Oral Endocannabinoids in People With Prediabetes and Diabetes (SMILE)

Molecular Study of Oral Dysbacteriosis in People With Prediabetes and Diabetes

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

Study Overview

• Status: Not yet recruiting
• Conditions: Obesity; Diabetes Mellitus, Type 2; PreDiabetes; Mouth Disease; Oral Dysbiosis
• Intervention / Treatment: Other: Observational study

Detailed 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.

• Study Type: Observational
• Enrollment (Estimated): 60

Contacts and Locations

• Study Contact: Name: Rodolfo M Ortiz Flores, PhD; Phone Number: 951 29 03 43 / 951 03 01 17; Email: rodolfo.ortiz@ibima.eu
• Study Contact Backup: Name: Francisco J Bermúdez-Silva, PhD; Phone Number: 951 29 03 43 / 951 03 01 17; Email: javier.bermudez@ibima.eu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

The patients to enroll will come from three clinical studies led by our unit: The Pizarra study, an epidemiological study of the Endocrinology and Nutrition unit of the Regional Hospital of Malaga that has provided detailed information on anthropometric and biochemical parameters, eating habits and lifestyle in a cohort of about 1700 subjects; the di@bet.es study, a national epidemiological study carried out on a sample of more than 5,000 people; and the April study, a nutritional intervention study in people with obesity and prediabetes. In addition, the obesity databases of the Endocrinology and Nutrition unit of the Regional Hospital of Malaga will also be used.

Description

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 Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Ob/Pre/H; obesity, prediabetes and healthy mouth	Other: Observational study; No intervention will be performed
Ob/Pre/OCD; obesity, prediabetes and oral cavity disease	Other: Observational study; No intervention will be performed
Ob/Diab/H; obesity, diabetes and healthy mouth	Other: Observational study; No intervention will be performed
Ob/Diab/OCD; obesity, diabetes and oral cavity disease	Other: Observational study; No intervention will be performed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 2-arachidonoyl-glycerol (2-AG) levels in saliva and plasma	Measured in pmol/ml	Basal
Change in N-arachidonoylethanolamine (AEA) levels in saliva and plasma	Measured in pmol/ml	Basal
Change in N-palmitoylethanolamine (PEA) levels in saliva and plasma	Measured in pmol/ml	Basal
Change in N-oleoylethanolamine (OEA) levels in saliva and plasma	Measured in pmol/ml	Basal
Change in N-palmitoylethanolamine (DHEA) levels in saliva and plasma	Measured in pmol/ml	Basal
Change in 2-linoleoyl-glycerol (2-LG) levels in saliva and plasma	Measured in pmol/ml	Basal
Change in 2-oleoyl-glycerol (2-OG) levels in saliva and plasma	Measured in pmol/ml	Basal

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in interleukin-1β levels in saliva and plasma	Measured in pmol/ml	Basal
Change in interleukin-6 levels in saliva and plasma	Measured in pmol/ml	Basal
Change in interleukin-8 levels in saliva and plasma	Measured in pmol/ml	Basal
Change in interleukin-10 levels in saliva and plasma	Measured in pmol/ml	Basal
Change in interleukin-17 levels in saliva and plasma	Measured in pmol/ml	Basal
Change in leptin levels in saliva and plasma	Measured in pmol/ml	Basal
Change in vascular endothelial growth factor (VEGF) levels in saliva and plasma	Measured in pmol/ml	Basal
Change in Interferon gamma (IFN)-γ levels in saliva and plasma	Measured in pmol/ml	Basal
Change in Tumor necrosis factor alpha (TNF)-α levels in saliva and plasma	Measured in pmol/ml	Basal
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
Changes in Fasting glucose levels	Measured in mg/dl	Basal
Changes in insulin levels	Measured in mUI/mL	Basal
Changes from baseline HOMA-IR levels	HOMA-IR = [blood insulin (mu/L) × Blood glucose (mmol/L)]/22.5	Basal
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
Changes from baseline HOMA2%S levels	Measured in %	Basal
Changes from baseline HOMA2%B levels	Measured in %	Basal
Changes from baseline QUICKY levels	QUICKY = 1 / (log(fasting insulin μU/mL) + log(fasting glucose mg/dL))	Basal
Changes from baseline HbA1c levels	Measured in %	Basal
BMI (body mass index) changes	Calculated as weight ⁄ height (kg/m2)	Basal
Changes in waist circumference	Measured in cm	Basal
Changes in waist/hip ratio	Calculated as waist measurement (cm) divided by hip measurement (cm) (W⁄H)	Basal
Changes in waist/height ratio	Calculated as waist measurement (cm) divided by height measurement (cm), (W/He)	Basal
Changes in blood pressure	Measured in mmHg	Basal
Changes in triglycerides	Measured in mg/dL	Basal
Changes in total cholesterol	Measured in mg/dL	Basal
Changes in HDL cholesterol	Measured in mg/dL	Basal
Changes in LDL cholesterol	Measured in mg/dL	Basal
Changes in sialometry	Measured in mL/min	Basal
Changes in salivary viscosity	Measured in poise (1 g·(s·cm)-1)	Basal
Changes in salivary pH	Logarithm of hydrogen ion concentration	Basal
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

Collaborators and Investigators

• Sponsor: Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud
• Investigators: Principal Investigator: Francisco J Bermúdez-Silva, PhD, Hospital Regional Universitario de Málaga - FIMABIS

Publications and helpful links

General Publications

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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.
• 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.
• 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.
• IDF Diabetes Atlas 10th edition. Accessed September 29, 2022. www.diabetesatlas.org
• Aleixandre MA, Miguel M. Síndrome metabólico. Endocrinologia y Nutricion. 2007;54(9). doi:10.1016/S1575-0922(07)71487-0
• Bissett SM, Stone KM, Rapley T, Preshaw PM. An exploratory qualitative interview study about collaboration between medicine and dentistry in relation to diabetes management. BMJ Open. 2013 Feb 14;3(2):e002192. doi: 10.1136/bmjopen-2012-002192. Print 2013.
• 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.
• 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.
• Canepari P, Zerman N, Cavalleri G. Lack of correlation between salivary Streptococcus mutans and lactobacilli counts and caries in IDDM children. Minerva Stomatol. 1994 Nov;43(11):501-5.
• 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.
• 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.
• 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
• Di Marzo V, Silvestri C. Lifestyle and Metabolic Syndrome: Contribution of the Endocannabinoidome. Nutrients. 2019 Aug 20;11(8):1956. doi: 10.3390/nu11081956.
• 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.
• 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.
• 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.
• 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.
• Fabio Arturo, Iannotti and Fabiana, Piscitelli (November 2018)Endocannabinoidome. In: eLS. John Wiley & Sons, Ltd:Chichester.DOI: 10.1002/9780470015902.a0028301
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• 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.
• 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.
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• 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.
• 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.
• 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.
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• Andreis K, Billingsley J, Naimi Shirazi K, Wager-Miller J, Johnson C, Bradshaw H, Straiker A. Cannabinoid CB1 receptors regulate salivation. Sci Rep. 2022 Aug 19;12(1):14182. doi: 10.1038/s41598-022-17987-2.
• 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

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2023
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: July 19, 2023
• First Submitted That Met QC Criteria: September 13, 2023
• First Posted (Actual): September 15, 2023

Study Record Updates

• Last Update Posted (Actual): September 15, 2023
• Last Update Submitted That Met QC Criteria: September 13, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Obesity; Prediabetes; Diabetes Mellitus Type 2; Cannabinoids; Endocannabinoids; Oral Disease; Oral Dysbiosis
• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Stomatognathic Diseases; Hyperglycemia; Diabetes Mellitus; Diabetes Mellitus, Type 2; Prediabetic State; Glucose Intolerance; Mouth Diseases; Dysbiosis
• Other Study ID Numbers: SMILE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No