Chronic Low Back Pain Comorbidities: Unravelling Impaired Glucose Metabolism

Overview

Chronic low back pain (CLBP) is a global health problem. The first step for developing effective treatments is a better understanding of underlying mechanisms, including its comorbidities. Cumulative findings, including breakthrough findings from our own group, point to impaired glucose metabolism as an important CLBP comorbidity. In addition to its metabolic role, the insulin-like growth factor 1 (IGF1)/ growth hormone (GH) axis plays a key role in pain modulation. Therefore, the project aims to examine whether DNA methylation and functional protein levels predicts postprandial glycemic responses to standardized drinks, standardized meals, and real-life meals in patients with CLBP. This will be examined using two (i.e., 1 in CLBP and 1 in healthy controls) double-blind, randomized cross-over experiments (high versus low glycaemic index beverages). After the 14-day experimental phase, all participants will be studied for an additional week to examine whether the experimental findings have ecological validity, i.e., whether they can be confirmed in response to real-life meals in their home environment. Genome-wide changes in DNA methylation will be studied using whole genome bisulfite sequencing and targeted next-generation sequencing. The project allows identification of a biomarker for a potentially very significant CLBP comorbidity, including identifying targetable mechanisms to develop innovative, personalized treatments.

Detailed description

With this collaboration between KU Leuven and Vrije Universiteit Brussel, we aim to investigate the role of epigenetic mechanisms in impaired glucose tolerance in patients with CLBP by assessing DNA methylation patterns in genes related to the IGF1/GH-axis. The main objective is to identify whether DNA methylation in these genes predict postprandial glycaemic response (PPGR) to standardized drinks, standardized meals, and real-life meals in patients with CLBP. Secondary objectives are to investigate whether CLBP patients differ from healthy controls in DNA methylation; whether DNA methylation in these genes is associated with serum levels of their functional proteins, pain sensitivity and quality of life in CLBP patients; and whether dietary factors relate to DNA methylation in these genes and impaired glucose metabolism in CLBP patients. We hypothesize that CLBP patients display significantly higher DNA methylation in IGF1/GH-axis genes, accounting for lower serum levels of their proteins, and contributing to impaired glucose metabolism. Moreover, we expect that these epigenetic changes predict PPGR and relate with pain sensitivity and quality of life in patients with CLBP. We will perform a 2-arm, double-blind, randomized, cross-over experiment on 62 patients with CLBP and 62 healthy controls. During the first lab visit, the participants will fill out questionnaires on demographic and medical data, mental health, quality of life and pain, and autonomic nervous system (ANS) function and pain sensitivity will be assessed. Then the participants are randomized (1:1) to one of the interventions. This beverage is either a glucose solution or an isomaltulose solution (high vs low glycaemic index (GI)). For the third visit, they are crossed over to the other beverage. During the second and third visit, identical assessments will be performed. Preprandial assessments include questionnaires on anxiety and pain, blood collection, and ANS measurement. Then the participants consume the standardized drink within 5 minutes and remain seated for 2 hours, after which a postprandial blood collection is done. During the last week of the study the participants will consume a standardized meal (55g of white bread and 50g of dark chocolate) once daily after an overnight fast. For the full duration of the study, glucose levels, nutrition, sleep and physical activity will be measured continuously.

Interventions

• Other Glucose beverage
  This beverage is made by dissolving 75 g of glucose in 200 ml of water.
• Other Isomaltulose beverage
  The isomaltulose beverage consists of 75 g of isomaltulose dissolved in 200 ml of water.
• Other Standardized breakfast
  During week 3 of the study, all partcipants consume a standardized breakfast after an overnight fast for seven days. This breakfast consists of 55g of white bread and 50g of dark chocolate. The participants are asked not to eat or perform strenuous exercise for up to two hours after consuming the breakfast.

Primary outcome measures

• Postprandial glycaemic response (PPGR) [Time frame: During the first and last week of the study, for PPGR to real-life meals and standardized meals respectively, and during the second and third study visit (day 7 and day 14).]

Secondary outcome measures (12)

• DNA methylation of IGF1/GH-axis genes [Time frame: PBMCs will be isolated after blood collection on day 7 and day 14.]
• Serum levels of IGF1/GH-axis genes [Time frame: Blood collection will be done on day 7 and day 14.]
• Temperature pain thresholds [Time frame: During the first study visit (day 1).]
• Pressure pain thresholds [Time frame: During the first study visit (day 1).]
• 36-item Short Form Health Survey (SF-36) [Time frame: This questionnaire is completed by the participants at baseline (day 1).]
• Brief Pain Inventory (BPI) [Time frame: The BPI is completed during every study visit (day 1, day 7 and day 14).]
• Central Sensitization Inventory (CSI) [Time frame: The CSI is completed during the baseline visit on day 1.]
• Douleur Neuropathic 4 (DN4) [Time frame: This assessment will be performed during the baseline visit on day 1.]
• Pain Catastrophizing Scale (PCS) [Time frame: This assessment will be performed during the baseline visit on day 1.]
• Pain Vigilance and Awareness Questionnaire (PVAQ) [Time frame: This assessment will be performed during the baseline visit on day 1.]
• Widespread Pain Index (WPI) [Time frame: This assessment will be performed during the baseline visit on day 1.]
• Calorie intake [Time frame: During the first week, they will complete a 3-day dietary diary with details on the type of food, the amount consumed and the timing of the meals. During the last week, the same diary is filled out for seven days.]

Eligibility criteria

Inclusion criteria

• Between 18 and 65 years old
• For patient group: participants must comply to the non-specific CLBP criteria which are low back pain every day for three months or pain for at least half the days in the last six months, without leg pain that exceeds 7 out of 10 on a numeric rating scale and without evidence of specific spinal pathologies.
• For healthy volunteers: pain-free for the entire duration of the study

Exclusion criteria

• Systemic diseases (e.g., hypertension, cardiovascular disease, chronic gastrointestinal disorder, skin disease, active neuropathic disorder, severe eating disorders, myocardial infarction or cerebrovascular accident in the 6 months prior to the study)
• Current pregnancy or pregnancy in the last year
• Start-up of new medication or (dietary) treatment in the six weeks before the study
• Antibiotic use in the three months prior to the study
• History of bariatric surgery
• Use of analgesics, alcohol, immunosuppressive drugs or smoking 48 hours prior to study participation
• Classified as diabetic according to the American Diabetes criteria: fasting blood glucose ≥ 126 mg/dl, blood HbA1c ≥ 6.5%, or 2-hour PPGR ≥ 200 mg/dl

Additionally, study participation will be postponed in case the participant donated blood < 8 weeks before baseline and participants will be asked not to donate blood for the duration of the trial.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Crossover

Masking

Quadruple blind

Primary purpose

Basic science

Study locations

Belgium · 1 center

• Universitair Ziekenhuis Brussel — Jette

Identifiers

NCT: NCT07734714 · 25386_GLOW

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗