Primary objective is to evaluate and compare the glycaemic control in T2DM within the first year of LRYGB and LMBG. Secondary aim is to gain insight in the pathophysiological mechanisms that drive the conversion of malign to benign obesity.
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Gastrointestinal conditions NEC
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameter is to assess glycaemic control as measured by the
difference in Hba1C at twelve months after LRYGB and LMGB.
Secondary outcome
Glycaemic control (as measured by the difference in HBa1c) at 6, 24, 36, 48, 60
months and 10 years after surgery. The remission of T2DM (as determined by use
of anti-diabetic medication) at 6, 12, 24, 36, 48, 60 months and 10 years after
LRYGB and LMGB.
To identify microbial, immunological and metabolic markers for NAFLD/NASH and
metabolic response before and after LMGB or LRYGB and to apply systems biology
approach to identify hierarchy of driving mechanisms (microbial, immunological
and metabolic markers) involved in the long term beneficial effects of LRYGB
and LMGB that can be used for personalised medicine. To study the (long-term)
effects of bariatric surgery on blood pressure, cardiac output and baroreflex
sensitivity. To correlate changes in blood pressure, cardiac output and
baroreflex sensitivity to changes in metabolic and other parameters. To
determine the relation of NAFLD/NASH and the development of gallstones in
relation to gallbladder bile composition and its combined effect on metabolism,
T2DM and weight loss after bariatric surgery.
To this end, we will collect before, during surgery and up to 10 years follow
up:
1. NAFLD/NASH parameters in liver biopsy
2. 2h Mixed meal tolerance test for level of insulin sensitivity and dietary
and satiety lists and excreted metabolites (24h faeces and urine as well as BIA
and questionnaires) and Electrocardiogram (ECG) at 12 and 24 months;
3. Presence of bacterial DNA/bacterial metabolites in portal vein blood, liver
and abdominal adipose tissue depots
4. Small intestinal and faecal microbiota composition and peripheral blood
inflammatory markers at 2, and 6 weeks, 6 months, as well as 12, 24, 36, 48,60
months and 10 years after surgery; also oral microbioma at baseline, 12, 24,
36, 48,60 months and 10 years.
5. Expression and differentiation of intestinal immunological cells in GALT
(Peyer*s patches), visceral/subcutaneous adipose tissue, liver and peripheral
blood (notably ILC*s, macrophages, T/B-cells and dendritic cells) in relation
to inflammation gene expression (IL -1β, IL-6, IL-8, IL-18, CXCR2 TNF-α and TLR
1, 2, 4, 5 and 6) in PBMCs.B cells will be isolated from peripheral blood and B
cells will be sorted on CD19, CD27, CD20, IgA; CD19, CD27, CD20, IgM, or CD19,
CD27, CD20, IgG and will be cultured with CD40L expressing feeder cells and
IL-21 to induce antibody production. RNA will be isolated from CD19 cells. DNA
will be isolated from whole blood to measure bacterial DNA.
6. Clinical data (body weight, waist circumference, medication, blood pressure
and assessment of cardiac output, systemic vascular resistance and baroreflex
sensitivity (with use of a nexfin device), bioelectrical impedance analysis
(BIA) comorbidity, complications of surgery, presence of mental problems,
smoking, use of alcohol and DNA sample (for epigenetic testing, taken from EDTA
sample))
7. Expression and differentiation of immunological cells (notably ILC*s,
macrophages) and inflammatory markers (IL6, IRX3 and 5) at 12, 24, 36, 48,60
months and 10 years months after surgery
8. Ultrasonography for detection of gallstones
9. Gallbladder tissue and bile acid collection after cholecystectomy, if
applicable
10. Subjects with clinical suspicion of NASH or advanced fibrosis based on
liver biopsy obtained during the primary bariatric surgery will be referred to
the NAFLD outpatient clinic. If the clinician deems it necessary to repeat the
liver biopsy based on clinical grounds during this consultation, a small part
of the liver sample taken for clinical diagnosis will be collected for gene
expression/protein westernblot if the subjects has given permission. In
addition, in the case of referral to a gastroenterologist for clinical
evaluation of upper gastro-intestinal complaints after surgery, the subjects
might undergo an gastroduodenoscopy. If that is the case and the
gastroenterologist finds it necessary to perform a gastroduodenoscopy based on
clinical grounds, a small part of the small intestinal biopsy will be collected
for gene expression/protein westernblot if the subjects has given permission.
Background summary
It is estimated that there will be 439-552 million people with type 2 diabetes
mellitus (T2DM) globally in 2030. Type 2 Diabetes Mellitus is present in one
quarter of patients at the bariatric outpatient clinic. It is undecided which
metabolic surgery grants best results in the remission of T2DM and which
procedure does that at the lowest rate of surgical complications, long term
difficulties and side effects.
Non alcoholic fatty liver disease (NAFLD) is present in 80% of all morbidly
obese subjects and is a major risk factor for development of insulin resistance
and non alcoholic steatohepatis (NASH). It is increasingly recognized that the
immune system, possibly driven by innate lymphoid cells (ILC*s), and the
intestinal microbiome are major players in this obesity related disease and the
switch from benign to malign (insulin resistance and T2DM) obesity. However,
the exact mechanisms of action behind the surgery-driven switch back from
malign to benign obesity are unknown.
Study objective
Primary objective is to evaluate and compare the glycaemic control in T2DM
within the first year of LRYGB and LMBG. Secondary aim is to gain insight in
the pathophysiological mechanisms that drive the conversion of malign to benign
obesity.
Study design
Multi-center, open randomized controlled clinical trial with two arms: LRYGB
(control) versus LMGBP (intervention).
Intervention
Randomisation between the Laparoscopic Roux-en-Y Gastric Bypass (control) and
the Laparoscopic Mini Gastric Bypass (intervention)
Study burden and risks
Patients will be recruited from the bariatric outpatient clinic at MC
Slotervaart during regular screening for bariatric/metabolic surgery and will
be included in the study after informed consent is obtained. Following this,
the patient will be randomized in the LRYGB (control) or LMGB (intervention)
group. Subsequently, the patient will have an appointment with the researcher
to undergo a mixed meal test, Bioelectrical impedance analysis (BIA). Blood
pressure, cardiac output, systemic vascular resistance and baroreflex
sensitivity will be measured (with use of a nexfin device) and patients will
fill out questionnaires. An ultrasound of the gallbladder will be performed as
well. Within one week prior to surgery patients will be asked to fill out a
meal-list and to collect a 24 hour feces and urinary sample. An oral swab will
be used to collect the oral micriobiome. During surgery, samples of peripheral
and portal blood are collected and samples of liver, mesenterial and
subcutaneous fat are taken. Two weeks, six weeks and six months after surgery,
three regularly scheduled visits will be used for sample collection of blood
and feces. In the two years following surgery, two visits to Spaarne Gasthuis
or AMC will be scheduled for 24-hour feces and urine sample collection, oral
microbiome, subcutaneous fat biopsies and performing 2h mixed meal tests,
together with BIA. Blood pressure, cardiac output, systemic vascular resistance
and baroreflex sensitivity will be measured (with use of a nexfin device). The
ultrasound of the gallbladder will be repeated as well. An ECG will be made
and patients will fill out questionnaires. This will amount to a total of 30
hours of study time in addition to regular procedures and ends ten years after
surgery. After the patients ended the first two years of follow up, we will ask
them if they want to continue follow up. In the upcoming years at 3,4,5 and 10
years after surgery we will collect fecal and urine samples, oral microbiome,
bloodsamples, dietlist,circumference measurement and questionnaires.
The two treatments, i.e. the LRYGB and the LMGB, are established surgical
procedures for more than 20 years, with known specific risks. The effect of
treatment in the control and the intervention arm are the same, possibly more
favourable in terms of expected weight loss and complication rate (within 30
days of surgery) in the LMGB arm. Metabolic remission is thought to be good in
both arms, with a hypothesized and suggested (unpublished data) benefit on
diabetic remission in the intervention arm encompassing faster and greater
effect on glycaemic control. Other possible benefits of LMGB are seen during
surgery and are related to the need of one instead of two anastomoses and
tension-free anastomosis of the gastrojejunostomy after LMGB, which can be
challenging in the superobese patients in LRYGB. After LMGB internal
herniations (IHs) are rarely seen, as opposed to the LRYGB. After LRYGB
IH-rates up to 6,2% are reported and reoperation is urged to prevent HIs and/or
cure small bowel obstruction due to IH, which is considered a particularly
serious complication. A concern of the LMGBP is the possibility of biliary
reflux into the gastric remnant and esophagus and mucosal changes after long
term exposure; however, the evidence is conflicting. Symptomatic biliary reflux
can give reason to revise LMGB to LRYGB. Extensive experience is present among
the surgeons performing the necessary liver and fat biopsies following the METC
approved BARIA protocol (P1633). The risk of bleeding from the biopsy sites is
minimised as the biopsy sites are visible to the surgeon and the surgeon will
check upon local haemostasis before termination of the surgery. Upon the
proposal of this study multiple portal vein samples are taken by one surgeon
within the context of the BARIA protocol. Patients with bleeding disorders will
be excluded from participation. The adipose tissue biopsies after surgery will
be performed under local anaesthesia, there is a chance of a localized
temporary haematoma. Total blood amount taken is 250 ml (3x mixed meal test at
50 ml per test, 1x baseline+DNA 40ml, 10 ml for portal vein plasma and 5x 10ml
follow up).
This study will evaluate whether the LRYGB or the LMBG is more beneficial to
patients with T2DM and it will identify the subjects that will have metabolic
response upon the surgery (responders) and those that have no response. We
therefore believe that the scientific insight of our findings will outweigh the
risks for the participating subjects in this study.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
Age >=18 and <=65 years
BMI >=35 at the day of the intake on the bariatric ward and <=50 kg/m2 on the day
of surgery
Diagnosis and (starting of) treatment of T2DM at intake at bariatric ward with
anti-diabetic medication
American Society of Anaesthesiologist Classification (ASA) <=3
All patients are required to lose 6 kilograms of weight prior to surgery
Exclusion criteria
Known genetic basis for insulin resistance or glucose intolerance
Type 1 DM
Prior Bariatric surgery
Patients requiring a concomitant intervention (such as cholecystectomy, ventral
hernia repair)
Auto-immune gastritis
Known presence of gastro-esophageal reflux disease confirmed by endoscopic
investigation or the use of proton-pump inhibitor indicated by complaints of
gastro-esophageal reflux (i.e. not indicated by polyfarmacia).
Known presence of large hiatal hernia requiring concomitant surgical repair
Coagulation disorders (PT time > 14 seconds, aPTT ((dependent on laboratory
methods) or known presence of bleeding disorders (anamnestic))
Known presence of hemoglobinopathy
Uncontrolled hypertension (RR > 150/95 mmHg)
Renal insufficiency (creatinine > 150 umol/L)
Pregnancy
Breastfeeding
Alcohol or drug dependency
Patients who are considered incapable to fully understand the study and
implications of participation in the study, as a consequence of a language
barrier, psychiatric disease or mental disabilities, as judged by the surgeon
or the coordinating researcher
Participation in any other (therapeutic) study that may influence primary or
secondary outcomes, Notably, patients that use vitamin K antagonists or
non-vitamin K antagonist oral anticoagulants (i.e. NOACs (Factor Xa
inhibitors)) and in whom peri-operative bridging with a therapeutic dose of
heparin is indicated, will not undergo intra-operative tissue and/or portal
vein sampling.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL61882.048.17 |