Prediabetic State, Metabolic Syndrome, Insulin Resistance, Thrombosis, Hypercoagulable State, Cardiovascular (CV) Risk, Cardiovascular Risk Factors, Cardiovascular Diseases (CVD), Prediabetes, Prediabetes / Type 2 Diabetes, Sweeteners
Conditions
Brief summary
The aim of this prospective interventional study is to investigate the metabolic effects of consuming artificial and natural sweeteners in persons with prediabetes. Prediabetes is a condition characterized by blood sugar levels that are elevated above normal but not yet meeting the criteria for type 2 diabetes. This condition markedly increases the risk of progressing to type 2 diabetes, which in turn can lead to complications including cardiovascular diseases. Artificial sweeteners such as saccharin and sucralose, as well as natural sugar substitutes like erythritol, are increasingly used as alternatives to sugar and are recommended for individuals at cardiometabolic risk - including overweight individuals, patients with prediabetes, or diabetics - to help reduce caloric intake. Recent literature has reported possible negative associations between artificial sweeteners and blood sugar regulation in healthy subjects (1). Additionally, effects on various blood cells have been observed. For example, erythritol has been shown to alter platelet function leading to increased reactivity in healthy study participants following consumption (2). However, the impact of alternative sweeteners on metabolic processes and their effects on blood coagulation in patients with prediabetes-a population at increased risk-has not been systematically studied. In this planned interventional study, 80 patients meeting laboratory criteria for prediabetes will be randomly assigned to one of four groups, each receiving a different intervention for two weeks: saccharin, sucralose, erythritol, or a control group receiving water. The doses reflect the acceptable daily intake or known doses that are considered safe. After enrollment, participants will visit the study center 2 times: before starting the intervention and after completing the intervention. During these visits, biological samples such as blood, urine, and stool will be collected to study metabolism, gut bacteria, immune and blood cell function. Tests will include an oral glucose tolerance test, coagulation tests, and additional blood analyses. Additionally, participants will wear a glucose monitor to track blood sugar fluctuations during the intervention. The investigators hypothesize that consumption of alternative sweeteners negatively affects blood sugar regulation and insulin sensitivity in patients with prediabetes. Furthermore, this study will explore how the candidate sweeteners influence the gut microbiome, blood cells and other metabolic factors in this population.
Interventions
DIETARY_SUPPLEMENTSaccharin
Participants in the saccharin group will consume 5 mg/kg body weight of saccharin daily, dissolved in 500 mL of water. This corresponds to the maximum recommended daily intake as determined by EFSA and JECFA (the joint FAO/WHO Expert Committee on Food Additives).
DIETARY_SUPPLEMENTSucralose
Participants in the sucralose group will consume 15 mg/kg body weight of sucralose daily in 500 mL of water, representing the maximum recommended daily intake.
DIETARY_SUPPLEMENTErythritol
Those in the erythritol group will consume 0.5 g/kg body weight of erythritol daily in 500 mL of water, a dose considered safe and below levels that cause digestive discomfort (European Food Safety Authority \[EFSA\], 2023).
DIETARY_SUPPLEMENTVehicle
Participants in the control group (vehicle) will receive a vehicle consisting of 500 mL unsweetened lemon soda
Sponsors
Charite University, Berlin, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Presence of prediabetes (HbA1c 5.7-6.4% or glucose after oral glucose tolerance test 140 to 199 mg/dL) * Written informed consent available
Exclusion criteria
* Inability to communicate sufficiently in the required language * Dementia or other significantly cognitively impairing condition * Current pregnancy or breastfeeding * Other severe internal, neurological, or psychiatric condition * History of gout * History of gallstones / diagnosis of cholelithiasis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of glucose tolerance | Baseline vs. within 1 week after intervention | Measured by AUC of oral glucose tolerance test |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change of microbiome | Baseline vs. within 1 week after intervention | RNA-Sequencing of stool samples |
| Flow cytometry analysis of changes in frequency of circulating monocyte subsets (%) | Baseline vs. within 1 week after intervention | Measured by flow cytometry in isolated PBMCs (Peripheral Blood Mononuclear Cells) using specific antibodies with binding to CD45, CD14, CD15 and CD16 to define monocyte subsets. Values will be reported as percent of CD45+ leukocytes |
| Flow cytometry analysis of changes in platelet activation marker expression (% positive platelets) | Baseline vs. within 1 week after intervention | Whole blood samples will be analyzed using flow cytometry. Platelets will be detected based on size and using well-established surface markers (CD41). Activation markers will be assessed (CD62P and PAC1) and reported as percent of positive cells. |
| Flow cytometry analysis of changes in platelet activation marker expression (MFI) | Baseline vs. within 1 week after intervention | Whole blood samples will be analyzed using flow cytometry. Platelets will be detected based on size and using well-established surface markers (CD41). Activation markers will be assessed (CD62P and PAC1) and reported as mean fluorescence intensity. |
| Changes in lipid profile | Baseline vs. within 1 week after intervention | Serum analysis of Total cholesterol, HDL and LDL cholesterol, triglycerides |
| Changes in blood metabolite profiles by liquid chromatography / mass spectrometry | Baseline vs. within 1 week after intervention | Untargeted metabolomics analysis of plasma samples using liquid chromatography-mass spectrometry (LC/MS). Data will be reported as relative ion intensity changes from baseline (log2 fold change, mean ± SD) for significantly altered features. |
| Changes in body mass index (BMI) | Baseline vs. within 1 week after intervention | To observe changes in anthropometric measures. Measurement of height in meters and weight in kilograms to calculate body mass index (BMI = weight/height\^2) in kg/m\^2 |
| Changes in waist to hip ratio (WHR) | Baseline vs. within 1 week after intervention | To observe changes in anthropometric measures. Measurement of waist circumference and hip circumference to calculate waist-to-hip-ratio WHR (waist circumference divided by hip circumference). |
| Changes in body fat percentage | Baseline vs. within 1 week after intervention | Measured by Bioelectrical Impedance Analysis (BIA) |
Contacts
CONTACTMarco Witkowski, MD, PhD
Outcome results
None listed