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Clinical Trial Details — Status: Not yet recruiting

Administrative data

NCT number NCT06040164
Other study ID # SMILE
Secondary ID
Status Not yet recruiting
Phase
First received
Last updated
Start date October 1, 2023
Est. completion date December 31, 2024

Study information

Verified date March 2023
Source Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud
Contact Rodolfo M Ortiz Flores, PhD
Phone 951 29 03 43 / 951 03 01 17
Email rodolfo.ortiz@ibima.eu
Is FDA regulated No
Health authority
Study type Observational

Clinical Trial Summary

This study evaluates the relationship of endocannabinoids in saliva with inflammation and oral dysbacteriosis present in people with periodontal disease and prediabetes/type 2 diabetes


Description:

Diabetes is a disease that affects millions of people worldwide, and the number of cases is expected to continue to increase in the coming years. Type 2 diabetes (T2D) is the most common form of diabetes and is closely related to prediabetes, a condition in which blood glucose levels are high but not high enough to be diagnosed as diabetes. Both prediabetes and T2D increase the risk of cardiovascular disease and are also associated with diseases of the oral cavity, such as dental caries and periodontal disease. The presence of pathogenic bacteria in the mouth has been linked to these diseases. The endocannabinoid system, a signaling system in the body that regulates various biological processes, has been found to play an important role in energy homeostasis and is implicated in obesity, prediabetes, and T2D. This study seeks to investigate the role of endocannabinoids and related lipids in diseases of the oral cavity in the context of prediabetes and T2D. A bidirectional relationship has been observed between periodontitis and T2D, with inflammation playing a central role in both diseases. Although subtle differences in the microbial composition of the mouth have been identified in people with diabetes, the exact mechanisms remain unclear. Our findings could open up a promising line of research on the therapeutic potential of cannabinoid drugs for the treatment of this type of complications in people with prediabetes/T2D.


Recruitment information / eligibility

Status Not yet recruiting
Enrollment 60
Est. completion date December 31, 2024
Est. primary completion date June 30, 2024
Accepts healthy volunteers No
Gender All
Age group 40 Years to 65 Years
Eligibility Inclusion Criteria: - Adults, both sexes (40-65 years) - With obesity and prediabetes: BMI 30-40 and HbA1c 5.7-6.4 - With obesity and diabetes: BMI 30-40 and previous diagnosis of diabetes Exclusion Criteria: - Pregnant women - Diagnosis of some type of neoplasia or treated with radiotherapy and/or chemotherapy in the last year. - Ongoing inflammatory diseases (Crohn's disease, ulcerative colitis, arthritis, etc.) and/or anti-inflammatory treatments - Presence of systemic diseases of vital organs - Participants in treatment with drugs that could alter salivary flow - Smokers - Participants who have not followed the specifications prior to sampling - Participants who did not sign the informed consent

Study Design


Intervention

Other:
Observational study
No intervention will be performed

Locations

Country Name City State
n/a

Sponsors (1)

Lead Sponsor Collaborator
Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud

References & Publications (30)

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Artur C, Otto-Buczkowska E (2014) Oral Health Problems among Diabetic Patients - Part of Dental Professionals in Diagnostic and Therapy. J Oral Hyg Health 2:167. doi:10.4172/2332-0702.1000167

Bermudez-Silva FJ, Cardinal P, Cota D. The role of the endocannabinoid system in the neuroendocrine regulation of energy balance. J Psychopharmacol. 2012 Jan;26(1):114-24. doi: 10.1177/0269881111408458. Epub 2011 Aug 8. — View Citation

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Cani PD, Plovier H, Van Hul M, Geurts L, Delzenne NM, Druart C, Everard A. Endocannabinoids--at the crossroads between the gut microbiota and host metabolism. Nat Rev Endocrinol. 2016 Mar;12(3):133-43. doi: 10.1038/nrendo.2015.211. Epub 2015 Dec 18. — View Citation

Davis, M.P. (2022). Overview of the Endocannabinoid System and Endocannabinoidome. In: Cannabis and Cannabinoid-Based Medicines in Cancer Care. Springer, Cham. https://doi.org/10.1007/978-3-030-89918-9_1

Di Marzo V, Silvestri C. Lifestyle and Metabolic Syndrome: Contribution of the Endocannabinoidome. Nutrients. 2019 Aug 20;11(8):1956. doi: 10.3390/nu11081956. — View Citation

Di Marzo V. New approaches and challenges to targeting the endocannabinoid system. Nat Rev Drug Discov. 2018 Sep;17(9):623-639. doi: 10.1038/nrd.2018.115. Epub 2018 Aug 17. Erratum In: Nat Rev Drug Discov. 2018 Aug 30;17(9):688. — View Citation

Estrich CG, Araujo MWB, Lipman RD. Prediabetes and Diabetes Screening in Dental Care Settings: NHANES 2013 to 2016. JDR Clin Trans Res. 2019 Jan;4(1):76-85. doi: 10.1177/2380084418798818. Epub 2018 Sep 6. — View Citation

Fabio Arturo, Iannotti and Fabiana, Piscitelli (November 2018)Endocannabinoidome. In: eLS. John Wiley & Sons, Ltd:Chichester.DOI: 10.1002/9780470015902.a0028301

Gatta-Cherifi B, Cota D. New insights on the role of the endocannabinoid system in the regulation of energy balance. Int J Obes (Lond). 2016 Feb;40(2):210-9. doi: 10.1038/ijo.2015.179. Epub 2015 Sep 16. — View Citation

Hillard CJ. Circulating Endocannabinoids: From Whence Do They Come and Where are They Going? Neuropsychopharmacology. 2018 Jan;43(1):155-172. doi: 10.1038/npp.2017.130. Epub 2017 Jun 27. — View Citation

IDF Diabetes Atlas 10th edition. Accessed September 29, 2022. www.diabetesatlas.org

Kocher T, Holtfreter B, Petersmann A, Eickholz P, Hoffmann T, Kaner D, Kim TS, Meyle J, Schlagenhauf U, Doering S, Gravemeier M, Prior K, Rathmann W, Harks I, Ehmke B, Koch R. Effect of Periodontal Treatment on HbA1c among Patients with Prediabetes. J Dent Res. 2019 Feb;98(2):171-179. doi: 10.1177/0022034518804185. Epub 2018 Oct 16. — View Citation

Kriebel K, Hieke C, Muller-Hilke B, Nakata M, Kreikemeyer B. Oral Biofilms from Symbiotic to Pathogenic Interactions and Associated Disease -Connection of Periodontitis and Rheumatic Arthritis by Peptidylarginine Deiminase. Front Microbiol. 2018 Jan 30;9:53. doi: 10.3389/fmicb.2018.00053. eCollection 2018. — View Citation

Lalla E, Papapanou PN. Diabetes mellitus and periodontitis: a tale of two common interrelated diseases. Nat Rev Endocrinol. 2011 Jun 28;7(12):738-48. doi: 10.1038/nrendo.2011.106. — View Citation

Matias I, Gatta-Cherifi B, Tabarin A, Clark S, Leste-Lasserre T, Marsicano G, Piazza PV, Cota D. Endocannabinoids measurement in human saliva as potential biomarker of obesity. PLoS One. 2012;7(7):e42399. doi: 10.1371/journal.pone.0042399. Epub 2012 Jul 31. — View Citation

Oral health. Global Burden of Disease Study 2019. Published 2019. Accessed September 30, 2022. https://www.who.int/news-room/fact-sheets/detail/oral-health

Piscitelli F, Di Marzo V. "Redundancy" of endocannabinoid inactivation: new challenges and opportunities for pain control. ACS Chem Neurosci. 2012 May 16;3(5):356-63. doi: 10.1021/cn300015x. Epub 2012 Feb 27. — View Citation

Prestifilippo JP, Fernandez-Solari J, de la Cal C, Iribarne M, Suburo AM, Rettori V, McCann SM, Elverdin JC. Inhibition of salivary secretion by activation of cannabinoid receptors. Exp Biol Med (Maywood). 2006 Sep;231(8):1421-9. doi: 10.1177/153537020623100816. — View Citation

Ramfjord SP. The Periodontal Disease Index (PDI). J Periodontol. 1967 Nov-Dec;38(6):Suppl:602-10. doi: 10.1902/jop.1967.38.6.602. No abstract available. — View Citation

Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988 Dec;37(12):1595-607. doi: 10.2337/diab.37.12.1595. — View Citation

Rohani B. Oral manifestations in patients with diabetes mellitus. World J Diabetes. 2019 Sep 15;10(9):485-489. doi: 10.4239/wjd.v10.i9.485. — View Citation

Romero-Zerbo SY, Bermudez-Silva FJ. Cannabinoids, eating behaviour, and energy homeostasis. Drug Test Anal. 2014 Jan-Feb;6(1-2):52-8. doi: 10.1002/dta.1594. Epub 2013 Dec 26. — View Citation

Sanz M, Ceriello A, Buysschaert M, Chapple I, Demmer RT, Graziani F, Herrera D, Jepsen S, Lione L, Madianos P, Mathur M, Montanya E, Shapira L, Tonetti M, Vegh D. Scientific evidence on the links between periodontal diseases and diabetes: Consensus report and guidelines of the joint workshop on periodontal diseases and diabetes by the International Diabetes Federation and the European Federation of Periodontology. J Clin Periodontol. 2018 Feb;45(2):138-149. doi: 10.1111/jcpe.12808. Epub 2017 Dec 26. — View Citation

Takahashi K, Nishimura F, Kurihara M, Iwamoto Y, Takashiba S, Miyata T, Murayama Y. Subgingival microflora and antibody responses against periodontal bacteria of young Japanese patients with type 1 diabetes mellitus. J Int Acad Periodontol. 2001 Oct;3(4):104-11. — View Citation

Tavares RDCR, Ortigara GB, Tatsch KF, Ferreira CM, Boligon J, Moreira CHC. Association between periodontitis and glycated hemoglobin levels in individuals living in rural Southern Brazil. Clin Oral Investig. 2021 Dec;25(12):6901-6907. doi: 10.1007/s00784-021-03980-y. Epub 2021 May 31. — View Citation

Thorstensson H, Dahlen G, Hugoson A. Some suspected periodontopathogens and serum antibody response in adult long-duration insulin-dependent diabetics. J Clin Periodontol. 1995 Jun;22(6):449-58. doi: 10.1111/j.1600-051x.1995.tb00176.x. — View Citation

* Note: There are 30 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary Change in 2-arachidonoyl-glycerol (2-AG) levels in saliva and plasma Measured in pmol/ml Basal
Primary Change in N-arachidonoylethanolamine (AEA) levels in saliva and plasma Measured in pmol/ml Basal
Primary Change in N-palmitoylethanolamine (PEA) levels in saliva and plasma Measured in pmol/ml Basal
Primary Change in N-oleoylethanolamine (OEA) levels in saliva and plasma Measured in pmol/ml Basal
Primary Change in N-palmitoylethanolamine (DHEA) levels in saliva and plasma Measured in pmol/ml Basal
Primary Change in 2-linoleoyl-glycerol (2-LG) levels in saliva and plasma Measured in pmol/ml Basal
Primary Change in 2-oleoyl-glycerol (2-OG) levels in saliva and plasma Measured in pmol/ml Basal
Secondary Change in interleukin-1ß levels in saliva and plasma Measured in pmol/ml Basal
Secondary Change in interleukin-6 levels in saliva and plasma Measured in pmol/ml Basal
Secondary Change in interleukin-8 levels in saliva and plasma Measured in pmol/ml Basal
Secondary Change in interleukin-10 levels in saliva and plasma Measured in pmol/ml Basal
Secondary Change in interleukin-17 levels in saliva and plasma Measured in pmol/ml Basal
Secondary Change in leptin levels in saliva and plasma Measured in pmol/ml Basal
Secondary Change in vascular endothelial growth factor (VEGF) levels in saliva and plasma Measured in pmol/ml Basal
Secondary Change in Interferon gamma (IFN)-? levels in saliva and plasma Measured in pmol/ml Basal
Secondary Change in Tumor necrosis factor alpha (TNF)-a levels in saliva and plasma Measured in pmol/ml Basal
Secondary Changes in oral bacteriological profile Bacterial 16S rRNA amplicon of the following bacterial strains: Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Prevotella intermedia, Fusobacterium nucleatum, Parvimonas micra, Campylobacter rectus, Eikenella corroe, Veillonella parvula and Actinomyces naeslundii for periodontal disease; and Streptococcus mutans, S. sanguis, S. mitior, S. salivarius and S. milleri for dental caries. Unit of Measurement: Fold-increase over reference genes, delta-delta Ct method. Basal
Secondary Changes in Fasting glucose levels Measured in mg/dl Basal
Secondary Changes in insulin levels Measured in mUI/mL Basal
Secondary Changes from baseline HOMA-IR levels HOMA-IR = [blood insulin (mu/L) × Blood glucose (mmol/L)]/22.5 Basal
Secondary Changes from baseline HOMA2-IR levels The homeostasis model assessment computational method is used to estimate insulin resistance (HOMA2-IR) from fasting plasma glucose and insulin. The HOMA2-IR is the reciprocal of insulin sensitivity (%S), as a percentage of a normal reference population (normal young adult). A higher score indicates a lower insulin sensitivity. Basal
Secondary Changes from baseline HOMA2%S levels Measured in % Basal
Secondary Changes from baseline HOMA2%B levels Measured in % Basal
Secondary Changes from baseline QUICKY levels QUICKY = 1 / (log(fasting insulin µU/mL) + log(fasting glucose mg/dL)) Basal
Secondary Changes from baseline HbA1c levels Measured in % Basal
Secondary BMI (body mass index) changes Calculated as weight / height (kg/m2) Basal
Secondary Changes in waist circumference Measured in cm Basal
Secondary Changes in waist/hip ratio Calculated as waist measurement (cm) divided by hip measurement (cm) (W/H) Basal
Secondary Changes in waist/height ratio Calculated as waist measurement (cm) divided by height measurement (cm), (W/He) Basal
Secondary Changes in blood pressure Measured in mmHg Basal
Secondary Changes in triglycerides Measured in mg/dL Basal
Secondary Changes in total cholesterol Measured in mg/dL Basal
Secondary Changes in HDL cholesterol Measured in mg/dL Basal
Secondary Changes in LDL cholesterol Measured in mg/dL Basal
Secondary Changes in sialometry Measured in mL/min Basal
Secondary Changes in salivary viscosity Measured in poise (1 g·(s·cm)-1) Basal
Secondary Changes in salivary pH Logarithm of hydrogen ion concentration Basal
Secondary Oral health impact profile The Oral Health Impact Profile will be assessed by using the OHIP-14sp questionnaire, which is one of the most internationally spread indicators of oral health-related quality of life and it is used to measure the impact of oral conditions on quality of life to complement clinical data in cross-sectional and longitudinal studies. The OHIP-14 is a self-filled questionnaire that focuses on seven dimensions of impact (functional limitation, pain, psychological discomfort, physical disability, psychological disability, social disability and handicap) with participants being asked to respond according to frequency of impact on a 5-point Likert scale coded never (score 0), hardly ever (score 1), occasionally (score2), fairly often (score 3) and very often (score 4) using a twelve-months recall period. Basal
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