang ​et al.​, 2017). Sabila - ​Aloe vera Aloe vera is one of the many ​Aloe species, which is specifically classified under ​Aloe barbadensis Miller. Several literatures have reported its efficacy in lowering blood glucose level and lipid profile markers in diabetic patients. Studies show that this plant reduces serum glucose, HbA1c, total cholesterol, and LDL. Standard aloe preparations can therefore be offered as an adjunct to revert impaired fasting glucose and glucose tolerance in conditions of prediabetes and metabolic syndrome; however, an RCT in type 2 diabetic patients by Zarrintan ​et al. (2015) contradicted the previous conclusions and showed that Aloe vera supplement beside the main treatment for DM had no significant effect in blood glucose level and lipid profile. There was also no significant difference between the pre- and post-intervention levels, as well as those between intervention and placebo groups. 16 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM Saging - ​Musa paradisiaca Plantain (Musa paradisiaca) is a staple crop in the humid and sub-humid parts of Africa, Asia, Central and South America that is usually eaten as an energy yielding food. Its hypoglycemic actions in diabetic animals have been reported. Our review of the saging consists of eight experimental studies. Of the eight experimental studies, six reported significant reductions in serum glucose, while two of the studies, namely the studies by Eleazu ​et al.​ (2013) and Iroaganachi ​et al.​ (2015), did not report significant reductions when taken with other antidiabetic plant medications; They noted that their antidiabetic properties are better when saging is taken alone. Ajiboye ​et al (2017),​ the most recent study to date, showed significant reductions in body weight, triglycerides, LDL, and cholesterol when ​M. paradisiaca is used as an antidiabetic agent. Other plants Plants such as ​Cassia alata, Galium cordifolium, Pandanus odoratissimus, and Andrographis paniculata are not included in the analysis due to lack of studies about the aforementioned plants. Outcome Measures Figure 3 below shows that of the 93 journal articles included in this study, the majority focused on the following outcome measures: decrease in glucose levels (30%), decrease in TAG (16%), and decrease in total cholesterol (15%). Systematic review showed that nine plants were shown to control HbA1c levels, 19 plants were shown to decrease fasting plasma glucose, 12 plants were shown to decrease weight gain, 17 plants were shown to decrease total cholesterol, 19 plants were shown to decrease LDL, 14 plants were shown to increase HDL, and 18 plants were shown to decrease triacylglycerol levels. 17 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM Figure 3. Pie chart of outcome measures Figure 4 below shows that of the 26 Philippine plants included in this study, the most studied were: Ampalaya (studied by 52 journal articles), Malunggay (studied by 31 journal articles), and Sibuyas (studied by 27 journal articles). Figure 4. Bar graph of outcome measures for each medicinal plant Hemoglobin A1C HbA1C or glycated hemoglobin identifies the three-month average plasma glucose concentration. During states of hyperglycemia, the excess glucose present in the blood reacts with hemoglobin to form glycated hemoglobin (Ajiboye ​et al.,​ 2018). These red blood cells have an average lifespan of 120 days, 18 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM thus testing for HbA1C is limited to a three-month period. In the diagnosis of DM, an HbA1C of ≥ 6.5% is considered significant (Jameson et al.,​ 2018). Therefore, decreased levels of HbA1 is associated with better glycemic control in those with T2DM. Among the 93 journals included in the review, only 18 included HbA1C as a measurable outcome; making it the least used measure of hyperglycemia in studies of medicinal plants. This may be due to its aforementioned limited time frame as an indication of hyperglycemic state. Among the original list of this study’s 26 plants, 9 were shown to decrease HbA1c: Ampalaya, Caimito, Duhat, Kalingag, Kasuy, Luya, Malunggay, Okra and Sabita. ​Zingiber officinale (​ luya or ginger) had the most studied effects on HbA1C, due to its inhibition of enzymes in carbohydrate metabolism (particularly a-glucosidase and a-amylase) (Li et al, 2012). This is followed by ​Anacardium occidentale (Kasuy) with its HbA1c lowering properties of stimulating insulin secretion on B-cells (singh, 2010) and ​Aloe vera (Sabila), which ​normalizes membrane-bound enzyme activities of phosphatases and hydrolases and increased glucose metabolism ​(Grundmann, 2012, ​Li ​et al.​, 2013 & Azarati ​et al.​ , 2017). Glucose Level Among the articles gathered, decreasing glucose level is the most widely studied effect of medicinal plants. Controlling hyperglycemia in DM is important to avoid microvascular and macrovascular complications and adverse effects (Kumar & Sandhya 2017). Increased blood glucose has a damaging effect on cells which hinders internal glucose homeostasis. Postprandial glucose spikes compromises endothelial cell function and increases cardiovascular risk (Azad ​et al.,​ 2017). Decreasing glucose levels is most prominent in ​Momordica charantia (Ampalaya). This is attributed to its amelioration of insulin resistance by regulating the expression of SOCS-3 and JNK ​(Ma et al., 2017). Another plant known for effective for its hyperglycemic control is ​Allium cepa (Sibuyas), possibly due to its alpha glucosidase inhibition (Jafarpour-Sadegh, 2016). ​Moringa oleifera (M ​ alunggay) also has a beneficial effect by acting on alpha amylase which would delay sugar absorption and lower glycemic peak (Azad ​et al.​ , 2017). Most of the plants had a beneficial effect on glucose maintenance. Weight A pathologic increase in weight is highly associated with the development of type 2 diabetes mellitus (T2D), as obesity is a major driver in the development of T2D. It is considered a low-grade chronic inflammatory state, which has been related to insulin resistance and abnormalities in insulin secretion (Van Gaal & Sheen, 2015). Among the 22 plants included, ​Momordica charantia (Ampalaya) had the most articles reporting its effectivity against weight gain. This is attributed to its correlation with 19 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM increased expression of PPARγ ​(Joseph and Jini, 2013)​, PPARa, PPARg ​(Chan et al., 2016),​ its regulation of hepatic PEPCK, 11beta-HSD1 and AMPK phosphorylation ​(Shih et al., 2014). Ampalaya is followed by ​Citrus reticulata (Dalanghita), with its ability to inhibit uptake of oxidized LDL by macrophages, reduced LDL aggregation, and reduced oxidation of LDL cholesterol (Mallick & Khan, 2016), and ​Annona muricata (Guyabano), whose methanolic extracts lowers serum lipid profiles (Sovia, 2017). Guyabano was ranked as the second most cited plant among those used for treatment of obesity (Cercato ​et al.,​ 2016). Total Cholesterol & Triglycerides Total cholesterol is calculated by getting the sum of LDL, HDL, and 20% of the triglycerides. The desirable level for total cholesterol is less than 200 mg/dL, with 200-238 mg/dL already borderline. Levels of 240 mg/dL or greater is considered high. This indicates a greater risk not only for diabetes but also cardiovascular diseases, the main cause of death for diabetic patients (Schiwingshackl ​et al.,​ 2017). Of the 93 studies reviewed, 35 investigate the reduction of medicinal plants of total cholesterol levels. Momordica charantia ranks first with 7 studies supporting it, followed by ​Moringa oleifera with 5 and finally, ​Citrus reticulata, Annona muricata, ​and ​Cinnamomum zeylanicum with 3 each. Ampalaya increases expression of PPARγ ​(Joseph and Jini, 2013)​, PPARa, PPARg ​(Chan et al., 2016),​ regulation of hepatic PEPCK, 11beta-HSD1 and AMPK phosphorylation ​(Shih et al., 2014). Moringa isothiocynates (MICs) inhibits rate-limiting steps in liver gluconeogenesis ​(Waterman et al., 2015). Citrus reticulata (Dalanghita) leads to inhibition of uptake of oxidized LDL by macrophages, reduced LDL aggregation, and reduced oxidation of LDL cholesterol (Mallick & Khan, 2016). ​Annona muricate ​(Guyabano) methanolic extracts lowers serum lipid profiles ​(Sovia, 2017), and Cinnamomum zeylanicum (Kalingag) leaders to an up-regulation of LDL receptor gene expression ​(Kassaee et al., 2016) Triglycerides, sometimes interchangeably lipids, are an end product after digestion. Normal levels are below 150 mg/dL, while 150 to 200 is elevated and 200 to 500 is high and above 500 is very high. High levels have been associated with dysfunction of β-cells and interrupting the normal glucose-fatty acid cycle (Dorcely ​et al.,​ 2017). Many studies addressing diabetes focus on reducing the triglyceride levels. The medicinal plants whose triglyceride lowering effects have been most studied are ​Momordica charantia​, with 7 supporting studies, followed by ​Moringa oleifera with 5, and ​Garcinia mangostana with 4. The mechanisms of action of ​Momordica charantia ​and ​Moringa oleifera have been discussed above, but is is noted that ​Garcinia mangostana effect is via α-Mangostin has an antioxidant and protective effect on lipid peroxidation ​(Ibrahim et al., 2016; Tsai et al., 2016). 20 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM HDL/LDL High-density lipoproteins (HDL) are responsible for reverse cholesterol transport which reduces cholesteryl esters from remnant lipoprotein particles, and scavenges triglycerides which reduces the risk for hyperlipidemia (Assman & Gotto, 2004). HDL functions as a protective factor for the endothelium via mechanisms such as leukocyte-binding resulting to atheroma prevention (Dimayuga ​et al.​, 1999), vasorelaxation (Li ​et al.​, 2002), and prevention of inflammation through leukocyte adhesion molecule suppression (Cockreil ​et al.​, 2001). HDL also has antioxidant properties (Nofer ​et al.,​ 2002). An increase in HDL levels over LDL promotes vasoprotection, which reduces comorbidities such as hypertension, and prevents hyperlipidemia associated with diabetes. Low density lipoproteins (LDL), on the other hand, have the potential to deposit in the blood vessels resulting to increased risk for cardiovascular vascular diseases which are highly associated with obesity and diabetes. Plants that were found to exhibit an increase in HDL and decrease LDL levels based on the number of literature in descending order were: ​M. charantia, M. oleifera, ​and ​Z. officinale​. The effect was due to a certain cucurbitane‑type triterpenoid compound (K16) found in ​M. charantia (Jiang ​et al.​, 2016), ​Moringa isothiocyanates in ​M. oleifera (Waterman ​et al.​, 2015), and for ​Z. officinale​, the exact compound and mechanism is yet known (Arzati ​et al.​, 2017). 21 of 36 THE EFFECT OF PHILIPPINE MEDICINAL PLANTS IN T2DM CONCLUSION The Philippines is greatly affected by diabetes; however, many available plants in the country are said to have anti-diabetic properties. These may be used as potentially cheaper alternative or adjunct diabetic medications. Of the 26 plants included, 22 of those plants exhibit antidiabetic and anti-obesity properties, supported by various studies (Mina & Mina, 2017, and Mootoosamy & Mahomoodally, 2014). 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