Type 1 Diabetes Mellitus
Conditions
Keywords
type 1 diabetes mellitus, gut microbiome, probiotics, immunological parameters, residual beta cell function
Brief summary
The goal is to establish the effect of oral probiotic Desulfovibrio piger (D. piger) supplementation on immunological and metabolic parameters in individuals with longstanding type 1 diabetes with residual beta cell function. The investigators will perform a double-blind, randomized, placebo-controlled trial in 2x10 participants to measure effects of D. piger on parameters of systemic and intestinal inflammation and residual beta cell function.
Detailed description
The investigators perform a double-blind, randomized, placebo-controlled trial with two arms (10 participants per arm, total of 20 participants) in adults with longstanding type 1 diabetes with residual beta cell function. The study duration is 6 weeks, with 4 weeks of intervention in which participants will be given D. piger or placebo once daily and 2 weeks of washout period. The main study enpoints include the changes (versus baseline) in parameters of systemic/intestinal inflammation and beta cell function between the placebo and D.piger-treatment arms at the end of treatment (4 weeks). In addition, any long-lasting effects will be determined by assessing the changes in the above described markers after a 2 week washout period (6 weeks). Secondary endpoints include glucose variability (continuous glucose monitoring, CGM), fecal microbiome composition (including strain engraftment of D. piger, plasma metabolites), immune cell phenotype and frequency and validated questionnaires (gastro-intestinal complaints) at these three timepoints (0,4,6 weeks).
Interventions
DIETARY_SUPPLEMENTProbiotic dietary supplement
Probiotic bacteria D. piger (10\^9 colony forming units (CFU) in 10ml PBS containing 10% glycerol and 10% maltodextrin)
DIETARY_SUPPLEMENTPlacebo
Placebo (10ml PBS containing 10% glycerol and 10% maltodextrin)
Sponsors
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
The unblinded researcher will provide the study intervention to the blinded investigator in a coded fashion. Both the investigator and the participant are blinded. In case of emergency, an unblinding protocol is activated.
Intervention model description
2x10 participants will be randomly allocated to probiotic D. piger or placebo once daily for 4 weeks.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males or females, age \>18 years * A diagnosis of type 1 diabetes, with duration of more than 5 years, with minimally one of antiGAD65, IA2, ZnT8 autoantibodies present assessed at diagnosis or routine visits at Diabeter Centrum. * Evidence of remaining residual beta cell function with detectable UCPCR (more than 0.01 nmol/mmol C-peptide/creatinine ratio) and or fasting plasma C-peptide more than 0.2 mmol/L. * BMI 18-30 kg/m2
Exclusion criteria
* Use of antibiotics or proton-pump inhibitors within the last three months before screening or during study period * Use of other probiotic supplementation within the last month before screening or during study period * A history of cholecystectomy * Overt untreated gastrointestinal disease, inflammatory bowel disease or abnormal bowel habits * Absence of a large bowel (ie colostomy) * Evidence for comprised immunity (HIV infection, chemotherapy, other autoimmune diseases, systemic anti-inflammatory therapy) * History of cardiovascular disaeses (CVD) events * Hepatic enzymes\>2.5 higher than the upper limit of normal range, determined during MARVEL visits/routine visits * Kidney failure (eGFR \<15ml.min/1.73m2), dialysis, kidney transplantation, * Inability or unwillingness to donate feces or urine. * Smoking or illicit drug use (e.g. MDMA/amphetamine/cocaine/heroin/GHB) in the past three months or use during the study period. * Alcohol abuse (equal or above 21 units per week) * Inability or unwillingness to provide informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Parameters of systemic and intestinal inflammation | From start treatment to the end of treatment at 4 weeks and washout at 6 weeks. | systemic inflammation determined by measuring plasma CRP, and proinflammatory cytokines (IFNgamma, IFN alpha, TNFalpha) intestinal inflammation assessed by LB, iFABP, zonulin in plasma |
| Residual beta cell function | From start treatment to the end of treatment at 4 weeks and washout at 6 weeks. | Assessed by C peptide AUC during mixed meal tolerance test and/or post meal urine C-peptide/creatinine ratio levels. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glucose variability | From start treatment to the end of treatment at 4 weeks and washout at 6 weeks. | percentage time in euglycemic range, time above range, time below range and glucose variability measured by continuous glucose monitoring (CGM) |
| Immune cell phenotypes and frequency | From start treatment to the end of treatment at 4 weeks and washout at 6 weeks. | Immunophenotyping by flow cytometry of PBMC (peripheral blood mononuclear cells) to determine frequency of T cell subsets with activation/exhaustion marker expression |
| Fecal microbiome composition and strain engraftment | From start treatment to the end of treatment at 4 weeks and washout at 6 weeks. | using 16s rRNA sequencing, primer-specific quantitative PCR for D. piger detection in feces and plasma metabolites |
| Gastrointestinal Symptom Rating Scale (GSRS) | From start treatment to the end of treatment at 4 weeks and washout at 6 weeks. | Questionnaire. The minimum and maximum score are 15 and 105 points respectively, and a higher score in the scale reflects more gastro-intestinal complaints. |
Countries
Netherlands
Contacts
CONTACTMax Nieuwdorp, Prof. Dr.
PRINCIPAL_INVESTIGATORMax Nieuwdorp, Prof. Dr.
Amsterdam UMC
Outcome results
None listed