Systematic Reviews
Copyright ©The Author(s) 2019.
World J Diabetes. Feb 15, 2019; 10(2): 96-113
Published online Feb 15, 2019. doi: 10.4239/wjd.v10.i2.96
Table 1 Human trials examining acute effects of royal jelly treatment
Ref.Study designSubjectsTreatmentOutcome measuresEffectiveness
Iaconelli et al[24]Crossover studyN = 10 + 10 healthy individuals and individuals with type 2 diabetesEach subject went through three studies on different days: 0 g, 12 g, or 23 g of sebacic acid substituted fats in a mealGlucose clearance: PostprandialSignificantly improved glucose clearance in diabetic subjects only in dose-dependent manner (d = -1.70)
Insulin secretion/clearance rateSignificantly improved GLUT4 expression (d = 0.81) and glucose uptake in L6 cells (d = 0.67)
GLUT4 expression in L6 myotube cellsInsulin secretion/clearance decreases significantly in similar fashion between healthy and diabetic patients. Dose-response relationship. For diabetics, d = -1.12
Mobasseri et al[25]Randomized controlled trialN = 20 + 20 adults with type 2 diabetes aged 30-65 in control and treatment groups15 g of royal jelly ingested orally after overnight fastingHyperglycemia: Fasting blood glucose, glucose clearance after royal jelly consumptionNo significant difference in outcome measures between two groups
Hyperinsulinemia: Serum c-peptide and insulin
Münstedt et al[26]Controlled trialN= 10 + 10 healthy males, split into experimental and control groups20 g of fresh royal jelly ingested orallyGlucose clearance: Plasma samples during OGTTSignificantly increased rate of glucose clearance (insufficient information for effect size calculation)
Insulin resistance: Serum insulin and c-peptideNo significant change in serum insulin profile
Münstedt et al[27]Randomized controlled trialN = 15 healthy male adults aged 20-34, unspecified distribution between treatment and control groups0.55 g lyophilized royal jelly in enteric-coated capsule ingested orallyHyperglycemia: Glucose clearance (OGTT)Improved glucose clearance and decreased plasma insulin, unspecified statistical significance (insufficient information for effect size calculation)
Insulin resistance: Serum insulin and c-peptide
Table 2 Human trials examining effects of long-term royal jelly treatment
Ref.Study designSubjectsTreatmentOutcome measuresEffectiveness
Khoshpey et al[12]Randomized double-blind controlled trialN = 11 females + 12 males aged 20-65 with type 2 diabetes in control group (placebo)3000 mg royal jelly oral capsules once per day for 8 wk. Control received placeboMacronutrient intakeNo significant change in macronutrient intake
N = 13 females + 10 males aged 20-65 with type 2 diabetes in treatment groupHyperglycemia: Fasting blood glucoseFasting blood glucose significantly reduced in comparison to control group (d = -0.87)
Mobasseri et al[28]Randomized controlled trialN = 25 + 25 females with type 2 diabetes aged 30-65 in control and treatment groups200 mg royal jelly powder prepared in gel form and served with breakfast for 8 wk. Control group received placeboPlasma triglycerideSignificantly decreased plasma triglyceride in comparison to control (d = -0.476)
Morita et al[29]Randomized double-blind controlled trialN = 30 healthy adults 42-83 yr of age in control (placebo)3000 mg royal jelly in 100 mL liquid daily for 6 mo. Control received placebo identical in appearanceBody weight: BMISignificantly improved fasting blood glucose (d = -0.9596)
N = 31 healthy adults 42-83 yr of age in treatment groupInsulin resistance: HOMA-IRNo significant changes in other outcomes of interest
Hyperglycemia: HbA1c, fasting blood glucose
Plasma triglyceride
Pourmoradian et al[13]Human double-blinded randomized clinical trialN = 23 females aged 30-65 with type 2 diabetes in treatment group1000 mg lyophilized royal jelly in soft gel form served after breakfast for 8 wk. Control group received placebo soft gelBody weight: weight scale before and after study periodSignificantly decreased body weight within same group, before and after intervention (d = -0.3808)
N = 22 females aged 30-65 with type 2 diabetes in control groupMacronutrient intake: 24-h recall food questionnaire for 3 d before and after study periodSignificantly decreased energy intake within same group, before and after intervention (d = -9.52)
Pourmoradian et al[30]Human double-blinded randomized controlled trialN = 21 females aged 30-65 with type 2 diabetes in treatment group1000 mg lyophilized royal jelly in soft gel form served after breakfast for 8 wk. Control group received placebo soft gelPlasma insulinSignificantly decreased plasma insulin and HbA1c and insignificantly decreased fasting blood glucose compared to baseline within same group, before and after intervention.
N = 20 females aged 30-65 with type 2 diabetes in control groupHbA1cd = 0.016 (HbA1c)
Hyperglycemia: Fasting blood glucosed = -0.0785 (plasma insulin)
Shidfar et al[31]Human double-blinded randomized controlled trialN = 23 + 23 adults 25-65 yr old with type 2 diabetes in experimental and control (placebo) groups1000 mg royal jelly in soft gelatin capsules 3 times daily for 8 wk. Control group received placebo identical in appearance to treatmentFasting blood sugarSignificantly decreased fasting blood levels to more normal range (d = -0.3725)
Macronutrient intake: 24-h recall diet questionnaireDid not significantly alter macronutrient intake
Insulin resistance: HOMA-IRSignificantly decreased HOMA-IR: improved insulin sensitivity (d = -0.79)
Table 3 Animal and in vitro trials examining effects of long-term royal jelly treatment
Ref.Study designSubjectsTreatmentOutcome measuresEffectiveness
Ghanbari et al[14]Randomized controlled trialN = 8 healthy male Wistar rats aged 10-12 wk (control)100 mg/kg BW royal jelly dissolved in 1 mL of water daily for 6 wkHyperinsulinemia: ELISA test on plasma sampleTreatment significantly improved insulin levels (d = 1.67) and hyperglycemic fasting blood glucose (d = -2.72) levels to levels similar to healthy control group
N = 8 diabetic male Wistar rats aged 10-12 wkHyperglycemia: Fasting plasma glucose
N = 8 healthy male Wistar rats aged 10-12 wk receiving treatment
N = 8 diabetic male Wistar rats aged 10-12 wk receiving treatment
Fujii et al[32]Controlled trialN = 80 male streptozotocin-diabetic rats aged 5 wk equally split into three experimental groups and one control groupEach experimental group had one of 1, 10, and 100 mg/kg body weight royal jelly administered orally by force for 4 wk. Control group received purified waterHyperglycemia: Blood glucose (unknown whether fasting)Royal jelly administration overall slightly decreased blood glucose levels in non-dose dependent manner (no information on statistical significance)
Body weightNo significant change in body weight between groups
Membrez et al[33]Randomized controlled trialN = 15 male db/db mice aged 6-8 wk in control group1 g/kg body weight of sebacic acid was added to chow food in one experimental group, and 10 g/kg body weight SA to second experimental group’s chow for 6 wkHyperglycemia: OGTT and fasting (plasma samples)In more heavily supplemented group: Hyperglycemia significantly improved (d = -1.86) and improved glucose clearance (d = -3.20), HbA1c significantly decreased (d = -1.89), ketone bodies significantly increased (d = 1.16), dose response relationship observed, gluconeogenic and lipogenic enzyme expression significantly decreased (insufficient information for SMD estimation), food intake was significantly decreased (d = -1.82).
N = 30 male db/db mice aged 6-8 wk equally split in two experimental groupsHbA1c: Plasma samples
Liver gene expression: RNA extracted from liver samples
Food intake: Chow consumed
Takikawa et al[7]In vitroL6 myotubes grown in cell culture and collected from healthy male mice 7 wk of ageCell cultured myotubes treated with 10H2DAGlucose clearance: GLUT4 translocation to plasma membraneSignificantly improved GLUT4 translocation to plasma membrane in skeletal muscle cells compared to non-treated myotube cells (d = 0.4698)
Mice fed 1.6 mmol/kg 10H2DA
Yoneshiro et al[34]Controlled trialN = 8 3-wk old healthy male mice (control)High fat diet with 5% lyophilized royal jelly powder for 17 wkBody weight gainBody weight gain due to white adipose tissue significantly reduced compared to HFD group (d = -2.82)
N = 11 3-wk old healthy male mice fed HFDHyperlipidemia: Plasma sampleSignificantly decreased levels of NEFA compared to HFD (d = -1.6072)
N = 11 3-wk old healthy male mice fed high fat diet with treatmentHyperglycemia: Plasma sampleSignificantly improved hyperglycemia compared to HFD group (d = -2.04)
Insulin resistance: HOMA-IRHOMA-IR significantly decreased compared to HFD group, not significantly different from control group (d = -1.23)
Zamami et al[15]Controlled trialN = 6 6-wk old healthy male Wistar rats (control, received water)Two experimental groups: One fed 100 mg/kg and the other 300 mg/kg of dilute enzymatically treated royal jelly supplementation daily for 8 wkInsulin resistance: HOMA-IRHigh fructose diet induced insulin resistance in rats
N = 5 6-wk old healthy male Wistar rats as vehicle-treated group (received high fructose consumption)Food intakePlasma insulin levels and HOMA-IR similar between healthy control group and fructose drinking rats supplemented with 300 mg/kg royal jelly. Dose dependent relationship observed d = -0.7063 (effect size of 300 mg/kg royal jelly on fructose drinking rats)
N = 6 + 6 6-wk old healthy male Wistar rats (received high fructose consumption) in two treatment groupsBody weightNo significant difference in body weight and FBG between groups
Plasma triglyceridesPlasma triglycerides significantly decreased compared to control dose-dependently (d = -1.62)
Watadani et al[35]Controlled trialN = 7 female KK-Ay mice 5 wk of age in control group3 mg/kg 10H2DA for 4 wkHyperglycemia: Plasma glucose samples collected in intervals after OGTTSignificantly improved glucose clearance (d = -1.33) and fasting blood glucose (d = -1.23)
N = 8 female KK-Ay mice 5 wk of age in treatment groupBody weight: Adiposity index of abdominal, mesenteric and retroperitoneal fat tissueBody weight did not differ between groups
Insulin resistance: HOMA-IRSignificantly improved insulin sensitivity (d = -4.44)
Glucose regulatory proteins: AMPK, G6Pase, Pck1 levels, GLUT4, GS/GSK in tissue homogenatesSignificantly increased levels of G6Pase (d = 1.22) and Pck1(d = 0.77) mRNA in liver cells. Significantly increased levels of pAMPK in muscle (d = 3.13), but no change in liver. Insignificant increase in GLUT4 in muscle cells. No change in GS/GSK levels between groups
Yoshida et al[36]Controlled trial16 female KK-Ay mice split into control and experimental groups10 mg/kg royal jelly in 1/15M phosphate buffer 5 d/wk for 4 wkSignificantly improved rates of glucose clearance (d = -1.25)
Insignificantly decreased body weight
Significantly increased pAMPK levels in liver (d = 2.39) and skeletal muscle (d = 1.73). Significantly decreased G6Pase mRNA levels in liver (d = -1.65), but no change in Pck mRNA levels. Insignificantly increased GLUT4 levels in skeletal muscle
Significantly decreased plasma NEFA (d = -1.42). No change in plasma TG
No significant change in plasma insulin
Table 4 GRADE assessment for long-term effectiveness of RJ treatment on glycemic control
GRADE criteriaRatingSupport for judgementOverall quality of evidence
Outcome: Long term glycemic control (n = 14 studies)
RoB (assessed on Cochrane RoB Collaboration Tool)NoOnly one study had low RoB for all categories. Most studies had at least one item at high or unclear RoBHigh
Serious (-1)1
Very serious (-2)
InconsistencyNoGenerally, positive clinical effects demonstrated but some studies indicate null effects. There are also large variations in magnitude of effect. Heterogeneity is notable between the studies (in population, intervention and outcome assessment)Moderate
Serious (-1) 1
Very serious (-2)
IndirectnessNo1Evidence synthesized from studies addresses review question with respect to population, interventions and outcomeLow1
Serious (-1)
Very serious (-2)
ImprecisionNoAll studies have groups with small sample sizes (≤ 20), with no indication that they meet required sample sizes to detect difference in outcome; observable but statistically insignificant measures in many studies suggest sample sizes were too small to detect difference. 95% confidence intervals of effect size estimates mostly suggest an appreciable benefit for treatment, but there are several that suggest possibility of no meaningful effectVery low
Serious (-1)
Very serious (-2) 1
Publication biasUndetected1There is chance of publication bias considering the review is entirely “small-scale” trials; this area of research is not well-established and there is potential for publication bias, but none was overtly detected
Strongly suspected (-1)
OtherLarge effect (+11 or +2)Standardized mean difference of studies (effect size) indicates large magnitude of effect of treatment. Dose-response relationships observed
Dose response (+11 or +2)
No plausible confounding (+1 or +2)
Table 5 GRADE assessment for acute effects of RJ administration on glycemic control
GRADE criteriaRatingSupport for judgementOverall quality of evidence
Outcomes: Acute glycemic control outcomes (n = 4 studies)
RoB (assessed on Cochrane RoB Collaboration Tool)NoMajority of studies had overall high RoB, likely affecting the study resultsHigh
Serious (-1)
Very serious (-2)1
InconsistencyNoOutcome effects are somewhat consistent, and studied population are similar enough to not be considered detrimental to evidence quality. Intervention, however, was heterogeneous across all relevant studiesModerate
Serious (-1) 1
Very serious (-2)
IndirectnessNo1Research question is addressed by majority of the animal studiesLow
Serious (-1)
Very serious (-2)
ImprecisionNoAll studies have groups with small sample sizes (≤ 20), with no indication that they meet required sample sizes to detect difference in outcome. For those with calculable effect sizes, the confidence intervals suggest potential for no appreciable benefitVery low1
Serious (-1)
Very serious (-2) 1
Publication biasUndetected1There is chance of publication bias considering the review is entirely “small-scale” trials; this area of research is not well-established and there is potential for publication bias, but none was overtly detected
Strongly suspected (-1)
OtherLarge effect (+1 or +2)Some dose response relationships observed, however not enough studies to confirm this relationship. Insufficient effect size estimates to determine if effect is large or not
Dose response (+1 or +2)
No plausible confounding (+1 or +2)