Propolis Improves Glycemic Control in Subjects With Type 2 Diabetes and Chronic Periodontitis
Condition: Diabetes Mellitus; Periodontitis
MeSH terms: Periodontitis; Chronic Periodontitis; Diabetes Mellitus
Study type: Interventional
Phase: Phase 4

Summary: 
      Background:

      Propolis is a natural resin made by bees from various plant sources. Propolis exerts
      antimicrobial, anti-inflammatory, immunomodulatory, antioxidant, and antidiabetic properties.
      The purpose of this study was to assess the adjunctive benefit of propolis supplementation in
      individuals with both chronic periodontitis and type 2 diabetes mellitus (T2DM) receiving
      scaling and root planing (SRP).

      Methods:

      A 6-month randomized blinded clinical trial comparing SRP with placebo (placebo+SRP group,
      n=26) or combined with a 6- month regimen of 400 mg oral propolis once daily (propolis+SRP
      group, n=26) was performed in patients with long-standing T2DM and chronic periodontitis.
      Treatment outcomes included hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), serum
      N€-(carboxymethyl) lysine (CML) and changes in periodontal parameters.
    

Detailed description: 
      INTRODUCTION

      Diabetes mellitus (DM) is a metabolic disorder characterized by frequent periods of
      hyperglycemia, which induce certain molecular pathways that seem to be crucial to the
      initiation of angiopathic complications of DM. Several mechanisms have been suggested to
      explain the pathogenicity of complications of hyperglycemia such as protein kinase C
      isoforms, enhanced polyol pathway flux, and increased accumulation of advanced glycosylated
      end-products. A dysregulated immune response stemming from an inappropriate cytokine
      production is a possible mechanism underpinning the cross-susceptibility between periodontal
      disease and DM. DM has been unambiguously determined as one of the major risk factors of
      periodontitis. It was reported that the risk of periodontitis increases to almost threefold
      in diabetic patients when compared to healthy individuals. The glycemic control level is
      believed to be of paramount importance as a determinant of the increased risk for developing
      complications. Diabetic patients with an HbA1c level more than 9% were found to have an
      increased prevalence of advanced chronic periodontitis in comparison to healthy people
      according to the US National Health and Nutrition Examination Survey (NHANES) III.

      Two decades ago, periodontitis was added to represent the sixth complication of DM.
      Individuals suffering from periodontal diseases often have increased serum levels of
      proinflammatory cytokines, such as IL-1, IL-6 and TNF-α. Diabetic patients with periodontitis
      possess hyperinflammatory immune cells that lead to enhanced release of proinflammatory
      cytokines, which eventually lead to insulin resistance resulting in a greater risk of poor
      glycemic control when compared to diabetic patients without periodontitis. The accumulation
      of irreversible advanced glycation end-products (AGEs), predominantly N€-(carboxymethyl)
      lysine (CML) has shown to alter cell function and tissue structure. Due to difficulty in
      managing diabetes; there is a critical need for new therapeutic modalities for prevention of
      diabetes-related complications.

      Propolis is a natural resin synthesized by honey bees from substances extracted from parts of
      some plants, buds and sap. Due to its physical characteristics, propolis is utilized by the
      honey bees to protect the hives against foreign invaders. Propolis has been used for
      centuries as a homeopathic medicine known for its anti-inflammatory properties, especially in
      Europe and ancient Egypt. It has traditionally been used for the management of numerous
      diseases, such as gastrointestinal disorders and mucocutaneous infections of fungal,
      bacterial and viral etiology.

      There are several types of propolis that differ in composition depending on the plant source
      which varies according to the geographic zone such as Brazil, Peru, China and Europe.
      Propolis contains more than more than 230 constituents, including flavonoids, cinnamic acids
      and their esters, caffeic acid and caffeic acid phenethyl ester. It has been found to have a
      wide array of biological activities, including antibacterial, antiviral, fungicidal,
      anti-inflammatory, antioxidant, hepatoprotective, free radical scavenging, immunomodulatory
      and anti-diabetic activity. Recently, investigations revealed that caffeic acid phenethyl
      ester (CAPE) is an important active molecule found in propolis and is responsible for most of
      its therapeutic properties.

      The actions of Chinese and Brazilian propolis in streptozotocin-induced type 1 diabetes
      mellitus in Sprague Dawley rats was explored and the results indicated that both types of
      propolis significantly inhibited more body weight loss and plasma glucose increase in
      experimental rats. Additionally, rats treated with Chinese propolis exhibited an 8.4%
      reduction in HbA1c levels in comparison to non-treated diabetic group.

      Hence, it was hypothesized that periodontal therapy with SRP in conjunction with oral daily
      supplementation of propolis in patients with chronic periodontitis and T2DM might improve
      both diabetic and periodontal outcomes. Thus, the aim of the current study is to evaluate
      whether the adjunctive therapy of oral propolis supplementation to SRP compared to SRP plus
      placebo, reduces glycated hemoglobin and improves clinical and periodontal parameters after 6
      months of therapy in individuals with chronic periodontitis and T2DM.

      MATERIALS AND METHODS

      Study Population:

      The study was approved by the Institutional Review Board of Mansoura University. Subjects
      were selected during their recall maintenance visits in the Internal Medicine Hospital,
      Mansoura University, between June and December in 2014. Patients filled out questionnaires
      gathering information on their dental and oral health care followed by a periodontal
      screening examination to determine eligible individuals. Patients were considered eligible
      for the study if they had T2DM with a minimum of five years duration and had been taking
      stable doses of oral hypoglycemic drugs and/or insulin for at least 6 months. In addition,
      they should have chronic periodontitis with probing pocket depth and clinical attachment loss
      ≥ 5 mm with detectable bleeding on probing in at least one site in each sextant. Patients
      should have a minimum of 20 teeth to be selected. All patients were diagnosed to have
      moderate to severe chronic periodontitis according to Armitage criteria (24). Exclusion
      criteria included smokers, recent extended use of antibiotics or non-steroidal
      anti-inflammatory drugs within the last 3 months, patients who had any periodontal therapy
      within one year, patients with grade 3 or 4 retinopathy, pregnancy or women using oral
      contraceptives. Enrolled patients signed written informed consents for study participation.

      Study Design:

      Fifty two people with T2DM diagnosed with moderate to severe chronic periodontitis were
      randomly assigned using computer-generated random tables to receive propolis (400 mg capsule
      orally once daily for six months) as adjuvant to scaling and root planing (Propolis+ SRP
      group, n = 26), or matching placebo capsules for 6 months in addition to scaling and root
      planing (Placebo+SRP group, n = 26) in this parallel randomized blinded controlled trial with
      an allocation ratio = 1:1. The generated allocation sequences were concealed in closed
      stapled envelopes until interventions were assigned. Investigators were not involved during
      randomization. Propolis commercially named BioPropolis (Sigma Pharmaceutical Industries for
      International Business Establishment Co. IBE Pharma, Cairo, Egypt) and matching placebo
      capsules were used in the study. All participants in both groups were assigned to receive
      equal number of capsules during the 6- month period. Vials which contain propolis and placebo
      drugs were labeled with specific codes unknown to patients and investigators. Patients were
      instructed to take only one capsule daily from the given vial. Patient compliance was
      calculated by counting the remaining capsules in each returned vial every month. Untoward
      side effects of both medications were queried and recorded at each visit during the study
      period.

      All individuals received meticulous full mouth scaling and root planing (SRP) with hand
      curettes and ultrasonic tips under local anesthesia until root surfaces were smooth by
      clinician (MA) in a single visit. Oral hygiene instructions and motivations for proper tooth
      brushing and dental flossing were given to the patients. Chlohexidine 0.12% mouthrinse was
      prescribed for all patients for only two weeks after SRP.

      Clinical Periodontal Measurements:

      Clinical periodontal parameters including probing pocket depth (PD), clinical attachment
      level (CAL) (distance from the CEJ to the base of the pocket), Eastman interdental bleeding
      (EIBI) , gingival (GI) and plaque (PI) indices were assessed at baseline, 3 months and 6
      months after therapy by the examiner (HE). Intra-examiner calibration was achieved by
      examination of 10 patients twice, 24 hours apart before starting the study. Calibration was
      accepted if measurements of PD and CAL (by using UNC-15 probe) at baseline and 24 hours were
      similar to 1 mm at the 90% level.

      Collection and analysis of Blood:

      10 mL of venous blood from the antecubital vein of all participants were collected in
      heparinized vacutainer tubes at baseline, 3 months and 6 months after treatment. Measurements
      of HbA1c were carried out via an automated affinity chromatography system (Bio-Rad Micromat
      II, Hercules, CA). Fasting plasma glucose levels (FPG) were measured by the standard glucose
      oxidase method. The serum concentration of N€-(carboxymethyl) lysine (CML) was assessed by
      N€-(carboxymethyl) lysine (CML) ELISA Kit of CML protein adducts (OxiSelect™, Catalog Number
      STA-316, Cell Biolabs Inc., San Diego, CA, USA). The amount of CML adduct in protein samples
      was evaluated by comparing the absorbance to a known CML-BSA standard curve as described by
      the manufacturer.

      Study outcomes:

      The primary outcome of the present clinical trial was the change in HbA1c levels after 6
      months of therapy. Secondary outcomes included the change in HbA1c levels after 3 months in
      addition to the amount of CAL gain, PD reduction and changes in FPG and serum CML levels
      after 3 and 6 months of therapy.

      Statistical Analysis:

      A power analysis was performed before commencement of the trial with type I error α = 0.05, β
      = 0.14 and (1-β) = 0.86. The power was calculated as p = 0.8641 and the estimated minimum
      sample size required was found to be 20 per each group to achieve a power of 80% based on
      achievement of 6-month reduction of HbA1c of the test group over the control by 0.8%. All
      data were explored by using Kolmogrov-Smirnov test of normality. Parametric data were
      presented as mean ± SD. Baseline comparisons were made using Student's t-test. One-way
      analyses of variance (ANOVA) with Holm-Sidak post hoc correction for multiple comparisons
      were used to determine significant changes at different time intervals. Wilcoxon signed rank
      test and Mann-Whitney test were used to detect differences per group and between groups over
      time. The α-level for significance was set at 0.05.Statistical analyses were calculated by a
      statistical software program (Statistical Package for the Social Sciences version 19.0, SPSS,
      Chicago, IL).
    

Intervention name(s): Propolis; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Propolis capsules was taken by the experimental group for 6 months after receiving scaling and root planing (SRP).; Placebo capsules was taken by the control group for 6 months after receiving scaling and root planing (SRP).
Other intervention name(s): BioPropolis; Starch capsules
Intervention MeSH terms: Propolis
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Diabetes mellitus; Chronic periodontitis; Propolis