Double-blind Randomized placebo-controlled Trials on controlling blood glucose level using the extract from Opuntia ficus-indica var. saboten
Article information
Abstract
Objectives
The aim of this study was to evaluate the effects of Opuntia ficus-indica var. saboten extract on blood glucose regulation in both healthy individuals and those with impaired fasting glucose (IFG). Additionally, the study assessed the safety of Opuntia extract regarding liver and kidney function over a 12-week period.
Methods
A double-blind, randomized, placebo-controlled clinical trial was conducted with 85 participants, including 47 healthy individuals and 38 individuals with impaired fasting glucose (IFG) or impaired glucose tolerance (IFG). Participants were randomly assigned to receive either Opuntia extract or a placebo for 12 weeks. Blood glucose control was evaluated using fasting blood glucose (FBS), oral glucose tolerance tests (OGTT), HbA1c, insulin, and C-peptide levels. Safety assessments included liver function tests (AST, ALT, γ-GTP, ALP) and kidney function tests (BUN, creatinine). Data were analyzed using independent and paired t-tests, with a significance level of p<0.05.
Results
A total of 85 participants were initially enrolled, and after excluding 13 participants due to dropout, consent withdrawal, or protocol violations, the final statistical analysis was conducted with 72 participants. In the IFG group, Opuntia extract significantly reduced fasting blood glucose levels compared to the placebo group (p=0.010). Additionally, Opuntia extract reduced postprandial blood glucose levels at 120 minutes during the OGTT in healthy participants (p=0.047). No significant changes were observed in HbA1c, insulin, or C-peptide levels. Importantly, no adverse effects on liver or kidney function were detected in either group during the 12-week intervention.
Conclusions
The administration of Opuntia ficus-indica var. saboten extract for 12 weeks demonstrated significant blood glucose-lowering effects in individuals with impaired glucose tolerance, without causing any liver or kidney toxicity. These findings suggest that Opuntia extract may be a safe and effective natural option for blood glucose regulation, particularly in pre-diabetic individuals. Further large-scale studies are recommended to confirm these results and explore its potential clinical applications.
Introduction
The global prevalence of diabetes has been increasing rapidly due to population aging, rising obesity rates, physical inactivity, and improved living standards. This trend has led to a significant socioeconomic burden from direct medical costs, complications, disabilities, and mortality. According to a report by the Korean Diabetes Association in 2016, the prevalence of diabetes in South Korea reached 13.7% in 2014 and continues to rise, with pre-diabetes affecting 24.8% of the population, meaning that one in four individuals is at high risk (1).
Treatment strategies for diabetes primarily include dietary therapy, exercise, pharmacotherapy, and insulin therapy. Common hypoglycemic agents include sulfonylureas, metformin, and rosiglitazone, either as monotherapy or in combination (2–4). If pharmacotherapy is insufficient, insulin therapy is often introduced (5,6). Currently developed drugs include gliclazide, acarbose, pioglitazone, and exenatide (2), and recent clinical studies are investigating newer agents such as dapagliflozin and sitagliptin (7,8). However, most diabetes treatments are symptomatic, aimed at managing blood sugar levels rather than providing a cure, and many carry risks of serious side effects like hypoglycemia. Thus, ongoing management is essential.
When pre-diabetic conditions such as impaired fasting glucose (IFG) or impaired glucose tolerance (IFG) are identified, consistent blood glucose control through exercise and dietary regulation is recommended. In such cases, interest in using herbal and natural substances for blood glucose control has grown. Previous randomized controlled trials have demonstrated the hypoglycemic effects of natural substances such as Coccinia indica, American ginseng, chromium, Gymnema sylvestre, Aloe vera, vanadium, Momordica charantia, and Nopal (9). Among these, Nopal (commonly known as prickly pear cactus) has recently garnered attention as a food source and traditional medicine used for its anti-inflammatory and antipyretic properties. Nopal has been traditionally used in Mexico as a treatment for diabetes, and several recent clinical studies have confirmed its efficacy in managing the condition (10). In Korea, Nopal (known as “Baeknyeoncho” or “Bogum Suninjeong”) has been widely cultivated in regions like Jeju Island. However, no clinical trials have been conducted in the Korean population to assess its effects on blood glucose regulation. Therefore, this study was designed to evaluate the clinical efficacy of Nopal extract in regulating blood glucose, and we report the meaningful clinical results obtained from the study.
Subjects and Methods
1. Subject Selection
1) Inclusion Criteria
The study included adults aged 19 to 65, classified as either healthy or having impaired fasting glucose (IFG, fasting plasma glucose of 100–125 mg/dL), impaired glucose tolerance (IFG, plasma glucose levels of 140–199 mg/dL two hours after a 75 g oral glucose load), or both IFG and IFG.
2) Exclusion Criteria
Exclusion criteria included minors under 18, individuals over 65, pregnant women, those who had taken hypoglycemic agents in the past three months, individuals with abnormal thyroid function, gastrointestinal disorders, other diseases requiring continuous treatment or medication, and individuals with alcohol-induced liver damage.
2. Study Design
This study was a single-center, randomized, double-blind, placebo-controlled trial (IRB approval number: 2015-09-02) designed to evaluate the functional efficacy and safety of Opuntia extract in controlling blood glucose levels. After a screening period, participants were randomly assigned in a 1:1 ratio to receive either Opuntia extract or a placebo for a 12-week intervention. The intervention involved taking two sachets of the assigned product (12 g per sachet, totaling 24 g per day) with sufficient water, divided into two daily doses.
Blood samples were collected in a fasting state (following an 8-hour fast) at the start and end of the study to measure fasting blood glucose, insulin, C-peptide, and glycated hemoglobin (HbA1c). HbA1c was measured using the Ez-A1c cartridge (INFOPIA), and insulin and C-peptide levels were analyzed by the Seoul Medical Science Institute.
For the oral glucose tolerance test (OGTT), participants consumed one sachet of the test product (or placebo) with water, followed 30 minutes later by 75 g of anhydrous glucose. Blood glucose levels were measured at 1 hour and 2 hours post-glucose consumption. To assess the effect of Opuntia on glucose absorption, OGTTs were conducted both at the start and at the end of the 12-week intervention period to observe changes in glucose absorption rates. Additionally, lipid metabolism was assessed by measuring total cholesterol, triglycerides (TG), LDL cholesterol, and HDL cholesterol.
For safety evaluation, liver and kidney function tests were performed, including measurements of AST, ALT, γ-GTP, ALP, total bilirubin, total protein, and albumin for liver function, and BUN, creatinine, uric acid, LDH, total calcium, and urinalysis for kidney function.
The significance of differences between groups was tested using independent t-tests and paired t-tests, with a significance level set at p < 0.05. Specifically, paired t-tests were conducted within each group to compare baseline (0 week) and post-intervention (12 week) values, assessing the effects of Opuntia over the intervention period. Independent t-tests were used to compare the Opuntia and placebo groups at both the baseline and 12-week points to determine any significant differences between the groups at each time point. This approach allowed for a comprehensive evaluation of both intra-group changes over time and inter-group differences at each time point.
Introduction
1. General Characteristics of the Participants
A total of 85 participants were enrolled in this study. Participants with a fasting blood glucose level above 100 mg/dL were classified into the impaired fasting glucose (IFG) group, while those with fasting blood glucose levels below 100 mg/dL were classified into the healthy group. A total of 47 participants were assigned to the healthy group, and 38 to the IFG group. After excluding 10 participants due to dropout or withdrawal of consent and an additional 3 participants who completed the trial but violated the protocol, a total of 72 participants were included in the final statistical analysis. This included 20 participants in the Opuntia group and 21 in the placebo group among the healthy participants, and 16 participants in the Opuntia group and 15 in the placebo group among the IFG participants (Fig. 1).
General Characteristics in Clinical Trial
2. Evaluation of Blood Glucose Regulation by Opuntia Extract
To evaluate the blood glucose regulation ability of Opuntia extract, fasting blood glucose and oral glucose tolerance tests (OGTT) were used as the primary efficacy endpoints. Secondary efficacy endpoints included measurements of glycated hemoglobin (HbA1c), insulin, C-peptide, and lipid components.
1) Primary Efficacy Evaluation
(1) Fasting Blood Glucose
In the healthy group, fasting blood glucose levels increased in both the Opuntia and placebo groups. However, since the levels remained within the normal range for fasting blood glucose, the results were not considered clinically significant.
In the group with impaired fasting glucose(IFG), fasting blood glucose levels significantly decreased in the Opuntia extract group, while no changes were observed in the placebo group over the 12-week period.
Fasting blood sugar in healthy group
(2) Oral Glucose Tolerance Test (OGTT)
To assess the effect of Opuntia extract on glucose tolerance, participants consumed the test product or placebo before undergoing an OGTT with 75 g of anhydrous glucose at baseline (week 0). Blood glucose levels were measured at 60 and 120 minutes post-glucose consumption. The same procedure was repeated at week 12. The results for the healthy group are shown in Table 9. In the Opuntia extract group, blood glucose levels at 120 minutes post-OGTT significantly decreased after 12 weeks of consumption. Although blood glucose levels at 60 minutes also decreased compared to baseline, the change was not statistically significant. Overall, the 12-week administration of Opuntia extract appears to help normalize blood glucose levels in healthy individuals after glucose intake. No significant changes were observed in the placebo group.
Fasting blood sugar in impaired fasting glucose group
Glucose tolerance test in healthy group
Renal function test in healthy group
The results of the oral glucose tolerance test (OGTT) for the semi-healthy group with impaired fasting glucose are shown in Table 4. In the Opuntia extract group, blood glucose levels at 60 minutes decreased at week 12 compared to week 0. In the placebo group, 60-minute blood glucose levels also decreased at week 12 compared to baseline, but the change was not statistically significant. Blood glucose levels at 120 minutes post-OGTT decreased in the Opuntia group at week 12 compared to week 0, while in the placebo group, the 120-minute blood glucose levels increased, though without statistical significance. The 12-week administration of Opuntia extract showed a significant reduction in 60-minute blood glucose levels in the semi-healthy group. Additionally, at week 12, there was a significant difference between the Opuntia extract group and the placebo group in 120-minute blood glucose levels.
Glucose tolerance test in impaired fasting glucose group
2) Secondary Efficacy Evaluation
(1) Glycated Hemoglobin (HbA1c), Insulin, and C-peptide
To assess the blood glucose regulation effects of Opuntia extract, HbA1c, insulin, and C-peptide levels were measured before and after the 12-week intervention. The results for the healthy group are shown in Table 5. No significant changes were observed in HbA1c, insulin, or C-peptide levels in either the Opuntia extract group or the placebo group over the 12-week period.
Fasting blood sugar, HbA1c, insulin and C-peptide in healthy group
The results for HbA1c, insulin, and C-peptide in the semi-healthy group with impaired fasting glucose are shown in Table 6. In the Opuntia extract group, there was no significant difference in HbA1c levels between week 0 and week 12. However, in the placebo group, HbA1c levels increased at week 12 compared to baseline. In both the Opuntia extract and placebo groups, there were no significant changes in insulin or C-peptide levels over the 12-week period.
Fasting blood sugar, HbA1c, insulin and C-peptide in impaired fasting glucose group
3) Safety Evaluation
To evaluate the safety of the investigational drug used in this study, hematologic tests were conducted both before and after 12 weeks of administration of the investigational drug and the control drug. Additionally, adverse events and side effects were assessed throughout the study period.
(1) Liver Function Test
The liver function test included measurements of AST, ALT, r-GTP, ALP, bilirubin, total protein, and albumin. The liver function test results for the group of healthy participants are presented in Table 7. While a decrease in protein levels was observed in both the Opuntia (investigational) group and the placebo group, these changes were within the normal range and are not considered clinically significant. The 12-week administration of Opuntia and placebo to healthy participants did not result in changes in liver function.
Liver function test in healthy group
The liver function test results for participants with impaired fasting glucose (IFG) are shown in Table 8. AST, ALT, r-GTP, ALP, bilirubin, total protein, and albumin levels were measured before and after the 12-week Opuntia administration. No abnormal findings were observed in any parameter, and although a decrease in protein levels was noted in the placebo group after 12 weeks, it was deemed clinically insignificant. Both the Opuntia and placebo groups showed an increase in albumin levels after 12 weeks, but these changes were within the normal range and were not clinically significant. In the IFG group, the 12-week administration of Opuntia and placebo did not result in any significant changes in liver function test results.
Liver function test in impaired fasting glucose group
(2) Kidney Function Test
To assess the safety of 12 weeks of Opuntia and placebo administration in healthy participants, kidney function indicators such as BUN, creatinine, and uric acid were measured. In the Opuntia group, BUN and creatinine levels increased between baseline and 12 weeks, but these changes were within the normal range and are not considered clinically significant. Similarly, in the placebo group, BUN levels showed a notable increase from baseline to 12 weeks, but this was also considered clinically insignificant. The kidney function test results for the healthy participants are shown in Table 9, with all parameters remaining within the normal range, confirming renal safety.
The kidney function test results for participants with IFG are shown in Table 10. Although the Opuntia group exhibited notable changes in creatinine levels from baseline to 12 weeks, the differences were within the normal range and were deemed clinically insignificant. The 12-week administration of Opuntia and placebo in the IFG group did not show any abnormal findings in kidney function tests.
Liver function test in impaired fasting glucose group
Discussion
In this study, we conducted a human clinical trial to assess the effects of Opuntia ficus-indica var. saboten (commonly known as Nopal) extract on blood glucose regulation and safety in healthy individuals and those with impaired fasting glucose or impaired glucose tolerance. Opuntia is a perennial cactus species belonging to the Cactaceae family, cultivated or growing wild in regions like Jeju Island in South Korea. It has been used for both culinary and medicinal purposes, commonly known as “prickly pear cactus.” The fruit of Opuntia has been reported to have beneficial effects on aging, degenerative arthritis, headaches, edema, hyperlipidemia, cancer, diabetes, and hypertension (12). In traditional Chinese medicine texts like the Bencao Gangmu, Opuntia is described as effective in treating hypertension, diabetes, arthritis, bronchial asthma, pulmonary disease, cough, gastritis, enteritis, nephritis, constipation, and neuralgia (13). Laboratory research has reported antimicrobial, antioxidant (14), hypoglycemic (15), and alcohol-induced hyperlipidemia-improving effects (16).
This study was conducted with IRB approval (2015-09-02) and initially included 85 participants, with 15 men and 70 women, and an average age of 49.8±8.46 years. Based on fasting blood glucose levels, participants with levels above 100 mg/dL were classified as the impaired fasting glucose (IFG) group, while those with levels at or below 100 mg/dL were classified as the healthy group. Among the 85 participants, 47 were classified as healthy and 38 as IFG. After excluding 10 participants due to withdrawal or dropout and an additional 3 due to protocol violations, a total of 72 participants were included in the final statistical analysis. Specifically, 20 participants in the healthy group were assigned to the Opuntia group and 21 to the placebo group, while in the IFG group, 16 participants received Opuntia and 15 received a placebo.
Primary efficacy endpoints included fasting blood glucose and oral glucose tolerance test (OGTT) results, which directly assess blood glucose control. Secondary efficacy endpoints included HbA1c, insulin, and C-peptide levels, providing additional information on glucose metabolism and long-term control. Safety assessments included liver function tests (AST, ALT, γ-GTP, ALP, total bilirubin, total protein, albumin) and kidney function tests (BUN, creatinine, uric acid, LDH, total calcium, and urinalysis). This study confirmed that Opuntia extract maintained safety across liver and kidney function tests, with no clinically significant adverse effects observed in either healthy or IFG participants. While slight changes in protein, albumin, BUN, and creatinine levels were recorded, these remained within the normal range throughout the intervention period. Therefore, Opuntia extract demonstrates a favorable safety profile for potential use in managing blood glucose levels without compromising liver or kidney function.
To evaluate the effect of Opuntia on lipid metabolism, total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol were measured before and after the 12-week intervention. In the healthy group, no significant changes were observed in these parameters in either the Opuntia or placebo groups. In the semi-healthy group, total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol levels increased in both the Opuntia and placebo groups, but these changes were within the normal range, and the concurrent rise in HDL and LDL cholesterol was not considered clinically significant.
Fasting blood glucose levels were measured at weeks 0 and 12, with blood samples collected after a minimum of 8 hours of fasting. In the healthy group, fasting blood glucose levels in the Opuntia group increased slightly from 90.45±5.56 mg/dL at week 0 to 91.65±6.43 mg/dL at week 12, while levels in the placebo group increased from 87.10±6.63 mg/dL to 92.29±10.42 mg/dL. Although the increase in the placebo group was statistically significant (p=0.036), it was not considered clinically relevant as all values remained within the normal range. In the semi-healthy group, fasting blood glucose levels in the Opuntia group decreased from 112.23±9.63 mg/dL at week 0 to 102.25±14.15 mg/dL at week 12 (p=0.010), while no significant changes were observed in the placebo group. These findings suggest that the 12-week administration of Opuntia extract may help lower fasting blood glucose levels in individuals with impaired fasting glucose.
For the oral glucose tolerance test (OGTT), participants consumed 75 g of glucose after taking the test product or placebo, and blood glucose levels were measured at 60 and 120 minutes post-glucose intake. In the healthy group, the 120-minute post-load glucose levels in the Opuntia group significantly decreased after 12 weeks (p=0.047), and the 60-minute glucose levels also showed a reduction, though not statistically significant (p=0.279). The 12-week administration of Opuntia extract appears to help normalize blood glucose levels in healthy individuals after a glucose load, with no significant changes observed in the placebo group.
In the semi-healthy group, 60-minute glucose levels in the Opuntia group decreased from 181.00±41.81 mg/dL at week 0 to 156.38±28.87 mg/dL at week 12 (p=0.022), while the placebo group showed a non-significant reduction (p=0.265). The 120-minute glucose levels in the Opuntia group also decreased from 142.31±39.66 mg/dL to 127.38±18.37 mg/dL, whereas levels in the placebo group increased from 157.87±40.04 mg/dL to 163.20±51.12 mg/dL, although not statistically significant. The Opuntia extract significantly reduced 60-minute post-load glucose levels, and at 120 minutes, the Opuntia group showed significantly lower glucose levels compared to the placebo group (p=0.020). This suggests that Opuntia may improve glucose regulation, particularly at 120 minutes after glucose intake.
No significant changes were observed in HbA1c, insulin, or C-peptide levels in the healthy group. In the semi-healthy group, HbA1c levels in the Opuntia group remained stable from 5.66±0.56% at week 0 to 5.83±0.45% at week 12, while the placebo group showed an increase from 5.49±0.46% to 5.77±0.50% (p=0.007). Insulin and C-peptide levels did not show significant changes in either group.
Our findings demonstrate that Opuntia extract did not lead to clinically significant adverse effects on liver function, as indicated by stable values in liver function tests, including ALP levels, over a 12-week period. Both healthy and IFG participants showed no abnormal findings outside the normal range before or after the intervention, supporting the safety of Opuntia intake for liver health.
In terms of glycemic control, while the primary endpoints (fasting blood glucose and OGTT results) did not show drastic reductions, the stabilization observed in the Opuntia group suggests a possible role of Opuntia in preventing further deterioration of glucose tolerance, particularly in participants with impaired fasting glucose (IFG). These findings align with previous studies that highlight potential benefits of Nopal (Opuntia ficus-indica) in regulating postprandial blood glucose and supporting metabolic health without causing hypoglycemia (17–19). However, its impact on HbA1c, insulin, and C-peptide levels was minimal, indicating that Opuntia extract may be more suitable for individuals with prediabetes or IFG, rather than those with established diabetes who require comprehensive glycemic control.
Furthermore, Opuntia’s high fiber content, along with its antioxidant and anti-inflammatory properties, may contribute to its safety and efficacy profile. Dietary fiber is known to slow glucose absorption, potentially reducing blood glucose spikes after meals, which is crucial in managing IFG and preventing progression to type 2 diabetes. The presence of antioxidant compounds in Opuntia could also play a role in reducing oxidative stress, closely associated with diabetes-related complications such as neuropathy and nephropathy (20).
Thus, this study suggests that Opuntia extract is a potentially valuable dietary supplement for individuals at risk of developing diabetes, offering a preventive approach to glycemic control without compromising liver or kidney function. As a preventive intervention, Opuntia extract may help delay or reduce the progression of impaired glucose tolerance to diabetes. Future studies with larger sample sizes and extended follow-up periods are recommended to confirm these findings and further explore the mechanisms underlying Opuntia’s effects on glucose metabolism and organ function, focusing on its long-term safety and efficacy in broader prediabetic populations.
Acknowledgement
This study was supported by the Rural Development Administration Joint Research Project (Project Number: PJ01164404).